IndraLab
Statements
CYLD is modified
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CYLD is phosphorylated.
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sparser
"To further elucidate the importance of CYLD phosphorylation at Ser418 for proximal TCR signal transduction, we generated CYLD knockout cells by CRISPR/Cas9 to subsequently reconstitute with CYLD(S418A) or CYLD(S418E) mutants that prevent or mimic CYLD phosphorylation at Ser418, respectively."
CYLD is methylated.
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49
CYLD is ubiquitinated.
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35
sparser
"First, co-transfection of haemagglutinin epitope tagged-MIB2 (HA-MIB2) [ xref ], CYLD (untagged) and His 6 -ubiquitin expression constructs clearly drove the ubiquitylation of CYLD compared to cells transfected with CYLD and His 6 -ubiquitin (Figure xref panel (i), compare lanes 1 and 2), suggesting that MIB2 may ubiquitylate CYLD."
sparser
"A proposed model explaining how p62 mutations lead to the Paget's disease of bone is the following: mutations of the UBA domain cause an impairment in the interaction between p62 and ubiquitinated TRAF6 and/or CYLD, an enzyme deubiquitinating TRAF6, which in turn enhances the activation of the NF-κB signaling pathway and the resulting increased osteoclastogenesis (Figure 3(b)) [160]."
CYLD is sumoylated.
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5
CYLD is degraded.
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2
reach
"A previous study found that Notch stimulates NF-κB activation by initiating the transcription of Hes1, which then suppresses the expression of CYLD, a negative regulator of IKK activity in T-ALL cells [23]; however, this finding does not rule out the possibility that other mechanisms co-exist."
reach
"Thus, the present study revealed that, in bladder cancer, NF-kappaB can maintain its activity by establishing a feedback loop, in which NF-kappaB induced the expression of miR-130b, which consequently inhibited the expression of CYLD, which in turn was an endogenous inhibitor of NF-kappaB activation."
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"For instance, CYLD negatively regulates NFkappaB activation and is involved in other immune response mechanisms.39 When TSGs such as CYLD are down-regulated, excessive inflammation occurs and tumorigenic factors can be promoted.40 Conversely, TSGs that were up-regulated were more likely to be involved in cell cycle regulation, apoptosis, and cell growth, possibly as a response to cell stress in early stages of tumorigenesis."
reach
"The cIAPs can ubiquitinate RIP1, which leads to activation of NF-κB and MAPK pathways to promote cell survival.39 40 Upon cIAP degradation, RIP1 can be de-ubiquitinated by deubiquitinase cylindromatosis (CYLD).41 Upon deubiquitination, Complex IIa forms (Fig. 3), which typically includes RIP1, caspase-8, and FADD.38 42 Formation of this complex can trigger cell death by apoptosis."
reach
"In contrast, overexpression of CYLD caused downregulation of RIPK1 in Mel-CV and ME1007 cells, which was nevertheless reversed by the treatment with the proteasome inhibitor MG132 (XREF_FIG), substantiating that downregulation of RIPK1 expression by CYLD is mediated by the proteasomal degradation XREF_BIBR."
reach
"These observations strongly suggest that in ATLL cells, either viral encoded oncogenic proteins or mutations sustain the early cell death checkpoint by driving multiple IKKs to phosphorylate and suppress CYLD in order to prevent RIPK1 from becoming a death-signaling molecule (Fig. 8a)."
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"Formation of the secondary, receptor-free cytoplasmic complex II is largely dependent on the activity of DUBs, specifically cylindromatosis (CYLD), A20 (also known as TNFAIP3) and ubiquitin thioesterase OTULIN, which destabilize complex I, abrogate NF-kappaB activation and release RIPK1 from complex I, which then forms the cytosolic complex II XREF_BIBR, XREF_BIBR."
reach
"In contrast, overexpression of CYLD caused downregulation of RIPK1 in Mel-CV and ME1007 cells, which was nevertheless reversed by the treatment with the proteasome inhibitor MG132 (XREF_FIG), substantiating that downregulation of RIPK1 expression by CYLD is mediated by the proteasomal degradation XREF_BIBR."
CYLD affects cell population proliferation
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CYLD inhibits cell population proliferation.
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CYLD inhibits cell population proliferation. 10 / 77
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"MiR-501-5p upregulation corresponded with a downregulation of CYLD in the same tissues and cell lines, and overexpression of MiR-501-5p decreased CYLD expression, increased expression of cyclin D1 and c-myc and promoted the proliferation of hepatocellular carcinoma cells in vitro."
CYLD activates cell population proliferation.
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1
28
reach
"SPIO, HA and SPIO@15HA could notably suppress marker genes expression during osteoclastogenesis stimulated by RANKL and M-CSF (Fig. 7A), showing the capability to inhibit osteoclast differentiation.In our previous work, we have found that clinically used SPIOs can increase p62 expression though TLR4 activation [37], thus induce recruitment of CYLD to inhibited TRAF6 ubiquitination, leading to suppression of RANKL induced signal transduction for osteoclast differentiation [30]."
sparser
"Given that this was seen within 1–2 h after stimulation, much earlier than increased p62 expression, the ordered interaction of p62 with TRAF6 and CYLD during macrophage activation is not likely to be entirely attributed to inducible p62 expression, but may involve posttrans-lational modification of p62, such as ubiquitination ( xref ) and phosphorylation ( xref )."
sparser
"Nonetheless, depletion of TRIP6 can significantly enhance the association of A20 or CYLD with TRAF6 in ovarian cancer cells and promote the binding of A20 to TRAF6 in glioblastoma cells, suggesting that targeting TRIP6 may prove to be an effective strategy to restore the function of A20 and CYLD in restricting the NF-κB activity in these cancer cells."
sparser
"Nonetheless, depletion of TRIP6 by either shRNA ( xref ) or Cas9/sgRNA ( xref ) not only enhanced the association of TRAF6 with A20, but also with CYLD in untreated and treated cells, suggesting a significant role for TRIP6 in antagonizing the binding of TRAF6 to both A20 and CYLD in ovarian cancer cells."
sparser
"In this regard, here we provide evidence that the adaptor protein TRIP6 (thyroid hormone receptor-interacting protein 6), a specific interacting protein of the LPA2 receptor but not other LPA receptors, recruits TRAF6 to the LPA2 receptor and enhances the E3 ligase activity of TRAF6 by antagonizing the association of A20 and CYLD to TRAF6."
reach
"Similarly, de-ubiquitinating enzyme cylindromatosis (CYLD) inhibits NF-kappaB signaling via de-ubiquitination and inactivation of TNFR associated factor 2 (TRAF2) and TRAF6 [XREF_BIBR, XREF_BIBR]; de-ubiquitinating protease A20 inhibits NF-kappaB activation induced by Toll like receptor 4 (TLR4) via removing K63 linked polyubiquitin chains of TRAF6 [XREF_BIBR]."
reach
"In support of this notion, in vivo poly-ubiquitination assays demonstrate that depletion of beta-TRCP impaired TRAF6 self ubiquitination likely due to enhancement of TRAF6 deubiquitination by CYLD, concomitant with a reduction in beta-TRCP-dependent ubiquitination of CYLD and impairment of auto-phosphorylation of TRAF6-downstream kinase IKKalpha."
reach
"In support of this notion, in vivo poly-ubiquitination assays demonstrate that depletion of beta-TRCP impaired TRAF6 self ubiquitination likely due to enhancement of TRAF6 deubiquitination by CYLD, concomitant with a reduction in beta-TRCP-dependent ubiquitination of CYLD and impairment of auto-phosphorylation of TRAF6-downstream kinase IKKalpha."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [32]."
sparser
"Our data indicate that CYLD-SPATA2, the IKK complex members, and WHIP itself are significantly enriched in isolates of endogenous UBASH3B. Using synthetic peptides spiked into the sample to perform absolute quantification of endogenously expressed proteins, we found that the binding of TNF-RSC components to UBASH3B was, with the exception of ubiquitin, highly substoichiometric ( xref )."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [ xref ]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [32]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [ xref ]."
sparser
"Together, these results show that SPATA2 contains two distinct domains that are responsible for mediating the interaction with CYLD and HOIP, respectively; while the N terminus of SPATA2 binds to the USP domain of CYLD, the interaction with HOIP is mediated via a highly conserved PIM located in the central portion of SPATA2, which is recognized by the PUB domain of HOIP."
CYLD affects apoptotic process
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CYLD activates apoptotic process.
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CYLD inhibits apoptotic process.
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CYLD inhibits apoptotic process. 10 / 25
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"Since the proapoptotic function of RIPK1 can be prevented by phosphorylation of Ser320 or Ser25 XREF_BIBR, we introduced the RIPK1 mutant with Ser320 or Ser25 constitutively phosphorylated into Mel-CV and ME1007 cells to test whether it impinges on apoptosis induced by silencing of CYLD."
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"As Fas associated protein with death domain (FADD), cellular inhibitor of apoptosis 1 (cIAP1), and cIAP2 are all known to regulate RIPK1 mediated apoptosis XREF_BIBR, we compared the expression levels of FADD, cIAP1, and cIAP2 between Mel-FH and Mel-CV cells that displayed different sensitivity to apoptosis induced by silencing of CYLD."
reach
"Here we described that the adenoviral vector expressing CYLD (Ad/hTERT-CYLD) augmented the cytotoxicity of TRAIL in HCC cells by negatively regulating NF-kappaB activity since CYLD could reverse the ubiquitination of TNF receptor associated factor 2 (TRAF2) and interact with the IkappaB kinasegamma (IKKgamma)."
"We conclude that PrP traps CYLD, preventing it from binding and deubiquitinating RIP1 and TRAF2."
reach
"Similarly, de-ubiquitinating enzyme cylindromatosis (CYLD) inhibits NF-kappaB signaling via de-ubiquitination and inactivation of TNFR associated factor 2 (TRAF2) and TRAF6 [XREF_BIBR, XREF_BIBR]; de-ubiquitinating protease A20 inhibits NF-kappaB activation induced by Toll like receptor 4 (TLR4) via removing K63 linked polyubiquitin chains of TRAF6 [XREF_BIBR]."
sparser
"In contrast to these findings, Draber et al. demonstrated that, although both OTULIN and CYLD interact with HOIP under basal conditions, OTULIN is absent from RSCs [ xref ] (Fig. xref ) and that knock-out of OTULIN resulted in an increase of Met1-linked poly-Ub chains in the cytosol but not at TNFR1 or NOD2 RSCs [ xref ]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [32]."
sparser
"Our data indicate that CYLD-SPATA2, the IKK complex members, and WHIP itself are significantly enriched in isolates of endogenous UBASH3B. Using synthetic peptides spiked into the sample to perform absolute quantification of endogenously expressed proteins, we found that the binding of TNF-RSC components to UBASH3B was, with the exception of ubiquitin, highly substoichiometric ( xref )."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [ xref ]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [32]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [ xref ]."
sparser
"Together, these results show that SPATA2 contains two distinct domains that are responsible for mediating the interaction with CYLD and HOIP, respectively; while the N terminus of SPATA2 binds to the USP domain of CYLD, the interaction with HOIP is mediated via a highly conserved PIM located in the central portion of SPATA2, which is recognized by the PUB domain of HOIP."
sparser
"Strikingly, GST-CYLD (470–684 aa) could pull down neither the NEMO-SUMO-3 nor the SUMOylated NEMO ( xref , left panel and xref ), whereas GST-IKKβ (644–756 aa) could pull down both the NEMO-SUMO-3 and the SUMOylated NEMO ( xref , right panel and xref ), indicating that the SUMO-3 modification specifically impaired the interaction between NEMO and CYLD."
"Other identified CYLD substrates include TNF receptor associated factor 7 (TRAF7), TRAF interacting protein (TRIP), transforming growth factor beta-activated kinase 1 (TAK1), NF-kappa-B essential modifier (NEMO), lymphocyte cell specific protein-tyrosine kinase (LCK), receptor-interacting protein 1 (RIP1), retinoic acid inducible gene (RIG), and polo-like kinase 1 (PLK1)"
reach
"Furthermore, the results indicated that CRAL mainly resided in the cytoplasm and could sponge endogenous miR-505 to upregulate cylindromatosis (CYLD) expression, which further suppressed AKT activation and led to an increase in the sensitivity of gastric cancer cells to cisplatin in vitro and in preclinical models."
IKK_complex affects CYLD
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IKK_complex phosphorylates CYLD.
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IKK_complex phosphorylates CYLD. 10 / 43
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"To examine if IKK directly phosphorylates CYLD, 0.25 mug of purified CYLD was incubated with purified IKKbeta, at a final concentration of 15 nM, in medium containing 1mM EGTA, 5 mM MgCl 2, 50 mug/uL leupeptin, 2.5 mM DTT, 1 mg/mL BSA, 6.5% glycerol, in 20 mM HEPES, pH 7.4, with or without 100 muM ATP in a final volume of 20 muL at 37degreesC for one hour."
IKK_complex phosphorylates CYLD on S436. 4 / 4
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IKK_complex phosphorylates CYLD on S432. 3 / 3
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rlimsp
"In further support of this finding, mutating Ser432 and Ser436 to Alanine abolished IKK-dependent, β-TRCP-mediated poly-ubiquitination of CYLD in 293T cells (Figure 3H). Together, these results demonstrate that IKK-mediated phosphorylation of Ser432 and Ser436 might play a pivotal role in triggering SCFβ-TRCP-dependent CYLD poly-ubiquitination."
IKK_complex phosphorylates CYLD on S418. 2 / 2
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IKK_complex phosphorylates CYLD on serine. 2 / 2
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IKK_complex binds CYLD.
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IKK_complex inhibits CYLD.
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IKK_complex ubiquitinates CYLD.
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"Genetic deletion of CYLD or ITCH, essential ubiquitin regulators for TAK1 deactivation, causes strong and sustained TAK1 activation with enhanced production of tumor promoting proinflammatory cytokines that mediate liver fibrosis, tumor development, and metastasis [XREF_BIBR, XREF_BIBR]."
eidos
"For instance , Ub-specific protease-14 ( USP14 ) negatively regulates the activity of proteasomes by removing Lys48-linked Ub chains , whereas cylindromatosis tumour suppressor ( CYLD ) only acts on lysine 63 linkage-specific Ub polymers.29 For example , CYLD attenuates TAK1 signalling by removing K63-linked polyubiquitin chain of TAK1 ."
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"Deficiency in ITCH or CYLD causes sustained activation of TAK1 and increased cytokine production in bone marrow derived macrophages, and tumorigenesis and metastasis of transplanted Lewis lung carcinoma, suggesting that sustained activation of TAK1 leads to the progression of non-small-cell lung cancer (NSCLC) [XREF_BIBR]."
reach
"It has been reported that an adequate amount of CYLD impairs the progression of NASH by inhibiting TAK1 signaling, and the E3 ligase TRIM47 has been revealed to be a key regulator of CYLD degradation, revealing that both of the above targets could be significant for the treatment of NAFLD.92 Caspase Inhibitor : Emricasan is a caspase inhibitor which can reduce the portal hypertension via blocking the activation of inflammatory caspase and inhibiting hepatocyte cell death."
rlimsp
"Of these potential substrates, serine 418 of the tumor suppressor CYLD was identified as a likely site of IKKepsilon phosphorylation. We confirmed that CYLD is directly phosphorylated by IKKepsilon and that IKKepsilon phosphorylates serine 418 in vivo. Phosphorylation of CYLD at serine 418 decreases its deubiquitinase activity and is necessary for IKKepsilon-driven transformation."
sparser
"CYLD physically interacts with Bcl3 through a specific region that is different from the domain that mediates binding to TRAF2 and NEMO. xref CYLD inhibits K63-linked ubiquitination and nuclear translocation of Bcl3, thus suggesting a role for ubiquitination in the regulation of Bcl3 nuclear expression ( xref )."
sparser
"In our experiments, the inhibitory effect of CYLD on the nuclear accumulation of phosphorylated STAT3 resembles CYLD-Bcl3 interaction, since CYLD also deubiquitinates Bcl-3 in perinuclear regions and prevents its translocation to the nucleus, a process which significantly contributes to the development of keratinocyte hyperproliferation and development of benign tumors of the skin appendage called cylindromatosis xref ."
"In this region, CYLD associates with its substrate Bcl-3 and prevents the nuclear localization of Bcl3"
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"In the present study, the cytoplasmic and perinuclear expression levels of CYLD suggest that CYLD may play a role in the deubiquitination of BCl-3 and/or TRAF in NF-kappaB signaling within the cytoplasm or perinuclear region in keratinocytes of normal skin and cholesteatoma, in agreement with previously reported results."
"Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation."
reach
"In agreement with the mechanism in keratinocytes, CYLD markedly reduced expression of Cyclin D1 (XREF_FIG), cyclin D1 promoter activity (XREF_FIG), and BCL-3 recruitment to the cyclin D1 promoter in a complex with p50 or p52 (XREF_FIG, left) as compared with cells transduced with viral vectors carrying a catalytically inactive mutant of CYLD (C/S-CYLD), a GFP expression cassette or noninfected cells."
CYLD affects inflammatory response
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CYLD inhibits inflammatory response.
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CYLD activates inflammatory response.
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sparser
"SDC4 likely promotes redistribution of RIG-I and CYLD in a perinuclear pattern post viral infection, and thus enhances the RIG-I–CYLD interaction and potentiates the K63-linked deubiquitination of RIG-I. Collectively, our findings uncover a mechanism by which SDC4 antagonizes the activation of RIG-I in a CYLD-mediated deubiquitination-dependent process, thereby balancing antiviral signalling to avoid deleterious effects on host cells."
sparser
"As shown in xref , similar to the sub-cellular pattern of RIG-I, SDC4 and CYLD were also accumulated in a perinuclear pattern on SeV infection, raising a possibility that SDC4 has a potential role in affecting the RIG-I–CYLD interaction and their perinuclear localization as well."
sparser
"USP4 and ovarian tumor-domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) stabilize RIG-I proteins by eliminating the K48-linked ubiquitin chains conjugated to RIG-I. xref , xref Conversely, CYLD , a tumor suppressor gene expressed in cylindromatosis, negatively regulates RIG-I activation by deubiquitinating the K63-linked ubiquitin chains on RIG-I. xref Moreover, syndecan-4 (SDC4), which is a TM protein, complexes with both RIG-I and CYLD to promote the CYLD-mediated deubiquitination of RIG-I, leading to subsequent signaling inhibition. xref Furthermore, USP3, xref USP21, xref USP14, xref and USP27X xref also deubiquitinate the K63-linked ubiquitin of RIG-I to inhibit RIG-I function."
reach
"For example, the 3C protein of enterovirus 71 (EV71), a member of the Picornaviridae family that causes hand, foot and mouth disease, and occasionally severe central nervous system diseases, downregulates the host microRNA miR-526a to increase the expression of the cellular DUB enzyme CYLD, thus inhibiting the activation of RIG-I 74."
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"For example, the 3C protein of enterovirus 71 (EV71), a member of the Picornaviridae family that causes hand, foot and mouth disease, and occasionally severe central nervous system diseases, downregulates the host microRNA miR-526a to increase the expression of the cellular DUB enzyme CYLD, thus inhibiting the activation of RIG-I ."
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"K63 linked ubiquitination of RIG-I by TRIM25, MEX3C, and TRIM4 and deubiquitination of RIG-I by CYLD, USP3, and USP21 occur in the CARDs, whereas K63 linked ubiquitination by the RNF135 and Riplet occurs in the RD (K788), which has a positive effect on TRIM25 mediated K63 linked ubiquitination in the CARDs XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR."
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"It was initially believed that CYLD inhibited IFN signaling by deubiquitinating the PRR, RIG-1, and downstream kinases TANK binding kinase 1 (TBK-1) and inhibitor of NF-kappaB kinase Epsilon (IKKEpsilon) 44; but, surprisingly, IFN response to vesicular stomatitis virus in CYLD knockout mice or cells from these mice was abrogated.45 On the basis of these reports, TRAF3 and CYLD may serve similar functions after viral infection, namely, to inhibit NF-kappaB and activate IFN."
reach
"To the best of our knowledge, at least nine DUBs, A20, CYLD, USP3, USP5, USP14, USP15, USP21, USP25, and USP27X, have been proposed to counteract the K63linked ubiquitination of RIG-I and, thereby attenuate downstream signaling and IFN-b production ( Table 1 and Figure 3 ) (58, 76, 93) ."
eidos
"Ubiquitylation events are reversible processes , and , accordingly , severaldeubiquitylating enzymes , in particular ubiquitin specific peptidase 3 ( USP3 ) , USP21 and CYLD lysine 63 deubiquitinase ( CYLD ) , modulate RIG-I signalling by removing K63-polyubiquitin chains , although with unique kinetics ( reviewed elsewhere112 ,118 ) ."
reach
"Ubiquitylation events are reversible processes, and, accordingly, several deubiquitylating enzymes, in particular ubiquitin specific peptidase 3 (USP3), USP21 and CYLD lysine 63 deubiquitinase (CYLD), modulate RIG-I signalling by removing K63-polyubiquitin chains, although with unique kinetics."
sparser
"Strikingly, GST-CYLD (470–684 aa) could pull down neither the NEMO-SUMO-3 nor the SUMOylated NEMO ( xref , left panel and xref ), whereas GST-IKKβ (644–756 aa) could pull down both the NEMO-SUMO-3 and the SUMOylated NEMO ( xref , right panel and xref ), indicating that the SUMO-3 modification specifically impaired the interaction between NEMO and CYLD."
reach
"SPIO, HA and SPIO@15HA could notably suppress marker genes expression during osteoclastogenesis stimulated by RANKL and M-CSF (Fig. 7A), showing the capability to inhibit osteoclast differentiation.In our previous work, we have found that clinically used SPIOs can increase p62 expression though TLR4 activation [37], thus induce recruitment of CYLD to inhibited TRAF6 ubiquitination, leading to suppression of RANKL induced signal transduction for osteoclast differentiation [30]."
sparser
"Given that this was seen within 1–2 h after stimulation, much earlier than increased p62 expression, the ordered interaction of p62 with TRAF6 and CYLD during macrophage activation is not likely to be entirely attributed to inducible p62 expression, but may involve posttrans-lational modification of p62, such as ubiquitination ( xref ) and phosphorylation ( xref )."
sparser
"Nonetheless, depletion of TRIP6 can significantly enhance the association of A20 or CYLD with TRAF6 in ovarian cancer cells and promote the binding of A20 to TRAF6 in glioblastoma cells, suggesting that targeting TRIP6 may prove to be an effective strategy to restore the function of A20 and CYLD in restricting the NF-κB activity in these cancer cells."
sparser
"Nonetheless, depletion of TRIP6 by either shRNA ( xref ) or Cas9/sgRNA ( xref ) not only enhanced the association of TRAF6 with A20, but also with CYLD in untreated and treated cells, suggesting a significant role for TRIP6 in antagonizing the binding of TRAF6 to both A20 and CYLD in ovarian cancer cells."
sparser
"In this regard, here we provide evidence that the adaptor protein TRIP6 (thyroid hormone receptor-interacting protein 6), a specific interacting protein of the LPA2 receptor but not other LPA receptors, recruits TRAF6 to the LPA2 receptor and enhances the E3 ligase activity of TRAF6 by antagonizing the association of A20 and CYLD to TRAF6."
CAMK2_complex affects CYLD
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CAMK2_complex phosphorylates CYLD.
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CAMK2_complex activates CYLD.
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CAMK2_complex binds CYLD.
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"The stable cell line of CYLD overexpressing A549 cells was treated with 10ng/mL of TNF-alpha alone, or 20ng/mL of TNF-alpha combinated with 10muM of a pancaspase inhibitor, z-VAD-fmk, for 12 hours, and the cell apoptosis rate and necrosis rate were determined by Annexin v-FITC/PI dual staining analysis following the kit protocols (Santa Cruz, USA)."
reach
"Although TNF was previously shown to trigger CYLD phosphorylation in Jurkat, HeLa, or HEK 293 cells, leading to the appearance of a slower migrating form of CYLD, stimulation of our Jurkat T cells with TNF did not lead to a band shift or detection of a band with the phospho (Ser418)-specific antibody, suggesting either no phosphorylation or phosphorylation at other sites."
sparser
"While the phosphorylation of A20, CYLD and p38 induced by TNFα was largely unaffected by ABIN-1 deficiency ( xref ), using an anti-phospho-S381 A20 antibody xref , the recruitment of phospho-A20 to TNF-RSC was significantly reduced inAbin-1 −/− MEFs compared to that of WT ( xref )."
reach
"Another protein, CYLD which deubiqitinates TRAF6, and is negatively regulated by specific TNF receptors, might play a role of a silencer of EDAR signaling, since mutations in CYLD predispose not only to skin tumors (cylidromatosis), but also to the development of tumors of eccrine sweat glands and hair follicles."
CYLD affects IKK_complex
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CYLD inhibits IKK_complex.
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CYLD inhibits IKK_complex. 10 / 31
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"Notch is capable of enhancing NF-kappaB activity by a Hes1 dependent mechanism (Hes1 mediated suppression of Cyld, a deubiquitinase that negatively regulates the IKK complex) 53 and Hes1 independent mechanisms (NICD induced expression of NF-kappaB, NICD enhanced IKKalpha activity, or NICD mediated NF-kappaB nuclear retention) XREF_BIBR - XREF_BIBR."
CYLD binds IKK_complex.
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CYLD deubiquitinates IKK_complex.
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CYLD activates IKK_complex.
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sparser
"In contrast to these findings, Draber et al. demonstrated that, although both OTULIN and CYLD interact with HOIP under basal conditions, OTULIN is absent from RSCs [ xref ] (Fig. xref ) and that knock-out of OTULIN resulted in an increase of Met1-linked poly-Ub chains in the cytosol but not at TNFR1 or NOD2 RSCs [ xref ]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [32]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [ xref ]."
reach
"In contrast, when the NF-kappaB pathway is overactive, as in mice expressing the constitutively activated IkappaB kinase in hematopoietic cells or mice deficient in the negative regulator of NF-kappaB signalling CYLD, NKT cellsdevelop but these cells fail to mature and to populate the periphery 61."
reach
"To determine the role of CYLD in NF-kappaB signaling of cholesteatoma, CYLD and NF-kappaB expression levels in middle ear cholesteatoma epithelium were examined by immunohistochemical analysis to determine protein level and localization and compared to those of normal retroauricular (RA) skin."
reach
"Thus, the present study revealed that, in bladder cancer, NF-kappaB can maintain its activity by establishing a feedback loop, in which NF-kappaB induced the expression of miR-130b, which consequently inhibited the expression of CYLD, which in turn was an endogenous inhibitor of NF-kappaB activation."
reach
"As expected, formation of the TBK1 and CYLD complex was also reduced during the G2/M phase, while CYLD-Optn interaction remained unaffected as shown by co-immunoprecipitation and in situ PLA experiments performed in RO treated cells (Fig XREF_FIG, XREF_FIG and XREF_FIG, middle and lower panels, respectively)."
reach
"Interestingly, the number of PLA specific dots observed using anti-TBK1 and anti-ubiquitin antibodies was increased in RO treated cells compared to untreated cells (XREF_FIG), strongly suggesting that disruption of the TBK1 and CYLD interaction during the G2/M transition led to increased ubiquitination of TBK1 and therefore to its activation [XREF_BIBR]."
sparser
"Our results led us to propose a model for the regulation of TBK1 activity by Optn: In uninfected cells, the complex formed by TBK1, Optn and CYLD would allow constitutive deubiquitination and inhibition of TBK1, thereby limiting its activity in the absence of upstream signaling."
reach
"It was initially believed that CYLD inhibited IFN signaling by deubiquitinating the PRR, RIG-1, and downstream kinases TANK binding kinase 1 (TBK-1) and inhibitor of NF-kappaB kinase Epsilon (IKKEpsilon) 44; but, surprisingly, IFN response to vesicular stomatitis virus in CYLD knockout mice or cells from these mice was abrogated.45 On the basis of these reports, TRAF3 and CYLD may serve similar functions after viral infection, namely, to inhibit NF-kappaB and activate IFN."
reach
"Ahmed et al. demonstrated that Itch forms a complex with the deubiquitinase Cyld downstream of TNFalpha signaling in bone marrow derived macrophages (BMDMs), and that this complex, much like the A20 complex, replaces a K63 linked ubiquitin chain with a degradative K48 linked chain."
E3_Ub_ligase binds ITCH and CYLD. 3 / 3
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"E3 ligase Itch and deubiquitinase CYLD form a complex that cleaves lysine (Lys) 63-linked ubiquitin chains and catalyze Lys48-linked ubiquitination on the kinase Tak1, which is a common substrate for these two proteins, thereby contributing to decreased inflammatory signalling [ xref ]."
sparser
"Recently, it has been demonstrated that E3 ligase ITCH and CYLD formed a complex which can sequentially cleave K63-linked ubiquitin-chain and catalyzes K48-linked ubiquitination to deactivate TAK1 and terminate NF-κB signaling (Ahmed et al., xref ), providing an example of how K48 and K63-linked ubiquitinations are closely linked and can be differentially utilized to control kinase activation and deactivation."
sparser
"DUB-E3 interactions are used for mutual ubiquitin-dependent regulation (e.g., to control each other’s stability, see above) or for editing ubiquitin chain architecture on particular substrates (as shown for the hybrid DUB/E3 enzyme A20 and CYLD-ITCH complexes during inflammatory signaling [ xref , xref ])."
CYLD affects cell death
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CYLD activates cell death.
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CYLD inhibits cell death.
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"Ahmed et al. demonstrated that Itch forms a complex with the deubiquitinase Cyld downstream of TNFalpha signaling in bone marrow derived macrophages (BMDMs), and that this complex, much like the A20 complex, replaces a K63 linked ubiquitin chain with a degradative K48 linked chain."
E3_Ub_ligase binds ITCH and CYLD. 3 / 3
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sparser
"E3 ligase Itch and deubiquitinase CYLD form a complex that cleaves lysine (Lys) 63-linked ubiquitin chains and catalyze Lys48-linked ubiquitination on the kinase Tak1, which is a common substrate for these two proteins, thereby contributing to decreased inflammatory signalling [ xref ]."
sparser
"Recently, it has been demonstrated that E3 ligase ITCH and CYLD formed a complex which can sequentially cleave K63-linked ubiquitin-chain and catalyzes K48-linked ubiquitination to deactivate TAK1 and terminate NF-κB signaling (Ahmed et al., xref ), providing an example of how K48 and K63-linked ubiquitinations are closely linked and can be differentially utilized to control kinase activation and deactivation."
sparser
"DUB-E3 interactions are used for mutual ubiquitin-dependent regulation (e.g., to control each other’s stability, see above) or for editing ubiquitin chain architecture on particular substrates (as shown for the hybrid DUB/E3 enzyme A20 and CYLD-ITCH complexes during inflammatory signaling [ xref , xref ])."
reach
"First, co-transfection of haemagglutinin epitope tagged-MIB2 (HA-MIB2) [XREF_BIBR], CYLD (untagged) and His 6 -ubiquitin expression constructs clearly drove the ubiquitylation of CYLD compared to cells transfected with CYLD and His 6 -ubiquitin, compare lanes 1 and 2), suggesting that MIB2 may ubiquitylate CYLD."
sparser
"First, co-transfection of haemagglutinin epitope tagged-MIB2 (HA-MIB2) [ xref ], CYLD (untagged) and His 6 -ubiquitin expression constructs clearly drove the ubiquitylation of CYLD compared to cells transfected with CYLD and His 6 -ubiquitin (Figure xref panel (i), compare lanes 1 and 2), suggesting that MIB2 may ubiquitylate CYLD."
reach
"XREF_BIBR, XREF_BIBR Interestingly, there is also evidence that p62 interacts with CylD, which suggests a potential dual role of p62 in regulating not only the ubiquitination and subsequent activation of NF-kappaB signaling intermediaries but also its inactivation by deubiquitination through CylD."
sparser
"CYLD, a de-ubiquitinating enzyme, physically interacts with p62, the CYLD/TRAF6 complex negatively regulates TRAF6 ubiquitination and regulates the sustained inhibitory actions of NF-kB and NFATc1 during RANKL-induced osteoclastogenesis ( xref ). xref demonstrated that Sesn2 interacts with Keap1, p62, and ubiquitin ligase and that the antioxidant activity of Sesn2 is mediated by activation of Nrf2 and p62-dependent autophagic degradation of Keap1 when ROS is increased as a result of an increase in mTORC1 activity and ER stress due to environmental stresses."
sparser
"As diagrammed in xref , whereas the p62-TRAF6 interaction was found immediately after IFN-γ/TLR stimulation, this interaction was largely replaced by the p62-CYLD interaction in a later stage, indicating that TRAF6 ubiquitination, triggered upon stimulation, was reversed at a later time, coinciding with the recruitment of CYLD."
sparser
"Given that this was seen within 1–2 h after stimulation, much earlier than increased p62 expression, the ordered interaction of p62 with TRAF6 and CYLD during macrophage activation is not likely to be entirely attributed to inducible p62 expression, but may involve posttrans-lational modification of p62, such as ubiquitination ( xref ) and phosphorylation ( xref )."
"Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress.| Collectively, our results identify CYLD as a deubiquitinase facilitating DNA damage-induced p53 activation and suggest that regulation of p53 responses to genotoxic stress contributes to the tumour suppressor function of CYLD."
reach
"Moreover, CYLD was predicted to regulate p53 in an unbiased bioinformatics approach aiming to build a functional human protein interaction network by combining protein interaction, gene expression and gene ontology annotations with genome-wide cancer data sets XREF_BIBR, further supporting that regulation of p53 signalling by CYLD is functionally relevant for human cancer."
reach
"XREF_BIBR, XREF_BIBR Interestingly, there is also evidence that p62 interacts with CylD, which suggests a potential dual role of p62 in regulating not only the ubiquitination and subsequent activation of NF-kappaB signaling intermediaries but also its inactivation by deubiquitination through CylD."
sparser
"CYLD, a de-ubiquitinating enzyme, physically interacts with p62, the CYLD/TRAF6 complex negatively regulates TRAF6 ubiquitination and regulates the sustained inhibitory actions of NF-kB and NFATc1 during RANKL-induced osteoclastogenesis ( xref ). xref demonstrated that Sesn2 interacts with Keap1, p62, and ubiquitin ligase and that the antioxidant activity of Sesn2 is mediated by activation of Nrf2 and p62-dependent autophagic degradation of Keap1 when ROS is increased as a result of an increase in mTORC1 activity and ER stress due to environmental stresses."
sparser
"As diagrammed in xref , whereas the p62-TRAF6 interaction was found immediately after IFN-γ/TLR stimulation, this interaction was largely replaced by the p62-CYLD interaction in a later stage, indicating that TRAF6 ubiquitination, triggered upon stimulation, was reversed at a later time, coinciding with the recruitment of CYLD."
sparser
"Given that this was seen within 1–2 h after stimulation, much earlier than increased p62 expression, the ordered interaction of p62 with TRAF6 and CYLD during macrophage activation is not likely to be entirely attributed to inducible p62 expression, but may involve posttrans-lational modification of p62, such as ubiquitination ( xref ) and phosphorylation ( xref )."
sparser
"Interaction between transfected CYLD and CASPASE 8 by co-immunoprecipitation was observed only when the activity of CASPASE 8 was blocked by the pan-caspase inhibitor zVAD-fmk, or by mutation of the CASPASE 8 active site, suggesting that CYLD is a substrate for proteolytic cleavage by CASPASE 8 ( xref )."
reach
"However, the precise mechanism that controls the balance between TRIM25/RNF135-mediated ubiquitination and CYLDmediated deubiquitination of RIG-I and the phosphorylation of CYLD by TBK1 in its inhibitory function remains to be elucidated.In addition to the mechanisms mentioned above, several proteins have been described as regulators in TLR-and RLR-mediated signaling."
rlimsp
"Interestingly, immunoprecipitation with the phospho(Ser418)-CYLD antibody, followed by immunoblotting with anti-CYLD, revealed that CYLD is phosphorylated by IKKε/TBK1 at Ser418 upon T cell stimulation, but that its direct detection with the phospho(Ser418)-CYLD-specific antibody in a western blot is masked by another inducible protein of the same size that is recognized by the same antibody."
reach
"Interestingly, immunoprecipitation with the phospho (Ser418)-CYLD antibody, followed by immunoblotting with anti-CYLD, revealed that CYLD is phosphorylated by IKKepsilon and TBK1 at Ser418 upon T cell stimulation, but that its direct detection with the phospho (Ser418)-CYLD-specific antibody in a western blot is masked by another inducible protein of the same size that is recognized by the same antibody."
reach
"As expected, formation of the TBK1 and CYLD complex was also reduced during the G2/M phase, while CYLD-Optn interaction remained unaffected as shown by co-immunoprecipitation and in situ PLA experiments performed in RO treated cells (Fig XREF_FIG, XREF_FIG and XREF_FIG, middle and lower panels, respectively)."
reach
"Interestingly, the number of PLA specific dots observed using anti-TBK1 and anti-ubiquitin antibodies was increased in RO treated cells compared to untreated cells (XREF_FIG), strongly suggesting that disruption of the TBK1 and CYLD interaction during the G2/M transition led to increased ubiquitination of TBK1 and therefore to its activation [XREF_BIBR]."
sparser
"Our results led us to propose a model for the regulation of TBK1 activity by Optn: In uninfected cells, the complex formed by TBK1, Optn and CYLD would allow constitutive deubiquitination and inhibition of TBK1, thereby limiting its activity in the absence of upstream signaling."
sparser
"These studies provide insights into the molecular mechanisms underlying the tight regulation of inflammation via inhibition of ERK by CYLD and identified vinpocetine as a potential therapeutic agent for suppressing the inflammatory response in the pathogenesis of OM via upregulating negative regulator CYLD expression."
reach
"These studies provide insights into the molecular mechanisms underlying the tight regulation of inflammation via inhibition of ERK by CYLD and identified vinpocetine as a potential therapeutic agent for suppressing the inflammatory response in the pathogenesis of OM via upregulating negative regulator CYLD expression."
reach
"Taken together, the CYLD suppression of ERK dependent IL-8 via MKP-1 may bring novel insights into the tight regulation of inflammatory responses and also lead to innovative therapeutic strategies for controlling these responses by targeting key negative regulators of inflammation."
reach
"Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFalpha)-induced mRNA expression of pro inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs)."
reach
"Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFalpha)-induced mRNA expression of pro inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic VSMCs (RASMCs)."
reach
"Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFalpha)-induced mRNA expression of pro inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs)."
reach
"Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFalpha)-induced mRNA expression of pro inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic VSMCs (RASMCs)."
CYLD inhibits CYLD.
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CYLD increases the amount of CYLD.
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CYLD decreases the amount of CYLD.
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CYLD activates CYLD.
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"CYLD physically interacts with Bcl3 through a specific region that is different from the domain that mediates binding to TRAF2 and NEMO. xref CYLD inhibits K63-linked ubiquitination and nuclear translocation of Bcl3, thus suggesting a role for ubiquitination in the regulation of Bcl3 nuclear expression ( xref )."
sparser
"In our experiments, the inhibitory effect of CYLD on the nuclear accumulation of phosphorylated STAT3 resembles CYLD-Bcl3 interaction, since CYLD also deubiquitinates Bcl-3 in perinuclear regions and prevents its translocation to the nucleus, a process which significantly contributes to the development of keratinocyte hyperproliferation and development of benign tumors of the skin appendage called cylindromatosis xref ."
sparser
"E6 interacts with Cylindromatosis (CYLD) deubiquitinase to inactivate the tumor suppressor CYLD and to activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in hypoxic conditions. xref E6 interacts with p300/cAMP response element binding protein (CREB) xref , xref and interferon regulatory factor 3 (IRF-3) xref to regulate gene expression and with c-Myc to induce upregulation of human telomerase reverse transcriptase to promote cell immortalization. xref , xref , xref HPV16 E6 in the cytoplasm is also important for the oncogenic activity through its regulation of signal transduction by interactions with cytoplasmic E6BP (Erc55), xref E6TP1, xref , xref tumor-necrosis factor (TNF) receptor 1 xref and protein tyrosine phosphatase H1. xref In addition to its oncogenic activities, HPV16 E6 also protects HPV16-infected keratinocytes from the innate immune system by suppressing pro-IL-1β expression. xref "
sparser
"We found that TAC-induced onset and progression of cardiac dysfunction towards heart failure were dramatically worsened by CR-CYLD overexpression independent of gender differences ( xref and xref – xref ), demonstrating a mediator role of CYLD in PO-induced cardiomyopathy and heart failure."
sparser
"CYLD may also control the substrate access to mTORC1 without affecting mTORC1 activation because CR-CYLD overexpression had minimal impact on TAC-induced phosphorylation of Unc 51-like autophagy activating kinase 1 (ULK1) at Serine (S) 757 ( xref ), which is phosphorylated by mTORC1 thus suppressing autophagy induction [ xref ]."
sparser
"In addition, CR-CYLD overexpression led to increased accumulation of autophagic vacuoles with undegraded contents without affecting the total number of autophagic vacuoles ( xref ), suggesting that CYLD could suppress autophagic degradation without affecting autophagosome or autolysosome formation."
sparser
"Indeed, CR-CYLD overexpression increased the steady protein level of LC3-II, an autophagosome marker in PO hearts and enhanced PO-induced accumulation of p62, an autophagy adaptor protein while dramatically suppressing autophagic flux, a more accurate measure of autophagy function [ xref ] in PO hearts ( xref and xref ), indicating a negative impact of CYLD on cardiac autophagy."
sparser
"SDC4 likely promotes redistribution of RIG-I and CYLD in a perinuclear pattern post viral infection, and thus enhances the RIG-I–CYLD interaction and potentiates the K63-linked deubiquitination of RIG-I. Collectively, our findings uncover a mechanism by which SDC4 antagonizes the activation of RIG-I in a CYLD-mediated deubiquitination-dependent process, thereby balancing antiviral signalling to avoid deleterious effects on host cells."
sparser
"As shown in xref , similar to the sub-cellular pattern of RIG-I, SDC4 and CYLD were also accumulated in a perinuclear pattern on SeV infection, raising a possibility that SDC4 has a potential role in affecting the RIG-I–CYLD interaction and their perinuclear localization as well."
sparser
"USP4 and ovarian tumor-domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) stabilize RIG-I proteins by eliminating the K48-linked ubiquitin chains conjugated to RIG-I. xref , xref Conversely, CYLD , a tumor suppressor gene expressed in cylindromatosis, negatively regulates RIG-I activation by deubiquitinating the K63-linked ubiquitin chains on RIG-I. xref Moreover, syndecan-4 (SDC4), which is a TM protein, complexes with both RIG-I and CYLD to promote the CYLD-mediated deubiquitination of RIG-I, leading to subsequent signaling inhibition. xref Furthermore, USP3, xref USP21, xref USP14, xref and USP27X xref also deubiquitinate the K63-linked ubiquitin of RIG-I to inhibit RIG-I function."
reach
"Based on the in vitro assessments, this miRNA directly targets cylindromatosis (CYLD) (a negative regulator of antiviral responses through removing lysine (K)-63-linked polyubiquitin of RIG-I), increases RIG-I ubiquitination and thereupon production of IFNs-I [109].7
hsa-miRNAs and SARS-CoV-2-induced interfering factors."
| PMC
sparser
"We found that TAC-induced onset and progression of cardiac dysfunction towards heart failure were dramatically worsened by CR-CYLD overexpression independent of gender differences ( xref and xref – xref ), demonstrating a mediator role of CYLD in PO-induced cardiomyopathy and heart failure."
sparser
"CYLD may also control the substrate access to mTORC1 without affecting mTORC1 activation because CR-CYLD overexpression had minimal impact on TAC-induced phosphorylation of Unc 51-like autophagy activating kinase 1 (ULK1) at Serine (S) 757 ( xref ), which is phosphorylated by mTORC1 thus suppressing autophagy induction [ xref ]."
sparser
"In addition, CR-CYLD overexpression led to increased accumulation of autophagic vacuoles with undegraded contents without affecting the total number of autophagic vacuoles ( xref ), suggesting that CYLD could suppress autophagic degradation without affecting autophagosome or autolysosome formation."
sparser
"Indeed, CR-CYLD overexpression increased the steady protein level of LC3-II, an autophagosome marker in PO hearts and enhanced PO-induced accumulation of p62, an autophagy adaptor protein while dramatically suppressing autophagic flux, a more accurate measure of autophagy function [ xref ] in PO hearts ( xref and xref ), indicating a negative impact of CYLD on cardiac autophagy."
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CYLD translocates.
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"In the absence of TSA, CYLD localized throughout the cytoplasm (XREF_FIG), while in the presence of TSA or in HDAC6 depleted cells, the levels of acetylated tubulin increased and CYLD translocated to the perinuclear region where it strongly colocalized with acetylated MTs (XREF_FIG and XREF_SUPPLEMENTARY)."
reach
"Firstly, the DUB CYLD is recruited to centrosomes and the basal body of cilia via its interaction with CAP350 (centrosome associated protein of 350kDa), where it has to be present and catalytically active to promote docking of basal bodies at the plasma membrane and hence ciliogenesis [XREF_BIBR]."
CYLD binds.
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CYLD is inactive.
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"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
CYLD is active.
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"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
reach
"Importantly, a phospho-mimetic CYLD mutant harboring serine to glutamic acid substitutions at the phosphorylation sites completely failed to deubiquitinate Tax, whereas a mutant harboring serine to analine mutations at the phsphorylation sites of CYLD (CYLD7SA) remained active in Tax deubiquitination."
CYLD affects Neoplasm Invasiveness
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CYLD inhibits Neoplasm Invasiveness.
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CYLD inhibits Neoplasm Invasiveness. 10 / 15
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"Studies found that miR-362-5p reduces the expression of tumor suppressor protein CYLD, which leads to activate the NF-kB pathway to promote the proliferation, migration, and invasion of hepatocellular carcinoma cells and human breast cancer cells (Ni et al., 2015; Ni et al., 2016)."
CYLD inhibits Neoplasm Invasiveness. 5 / 5
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CYLD activates Neoplasm Invasiveness.
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CYLD activates Neoplasm Invasiveness. 5 / 5
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"Studies found that miR-362-5p reduces the expression of tumor suppressor protein CYLD, which leads to activate the NF-kB pathway to promote the proliferation, migration, and invasion of hepatocellular carcinoma cells and human breast cancer cells (Ni et al., 2015; Ni et al., 2016)."
CYLD activates Neoplasm Invasiveness. 2 / 2
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"CYLD also negatively regulates the c-Jun N-terminal kinase (JNK) signaling pathway and mitogen activated protein kinase (MAPK) pathway, which are known to participate in a wide range of cellular processes, including proliferation, differentiation, and apoptosis of cholesteatoma [XREF_BIBR, XREF_BIBR]."
reach
"Expression of a non cleavable form of CYLD inhibited activation of the JNK pathway and expression of AP-1 target genes in a T-cell line, although CYLD silencing only minimally increased JNK activation [XREF_BIBR], possibly because of redundancy with other deubiquitinating enzymes."
sparser
"In agreement with the reported negative regulation of JNK and c-Myc activation by CYLD [ xref ], WB analysis of these molecules showed increased Akt, JNK and c-Myc activation (measured as levels of P-Akt, P-JNK and P-c-Myc respectively) in the skin of transgenic mice lacking the DUB function ( xref )."
reach
"In agreement with the reported negative regulation of JNK and c-Myc activation by CYLD [XREF_BIBR], WB analysis of these molecules showed increased Akt, JNK and c-Myc activation (measured as levels of P-Akt, P-JNK and P-c-Myc respectively) in the skin of transgenic mice lacking the DUB function (XREF_FIG)."
CYLD affects activation
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"Consistent with the notion that NF-kappaB signalling could be turned off through negative feedback mechanism involving CYLD mediated ubiquitin (Ub) deconjugation [XREF_BIBR], the CYLD depletion compromised and CYLD overexpression potentiated cell apoptosis are separately overrided by NF-kappaB inhibitor BAY 11-7085 and IkappaBalpha siRNA."
"?To dissect CYLD function we used a proteomics approach to identify CYLD interacting proteins and identified MIB2, an ubiquitin ligase enzyme involved in Notch signalling, as a protein which interacts with CYLD. Coexpression of CYLD and MIB2 resulted in stabilisation of MIB2 protein levels and was associated with reduced levels of JAG2, a ligand implicated in Notch signalling.?"
eidos
"Results ( Fig. 3a , b ) indicated that neither overexpression or knockdown of CYLD changed the expression of cyclin D or CDK4 or 6 , but influenced the protein level of p18 and pRb , and increasing CYLD expression caused an elevation in p18 levels in a dose-dependent manner in all cell lines ( Fig. 3c ) ."
reach
"In summary, our study demonstrates for the first time that (i) MALT1 modulates TLR7 agonist- and IAV induced MMP-9 response in alveolar macrophages; (ii) MALT1 mediates CYLD reduction in macrophages upon TLR7 stimulation; (iii) MMP-9 production in alveolar macrophages is through NF-kappaB but not AP-1; and that (iv) MALT1 deficiency results in reduced IAV induced disease severity."
sparser
"Here, we show that T-cell receptors (TCR) activation, as well as overexpression of the oncogenic API2-MALT1 fusion protein, results in proteolytic inactivation of CYLD by MALT1, which is specifically required for c-jun N-terminal kinase (JNK) activation and the inducible expression of a subset of genes."
reach
"Here, we show that T-cell receptors (TCR) activation, as well as overexpression of the oncogenic API2-MALT1 fusion protein, results in proteolytic inactivation of CYLD by MALT1, which is specifically required for c-jun N-terminal kinase (JNK) activation and the inducible expression of a subset of genes."
reach
"Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies."
reach
"At the same time, MALT1 could function as a protease activity upon TCR and CD28 co-stimulation to inactivate negative regulators of NF-kappaB signaling such as the A20 (also known as TNFAIP3), CYLD (cylindromatosis), RNase Regnase-1 as well as RelB and HOIL1 [XREF_BIBR - XREF_BIBR]."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
reach
"Thus, inhibition of RIPK2 by CYLD leads to impaired pathogen control due to a reduction in antimicrobial responses including pro inflammatory cytokine production, ROS and nitric oxide (NO) production.Another recent study used kinase inhibitors to demonstrate functional specificity of the kinase domain of RIPK2 in controlling bacterial pathogens."
| PMC
reach
"The authors showed that CYLD deubiquitinated RIPK2 in macrophages infected with L. monocytogenes, leading to impaired activation of NF-kappaB, reduced production of proinflammatory cytokines and reactive oxygen and nitrogen species, which ultimately resulted in impaired infection control."
"CYLD-mediated K63 deubiquitination of RIPK2 resulted in an impaired activation of both NF-kappaB and ERK1/2 pathways, reduced production of proinflammatory cytokines interleukin-6 (IL-6), IL-12, anti-listerial reactive oxygen species (ROS) and nitric oxide (NO), and, finally, impaired pathogen control."
CYLD affects necroptotic process
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CYLD activates necroptotic process. 10 / 14
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"Therefore, our data provides qualified support for the notion that Mtb infected macrophages, in vitro and in vivo, may be primed to undergo necroptotic death, with the exception of our finding that CYLD protein levels were strongly suppressed which, according to recent reports, impedes the induction of necroptosis."
CYLD inhibits necroptotic process.
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"Notably, the CYLD USP domain also deubiquitinated STING in vitro (S6D Fig), which is consistent with our observation in S4E Fig. To substantiate this finding, we transfected Flag-STING along with HA-tagged WT ubiquitin or ubiquitin mutants in the presence or absence of CYLD, followed by immunoblotting."
sparser
"Nonetheless, depletion of TRIP6 can significantly enhance the association of A20 or CYLD with TRAF6 in ovarian cancer cells and promote the binding of A20 to TRAF6 in glioblastoma cells, suggesting that targeting TRIP6 may prove to be an effective strategy to restore the function of A20 and CYLD in restricting the NF-κB activity in these cancer cells."
sparser
"Nonetheless, depletion of TRIP6 by either shRNA ( xref ) or Cas9/sgRNA ( xref ) not only enhanced the association of TRAF6 with A20, but also with CYLD in untreated and treated cells, suggesting a significant role for TRIP6 in antagonizing the binding of TRAF6 to both A20 and CYLD in ovarian cancer cells."
sparser
"In this regard, here we provide evidence that the adaptor protein TRIP6 (thyroid hormone receptor-interacting protein 6), a specific interacting protein of the LPA2 receptor but not other LPA receptors, recruits TRAF6 to the LPA2 receptor and enhances the E3 ligase activity of TRAF6 by antagonizing the association of A20 and CYLD to TRAF6."
sparser
"DUB-E3 interactions are used for mutual ubiquitin-dependent regulation (e.g., to control each other’s stability, see above) or for editing ubiquitin chain architecture on particular substrates (as shown for the hybrid DUB/E3 enzyme A20 and CYLD-ITCH complexes during inflammatory signaling [ xref , xref ])."
sparser
"Several DUBs, including A20, CYLD and USP7, have been reported to downregulate NF- κ B. Co-IP assays were thus carried out to examine the interactions between these enzymes and HSCARG, and the results showed that HSCARG interacts weakly with A20 or CYLD but strongly interacts with USP7 ( xref , xref )."
sparser
"In contrast to these findings, Draber et al. demonstrated that, although both OTULIN and CYLD interact with HOIP under basal conditions, OTULIN is absent from RSCs [ xref ] (Fig. xref ) and that knock-out of OTULIN resulted in an increase of Met1-linked poly-Ub chains in the cytosol but not at TNFR1 or NOD2 RSCs [ xref ]."
CYLD affects necrotic cell death
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CYLD affects Cell Survival
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2
CYLD inhibits Cell Survival.
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5
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CYLD activates Cell Survival.
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CYLD activates Cell Survival. 7 / 7
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"miR-19a is a member of the miR-17-92 cluster and has been shown to be overexpressed in T-cell acute lymphoblastic leukemia and multiple myeloma where it was revealed that miR-19a negatively regulates the expression of CYLD and SOCS-1 respectively to promote cell survival and pathogenesis [XREF_BIBR, XREF_BIBR]."
reach
"Strikingly, while CYLD silencing decreased cell viability as measured using CellTiter-Glo assays in Mel-CV and ME1007 cells, it resulted in a moderate yet statistically significant increase in cell viability in ME4405 cells and had no effect on the viability of Mel-FH cells (XREF_FIG)."
USP affects CYLD
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16
sparser
"Although the conserved CAP-GLY domains provide structural basis for the interactions of CYLD with microtubules and many other proteins, an interesting finding is that EB1 containing a known CAP-GLY domain-interacting motif interacts with the C-terminal USP domain of CYLD other than the CAP-GLY domains, implicating a previously unknown role for the USP domain in mediating protein-protein interactions."
sparser
"TNF-α stimulation also induces rapid ubiquitylation of components of the TNF-RSC Temporal analysis of the TNF-RSC composition identified SPATA2 as a novel component of the TNF-RSC The predicted PUB domain in the N-terminus of SPATA2 interacts with the USP domain of CYLD, whereas the C-terminus of SPATA2 interacts with HOIP SPATA2 is required for recruitment of CYLD to the TNF-RSC Downregulation of SPATA2 augments transcriptional activation of NF-κB and inhibits TNF-α-induced necroptosis, pointing to an important function of SPATA2 in modulating the outcomes of TNF-α signaling."
sparser
"Together, these results show that SPATA2 contains two distinct domains that are responsible for mediating the interaction with CYLD and HOIP, respectively; while the N terminus of SPATA2 binds to the USP domain of CYLD, the interaction with HOIP is mediated via a highly conserved PIM located in the central portion of SPATA2, which is recognized by the PUB domain of HOIP."
CYLD affects USP
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16
sparser
"Although the conserved CAP-GLY domains provide structural basis for the interactions of CYLD with microtubules and many other proteins, an interesting finding is that EB1 containing a known CAP-GLY domain-interacting motif interacts with the C-terminal USP domain of CYLD other than the CAP-GLY domains, implicating a previously unknown role for the USP domain in mediating protein-protein interactions."
sparser
"TNF-α stimulation also induces rapid ubiquitylation of components of the TNF-RSC Temporal analysis of the TNF-RSC composition identified SPATA2 as a novel component of the TNF-RSC The predicted PUB domain in the N-terminus of SPATA2 interacts with the USP domain of CYLD, whereas the C-terminus of SPATA2 interacts with HOIP SPATA2 is required for recruitment of CYLD to the TNF-RSC Downregulation of SPATA2 augments transcriptional activation of NF-κB and inhibits TNF-α-induced necroptosis, pointing to an important function of SPATA2 in modulating the outcomes of TNF-α signaling."
sparser
"Together, these results show that SPATA2 contains two distinct domains that are responsible for mediating the interaction with CYLD and HOIP, respectively; while the N terminus of SPATA2 binds to the USP domain of CYLD, the interaction with HOIP is mediated via a highly conserved PIM located in the central portion of SPATA2, which is recognized by the PUB domain of HOIP."
CYLD affects cell differentiation
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11
CYLD activates cell differentiation.
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CYLD activates cell differentiation. 10 / 12
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10
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"As a result, we have found that forced expression of wild-type CYLD (CYLD WT) both in HaCaT keratinocytes and in the skin equivalents enhances keratinocyte differentiation, while the inhibition of CYLD function by expression of a catalytically inactive form of CYLD impairs epidermal differentiation."
reach
"In addition to the skin appendages changes, the K5-CYLD C/S mice show epidermal alterations, mainly impaired keratinocyte differentiation, thus confirming in vivo the results that our group have previously described using a model of skin equivalents of human HaCaT keratinocytes [XREF_BIBR], in which we demonstrated that the overexpression of the wild-type CYLD (CYLD wt) promoted keratinocyte differentiation, whereas the expression of the mutant CYLD C/S prevented, through the activation of the JNK pathway, the epidermal differentiation [XREF_BIBR]."
CYLD inhibits cell differentiation.
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1
CYLD inhibits cell differentiation. 1 / 3
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1
reach
"The observation that siRNA mediated inhibition of CYLD in WT mice increased hepatic p-STAT3 and fibrin levels, diminished hemorrhage and significantly increased survival indicates that inhibition of CYLD might be a therapeutic option in severe listeriosis and potentially other infectious diseases including acute lung injury induced by S. pneumoniae XREF_BIBR."
sparser
"In contrast to these findings, Draber et al. demonstrated that, although both OTULIN and CYLD interact with HOIP under basal conditions, OTULIN is absent from RSCs [ xref ] (Fig. xref ) and that knock-out of OTULIN resulted in an increase of Met1-linked poly-Ub chains in the cytosol but not at TNFR1 or NOD2 RSCs [ xref ]."
CYLD affects Neoplasm Metastasis
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1
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CYLD inhibits Neoplasm Metastasis.
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1
8
CYLD activates Neoplasm Metastasis.
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5
sparser
"E6 interacts with Cylindromatosis (CYLD) deubiquitinase to inactivate the tumor suppressor CYLD and to activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in hypoxic conditions. xref E6 interacts with p300/cAMP response element binding protein (CREB) xref , xref and interferon regulatory factor 3 (IRF-3) xref to regulate gene expression and with c-Myc to induce upregulation of human telomerase reverse transcriptase to promote cell immortalization. xref , xref , xref HPV16 E6 in the cytoplasm is also important for the oncogenic activity through its regulation of signal transduction by interactions with cytoplasmic E6BP (Erc55), xref E6TP1, xref , xref tumor-necrosis factor (TNF) receptor 1 xref and protein tyrosine phosphatase H1. xref In addition to its oncogenic activities, HPV16 E6 also protects HPV16-infected keratinocytes from the innate immune system by suppressing pro-IL-1β expression. xref "
CYLD affects (-)-noscapine
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15
MiR-181b affects CYLD
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2
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CYLD affects signaling
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14
sparser
"First, CYLD inhibits NF- κ B signaling by deubiquitinating NF- κ B-positive regulators, such as TAK1 (TGF- β -activated Kinase 1), TRAF2 and NEMO/IKK γ . xref , xref Second, caspase 8-mediated cleavage of CYLD generates a survival signal, whereas the mutation of caspase 8-mediated cleavage site on CYLD switches cell survival to necrotic cell death in response to TNF α . xref Last but not least, CYLD interacts with and deubiquitinates RIP1. xref However, it is still controversial whether CYLD affects the ubiquitination of RIP1 in complex I or in the necrosome. xref , xref Given that the above DUBs can remove ubiquitin chains from RIP1, how is RIP1 ubiquitinated?"
sparser
"It was demonstrated by a biochemical study that CYLD has an ability to cleave not only Lys 63-linked ubiquitin chains, but also linear ubiquitin chains ( xref ), which discovery was followed up by a cellular signaling study showing that CYLD inhibits the NF-κB signaling by forming a complex with LUBAC ( xref )."
sparser
"It was initially believed that CYLD inhibited IFN signaling by deubiquitinating the PRR, RIG‐1, and downstream kinases TANK‐binding kinase 1 (TBK‐1) and inhibitor of NF‐κB kinase Ε (IKKΕ) xref ; but, surprisingly, IFN response to vesicular stomatitis virus in CYLD knockout mice or cells from these mice was abrogated. xref On the basis of these reports, TRAF3 and CYLD may serve similar functions after viral infection, namely, to inhibit NF‐κB and activate IFN."
CYLD affects Interferon
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CYLD inhibits Interferon.
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CYLD inhibits Interferon. 8 / 9
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"The deubiquitinating enzyme CYLD cleaves K63 linked polyubiquitin chains from specific substrates, including tumor necrosis factor receptor associated factors (TRAF)-2, TRAF6, transforming growth factor beta activated kinase 1 (TAK1), B cell lymphoma 3 (BCL3), STAT3, nuclear factor kappa B essential modulator (NEMO), and retinoic acid inducible gene 1 (RIG-1), and negatively regulates the activation of NF-kappaB, MAPKs, and type I IFN production."
CYLD activates Interferon.
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5
CYLD activates Interferon. 5 / 5
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"It was initially believed that CYLD inhibited IFN signaling by deubiquitinating the PRR, RIG-1, and downstream kinases TANK binding kinase 1 (TBK-1) and inhibitor of NF-kappaB kinase Epsilon (IKKEpsilon) 44; but, surprisingly, IFN response to vesicular stomatitis virus in CYLD knockout mice or cells from these mice was abrogated.45 On the basis of these reports, TRAF3 and CYLD may serve similar functions after viral infection, namely, to inhibit NF-kappaB and activate IFN."
reach
"Our findings highlight a unique role of CYLD in suppressing autophagy at the step of autolysosome efflux in pressure overloaded hearts and suggest that targeting CYLD may be a novel therapeutic approach for the treatment of adverse cardiac remodeling and dysfunction associated with hypertensive heart disease."
reach
"To test whether the Notch pathway and specifically Hes1 was directly repressing CYLD transcription, we used the Genomatix software to identify putative Hes1 binding sites, and found three distinct N-box consensus sites in the promoter and 5 ' UTR of the CYLD transcriptional start site (XREF_FIG, denoted as PRO1 and PRO2)."
reach
"Previous studies have reported that the Notch and Hes -1 pathway repressed the expression of CYLD XREF_BIBR, XREF_BIBR, a deubiquitination protease, and that CYLD can regulate the activation of TAK1 XREF_BIBR, XREF_BIBR, which is a member of the mitogen activated protein kinase kinase family."
reach
"Furthermore, suppression of Notch signaling by DAPT upregulated Cylindromatosis (CYLD) expression but downregulated TRAF6 expression, IκB kinase (IKK) α/β phosphorylation, and subsequently, phosphorylation and degradation of IκB-α, indicating that DAPT inhibited NF-κB activation triggered by TLR-4."
reach
"A previous study found that Notch stimulates NF-κB activation by initiating the transcription of Hes1, which then suppresses the expression of CYLD, a negative regulator of IKK activity in T-ALL cells [23]; however, this finding does not rule out the possibility that other mechanisms co-exist."
reach
"CYLD defective cylindroma cells were treated with MYB siRNAs for 6 consecutive days, after which cell proliferation was assayed using Alamar Blue Reagent (Thermo Fisher Scientific) and a VICTOR-3 multilabel reader (Perkin-Elmer), according to instructions supplied by the manufacturers."
reach
"This resulted in a significant inhibition of MYB target genes and proliferation of cylindroma cells from three independent tumours, suggesting that MYB activation drives the growth of CYLD defective cylindromas and potentially also the growth of MYB-NFIB-positive sporadic cylindromas."
CYLD affects signalling
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11
sparser
"Because S. pneumoniae induces TGF-β-signalling and TGF-β-signalling is known as a crucial signalling pathway involved in the development of lung fibrosis xref xref xref xref xref xref xref , we determined whether CYLD inhibits TGF-β-signalling using various approaches including short interfering RNA (siRNA)."
CYLD affects signal transduction
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1
CYLD inhibits signal transduction.
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7
1
CYLD activates signal transduction.
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CYLD activates signal transduction. 3 / 3
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3
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"Treatment of MEFs with either 12-O-tetradecanoylphorbol-13 acetate (TPA) (XREF_FIG) or TNF-alpha (XREF_FIG) which was shown earlier to regulate CYLD mediated signal transduction XREF_BIBR, XREF_BIBR, were unable to increase the proliferation rate of CYLD-/- MEFs compared to CYLD +/+ over a period of 24-96 hours (XREF_FIG)."
reach
"A proposed model explaining how p62 mutations lead to the Paget's disease of bone is the following: mutations of the UBA domain cause an impairment in the interaction between p62 and ubiquitinated TRAF6 and/or CYLD, an enzyme deubiquitinating TRAF6, which in turn enhances the activation of the NF-κB signaling pathway and the resulting increased osteoclastogenesis (Figure 3(b)) [160]."
CYLD affects cell migration
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CYLD inhibits cell migration.
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6
CYLD activates cell migration.
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CYLD activates cell migration. 4 / 4
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4
reach
"In contrast to the proliferation related activity, CYLD knockdown significantly decreased the cell migration of all the melanoma cell lines (n = 7, p < 0.05), and we demonstrated that the mechanism regulating melanoma cell migration was activation of RAC1 through the action of CYLD."
CYLD affects activity
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10
CYLD affects transcription, DNA-templated
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9
CYLD inhibits transcription, DNA-templated.
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6
CYLD inhibits transcription, DNA-templated. 6 / 6
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6
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"The tumor suppressor gene CYLD, which was recently identified as the cylindromatosis gene, has a deubiquitinating enzyme (DUB) activity and inhibits activation of the transcription factor NF-kappaB, which has key roles in inflammation, immune responses, carcinogenesis, and protection against apoptosis [XREF_BIBR]."
CYLD activates transcription, DNA-templated.
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CYLD activates transcription, DNA-templated. 3 / 3
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3
reach
"CYLD (the familial cylindromatosis tumor suppressor gene) enhances the activation of the transcription factor NFkapa-B [XREF_BIBR], RBBP6, (which binds to the retinoblastoma gene product pRB) [XREF_BIBR], and PNUTL2 (which is an apoptosis related protein in the TGF-beta signaling pathway) [XREF_BIBR]."
reach
"Our study supported the involvement of six candidate genes in susceptibility to psoriasis : SCL12A8, which belongs to the solute carrier gene family; FLG and TGM5, which are involved in epidermal differentiation; CARD15 and CYLD, which modulate the transcription factor NF-kB; and IL1RN, which encodes an IL receptor antagonist."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
"The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity."
Phorbol 13-acetate 12-myristate affects CYLD
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8
sparser
"Given that the extreme N-terminal CAP-Gly domain of CYLD is essential for its interaction with microtubules 17-19 , the above data indicate that the effect of CYLD on noscapine activity is dependent on the binding of CYLD to microtubules and is independent of its deubiquitinase activity."
sparser
"Although the conserved CAP-GLY domains provide structural basis for the interactions of CYLD with microtubules and many other proteins, an interesting finding is that EB1 containing a known CAP-GLY domain-interacting motif interacts with the C-terminal USP domain of CYLD other than the CAP-GLY domains, implicating a previously unknown role for the USP domain in mediating protein-protein interactions."
sparser
"For example, the cytoskeleton-associated protein-glycine-rich domain mediates the interaction of CYLD with microtubules, whereas calponin homology domain mediates the interaction of EB1 with microtubules. xref , xref , xref In this study, using a combination of taxol-based microtubule isolation and mass spectrometry, we have identified a list of proteins that may potentially associate with microtubules."
sparser
"The DUB CYLD can associate with microtubules through a CAP-Gly domain, regulate their dynamics, and control entry into mitosis ( xref ; xref ; xref ), whereas a ubiquitin C-terminal hydrolase, UCHL1, has also been found associated with microtubules in certain cell types ( xref )."
sparser
"Given that this was seen within 1–2 h after stimulation, much earlier than increased p62 expression, the ordered interaction of p62 with TRAF6 and CYLD during macrophage activation is not likely to be entirely attributed to inducible p62 expression, but may involve posttrans-lational modification of p62, such as ubiquitination ( xref ) and phosphorylation ( xref )."
reach
"The experiments performed by Espinosa and collaborators [XREF_BIBR] in T-ALL and HEK293T cells support the notion that HES1 induced CYLD repression results in increased IKK kinase activity, IkappaBalpha degradation, RelA nuclear translocation, and NF-kappaB transcriptional activity."
reach
"The mechanism of Notch induced NF-kappaB activation in T-ALL involves Hes1, which transcriptionally represses CYLD (cylindromatosis), a deubiquitinase which down-regulates NF-kappaB signaling by removing the activator K63 ubiquitin chains from different elements of the NF-kappaB signalosome [XREF_BIBR]."
reach
"To test whether the Notch pathway and specifically Hes1 was directly repressing CYLD transcription, we used the Genomatix software to identify putative Hes1 binding sites, and found three distinct N-box consensus sites in the promoter and 5 ' UTR of the CYLD transcriptional start site (XREF_FIG, denoted as PRO1 and PRO2)."
Delta-actitoxin-Avd1a affects CYLD
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CYLD binds Delta-actitoxin-Avd1a. 8 / 8
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sparser
"In summary, our study revealed that CYLD-AS1 affects the oxidative stress-related and inflammatory functions of RPE cells by sponging miR-134-5p to mediate NRF2/NF-κB signaling pathway activity, suggesting that targeting CYLD-AS1 could be a promising strategy for the treatment of AMD and related diseases."
CYLD affects innate immune response
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8
sparser
"Given that the extreme N-terminal CAP-Gly domain of CYLD is essential for its interaction with microtubules 17-19 , the above data indicate that the effect of CYLD on noscapine activity is dependent on the binding of CYLD to microtubules and is independent of its deubiquitinase activity."
sparser
"Although the conserved CAP-GLY domains provide structural basis for the interactions of CYLD with microtubules and many other proteins, an interesting finding is that EB1 containing a known CAP-GLY domain-interacting motif interacts with the C-terminal USP domain of CYLD other than the CAP-GLY domains, implicating a previously unknown role for the USP domain in mediating protein-protein interactions."
sparser
"For example, the cytoskeleton-associated protein-glycine-rich domain mediates the interaction of CYLD with microtubules, whereas calponin homology domain mediates the interaction of EB1 with microtubules. xref , xref , xref In this study, using a combination of taxol-based microtubule isolation and mass spectrometry, we have identified a list of proteins that may potentially associate with microtubules."
sparser
"The DUB CYLD can associate with microtubules through a CAP-Gly domain, regulate their dynamics, and control entry into mitosis ( xref ; xref ; xref ), whereas a ubiquitin C-terminal hydrolase, UCHL1, has also been found associated with microtubules in certain cell types ( xref )."
"Other identified CYLD substrates include TNF receptor associated factor 7 (TRAF7), TRAF interacting protein (TRIP), transforming growth factor beta-activated kinase 1 (TAK1), NF-kappa-B essential modifier (NEMO), lymphocyte cell specific protein-tyrosine kinase (LCK), receptor-interacting protein 1 (RIP1), retinoic acid inducible gene (RIG), and polo-like kinase 1 (PLK1)"
reach
"Later work studying signaling through the toll like receptor 2 (TLR2) performed cell based experiments to demonstrate that CYLD binds to TRAF6 and TRAF7 and that depletion of CYLD increases the ability of transfected TRAF6 or TRAF7 to activate an NFkappaB dependent reporter gene [XREF_BIBR]."
reach
"Further, the de-ubiquitinase CYLD has been shown to inactivate TRAF6 downstream of RANK in osteoclasts, as evidenced by removal of polyubiquitin chains, and the physiologic relevance of this mechanism is supported by the phenotype of CYLD deficient osteoclasts, which exhibit hyper-responsiveness to RANK."
sparser
"Given that this was seen within 1–2 h after stimulation, much earlier than increased p62 expression, the ordered interaction of p62 with TRAF6 and CYLD during macrophage activation is not likely to be entirely attributed to inducible p62 expression, but may involve posttrans-lational modification of p62, such as ubiquitination ( xref ) and phosphorylation ( xref )."
reach
"Alternatively, the existence of a constitutive CYLD and PKCtheta complex might suggest that PKCtheta, which shows activation dependent subcellular translocation, is important for removing CYLD from its NFkappaB related targets and attenuates the negative regulatory function of CYLD, enabling feedback control of NFkappaB activation."
reach
"In the present study, we found that high glucose dose- and time-dependently downregulated the protein and mRNA expressions of CYLD in GMCs (SV40 MES 13 and HBZY-1) and increased the expression levels of p-IkappaBalpha, NF-kappaBp65, and p-NF-kappaBp65, and furthermore induced the release of MCP-1, IL-6, and IL-8."
CYLD affects Delta-actitoxin-Avd1a
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CYLD binds Delta-actitoxin-Avd1a. 8 / 8
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sparser
"In summary, our study revealed that CYLD-AS1 affects the oxidative stress-related and inflammatory functions of RPE cells by sponging miR-134-5p to mediate NRF2/NF-κB signaling pathway activity, suggesting that targeting CYLD-AS1 could be a promising strategy for the treatment of AMD and related diseases."
reach
"In agreement with the mechanism in keratinocytes, CYLD markedly reduced expression of Cyclin D1 (XREF_FIG), cyclin D1 promoter activity (XREF_FIG), and BCL-3 recruitment to the cyclin D1 promoter in a complex with p50 or p52 (XREF_FIG, left) as compared with cells transduced with viral vectors carrying a catalytically inactive mutant of CYLD (C/S-CYLD), a GFP expression cassette or noninfected cells."
USP affects SPATA2
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7
sparser
"Together, these results show that SPATA2 contains two distinct domains that are responsible for mediating the interaction with CYLD and HOIP, respectively; while the N terminus of SPATA2 binds to the USP domain of CYLD, the interaction with HOIP is mediated via a highly conserved PIM located in the central portion of SPATA2, which is recognized by the PUB domain of HOIP."
sparser
"Nonetheless, depletion of TRIP6 can significantly enhance the association of A20 or CYLD with TRAF6 in ovarian cancer cells and promote the binding of A20 to TRAF6 in glioblastoma cells, suggesting that targeting TRIP6 may prove to be an effective strategy to restore the function of A20 and CYLD in restricting the NF-κB activity in these cancer cells."
sparser
"Nonetheless, depletion of TRIP6 by either shRNA ( xref ) or Cas9/sgRNA ( xref ) not only enhanced the association of TRAF6 with A20, but also with CYLD in untreated and treated cells, suggesting a significant role for TRIP6 in antagonizing the binding of TRAF6 to both A20 and CYLD in ovarian cancer cells."
sparser
"In this regard, here we provide evidence that the adaptor protein TRIP6 (thyroid hormone receptor-interacting protein 6), a specific interacting protein of the LPA2 receptor but not other LPA receptors, recruits TRAF6 to the LPA2 receptor and enhances the E3 ligase activity of TRAF6 by antagonizing the association of A20 and CYLD to TRAF6."
SPATA2 affects USP
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7
sparser
"Together, these results show that SPATA2 contains two distinct domains that are responsible for mediating the interaction with CYLD and HOIP, respectively; while the N terminus of SPATA2 binds to the USP domain of CYLD, the interaction with HOIP is mediated via a highly conserved PIM located in the central portion of SPATA2, which is recognized by the PUB domain of HOIP."
sparser
"Nonetheless, depletion of TRIP6 can significantly enhance the association of A20 or CYLD with TRAF6 in ovarian cancer cells and promote the binding of A20 to TRAF6 in glioblastoma cells, suggesting that targeting TRIP6 may prove to be an effective strategy to restore the function of A20 and CYLD in restricting the NF-κB activity in these cancer cells."
sparser
"Nonetheless, depletion of TRIP6 by either shRNA ( xref ) or Cas9/sgRNA ( xref ) not only enhanced the association of TRAF6 with A20, but also with CYLD in untreated and treated cells, suggesting a significant role for TRIP6 in antagonizing the binding of TRAF6 to both A20 and CYLD in ovarian cancer cells."
sparser
"In this regard, here we provide evidence that the adaptor protein TRIP6 (thyroid hormone receptor-interacting protein 6), a specific interacting protein of the LPA2 receptor but not other LPA receptors, recruits TRAF6 to the LPA2 receptor and enhances the E3 ligase activity of TRAF6 by antagonizing the association of A20 and CYLD to TRAF6."
eidos
"Tumor suppressor deubiquitinase ( DUB ) , cylindromatosis ( CYLD ) , inhibits TLR2 signaling responsible for the recognition of Gram-positive bacterial PAMPs [ PGN , LTA , MALP-2 ( Mycoplasma-derived lipopeptide 2 ) , and Pam3CSK4 ( a synthetic triacylated lipopeptide recognized by TLR1 / TLR2 heterodimer ] [ 174 ] ."
| PMC
reach
"CYLD also negatively regulates the c-Jun N-terminal kinase (JNK) signaling pathway and mitogen activated protein kinase (MAPK) pathway, which are known to participate in a wide range of cellular processes, including proliferation, differentiation, and apoptosis of cholesteatoma [XREF_BIBR, XREF_BIBR]."
reach
"In addition, Cyld gene gain- and/or loss-of-function approaches in vitro and in vivo demonstrated that CYLD mediated cardiomyocyte death associated with impaired reactivation of mechanistic target of rapamycin complex 1 (mTORC1) and upregulated Ras genes from rat brain 7 (Rab7), two key components for autolysosomal degradation."
reach
"These changes in sensitivity to TNF-alpha cytoxicity, mediated by the treatment of siCLIPR-59 or siCYLD, correlated with differences in RIP1 ubiquitination (XREF_SUPPLEMENTARY) These findings thus suggest that both CLIPR-59 and CYLD are essential for activation of Caspase-8 by TNF-alpha in the presence of Compound-3."
sparser
"Interaction between transfected CYLD and CASPASE 8 by co-immunoprecipitation was observed only when the activity of CASPASE 8 was blocked by the pan-caspase inhibitor zVAD-fmk, or by mutation of the CASPASE 8 active site, suggesting that CYLD is a substrate for proteolytic cleavage by CASPASE 8 ( xref )."
Valproic acid affects CYLD
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Valproic acid increases the amount of CYLD. 6 / 6
6
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Sponging miR-96-5p affects CYLD
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6
MiR-181b-1 affects CYLD
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6
reach
"Alternatively, the existence of a constitutive CYLD and PKCtheta complex might suggest that PKCtheta, which shows activation dependent subcellular translocation, is important for removing CYLD from its NFkappaB related targets and attenuates the negative regulatory function of CYLD, enabling feedback control of NFkappaB activation."
CYLD affects ubiquitination
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5
sparser
"In hepatic listeriosis, Cyld-deficiency increased K63-ubiquitination of STAT3, and further in vitro experiments demonstrated that CYLD inhibited K63-ubiquitination of STAT3 in the cytoplasm of IL-6-stimulated hepatocytes, which is in agreement with the exclusive cytoplasmic localisation of CYLD."
CYLD affects miR-181b
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6
CYLD affects localization
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6
CYLD affects cell cycle
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6
CYLD inhibits cell cycle.
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3
CYLD activates cell cycle.
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3
reach
"As shown in XREF_FIG, the si-miR, CYLD, si-miR + NC4 and si-miR + si-C groups exhibited significantly higher apoptotic rates, as well as increased Bax, cleaved caspase-3 and p-IkappaBalpha and IkappaBalpha expression levels, and decreased Bcl-2 and p-p65 and p65 levels compared with the BC group."
sparser
"To test whether Cyld cleaves K48- or K63-linked ubiquitination, we coexpressed Flag—NLRP6, Myc—Cyld and HA—UbK48 (in which all of the lysine residues within Ub except K48 were mutated to arginine) or HA—UbK63 (in which all of the lysine residues within Ub except K63 were mutated to arginine)."
reach
"In agreement with the reported negative regulation of JNK and c-Myc activation by CYLD [XREF_BIBR], WB analysis of these molecules showed increased Akt, JNK and c-Myc activation (measured as levels of P-Akt, P-JNK and P-c-Myc respectively) in the skin of transgenic mice lacking the DUB function (XREF_FIG)."
sparser
"In agreement with the reported negative regulation of JNK and c-Myc activation by CYLD [ xref ], WB analysis of these molecules showed increased Akt, JNK and c-Myc activation (measured as levels of P-Akt, P-JNK and P-c-Myc respectively) in the skin of transgenic mice lacking the DUB function ( xref )."
reach
"CYLD, another DUB, is reported to limit NF-kappaB activation by removing K63- and M1 linked poly-ubiquitin chains on several complex I components (including TRAF2, NEMO and RIPK1), thereby disrupting the ubiquitin scaffold required for the recruitment and activation of the TAB2/3-TAK 1 and NEMO-IKKalpha-IKKbeta complexes [XREF_BIBR, XREF_BIBR - XREF_BIBR]."
reach
"Previous studies report that CYLD negatively regulates NF-kappaB signaling by removing K63- and M1 linked polyubiquitin chains from key signaling molecules, including NF-kappaB essential modulator, tumor necrosis factor (TNF)-associated factor (TRAF) 2, TRAF6, and Receptor interacting serine/threonine protein kinase 1, in familial cylindromatosis tumors."
reach
"The observation that siRNA mediated inhibition of CYLD in WT mice increased hepatic p-STAT3 and fibrin levels, diminished hemorrhage and significantly increased survival indicates that inhibition of CYLD might be a therapeutic option in severe listeriosis and potentially other infectious diseases including acute lung injury induced by S. pneumoniae XREF_BIBR."
CYLD affects E3_Ub_ligase
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3
3
CYLD binds E3_Ub_ligase.
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3
E3_Ub_ligase binds ITCH and CYLD. 3 / 3
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sparser
"E3 ligase Itch and deubiquitinase CYLD form a complex that cleaves lysine (Lys) 63-linked ubiquitin chains and catalyze Lys48-linked ubiquitination on the kinase Tak1, which is a common substrate for these two proteins, thereby contributing to decreased inflammatory signalling [ xref ]."
sparser
"Recently, it has been demonstrated that E3 ligase ITCH and CYLD formed a complex which can sequentially cleave K63-linked ubiquitin-chain and catalyzes K48-linked ubiquitination to deactivate TAK1 and terminate NF-κB signaling (Ahmed et al., xref ), providing an example of how K48 and K63-linked ubiquitinations are closely linked and can be differentially utilized to control kinase activation and deactivation."
CYLD activates E3_Ub_ligase.
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3
Microtubule affects CYLD
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1
Microtubule binds CYLD. 1 / 5
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1
sparser
"To further assess whether the catalytic activity and/or HDAC6 and MT binding of CYLD are necessary to induce a delay in the cell cycle, we analysed the duration of the cell cycle in melanoma cells expressing full-length CYLD, catalytically inactive CYLD C/S , and a deletion mutant that lacks the first CAP-Gly domains (CYLD 222–956 ) and does not bind HDAC6."
reach
"In the present study, we found that high glucose dose- and time-dependently downregulated the protein and mRNA expressions of CYLD in GMCs (SV40 MES 13 and HBZY-1) and increased the expression levels of p-IkappaBalpha, NF-kappaBp65, and p-NF-kappaBp65, and furthermore induced the release of MCP-1, IL-6, and IL-8."
sparser
"However, the expression of USP4 is decreased in failing human heart as well as in experimental animals with pathological hypertrophy. xref Similarly, CYLD prevents activation and recruitment of TAKl by cleaving the K63 polyubiquitin chain of TRAF2,TRAF6 and NEMO (Figure xref ), which leads to inactivation of IKK and suppression of downstream of NF‐κB pathway. xref , xref Similarly, the ubiquitination of TRAF‐binding protein (TRIP) is required for the activation of TNFα‐induced NF‐κB. This signalling pathway is controlled by CYLD‐dependent removal of K63‐linked ubiquitination chains of TRIP, which leads to attenuation of TNFα‐dependent NF‐κB signalling. xref CYLD‐Nrf2 axis plays a key role in the cardiac remodelling."
IKK_family affects CYLD
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4
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IKK_family phosphorylates CYLD. 5 / 5
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1
reach
"It is likely that the IKK family phosphorylates multiple targets including RIPK1 and CYLD, all with the goal of inhibiting RIPK1-mediated cell death.To understand further the role that CYLD phosphorylation may be playing in ATLL pathogenesis, we analyzed this modification in HTLV-1 transformed T-cell lines, representative of ATLL, as well as in primary human ATLL samples."
reach
"A previous study found that Notch stimulates NF-κB activation by initiating the transcription of Hes1, which then suppresses the expression of CYLD, a negative regulator of IKK activity in T-ALL cells [23]; however, this finding does not rule out the possibility that other mechanisms co-exist."
HES1 binds CYLD.
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2
sparser
"Using a conventional ChIP assay in human Hes1 + T-ALL cells and a Hes1 antibody followed by PCR with specific primers flanking the identified putative N-box sites, we were able to show that endogenous Hes1 binds to the predicted PRO2 site in the CYLD 5’UTR ( xref ) and this association was lost following Hes1 knock-down ( xref ) as measured by qPCR."
CYLD affects response
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4
CYLD affects reactive oxygen species
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1
4
CYLD inhibits reactive oxygen species.
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3
CYLD activates reactive oxygen species.
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1
CYLD affects migration
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3
CYLD affects microtubule
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1
Microtubule binds CYLD. 1 / 5
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sparser
"To further assess whether the catalytic activity and/or HDAC6 and MT binding of CYLD are necessary to induce a delay in the cell cycle, we analysed the duration of the cell cycle in melanoma cells expressing full-length CYLD, catalytically inactive CYLD C/S , and a deletion mutant that lacks the first CAP-Gly domains (CYLD 222–956 ) and does not bind HDAC6."
CYLD affects expression
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5
CYLD affects beta1-integrin
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5
sparser
"However, the expression of USP4 is decreased in failing human heart as well as in experimental animals with pathological hypertrophy. xref Similarly, CYLD prevents activation and recruitment of TAKl by cleaving the K63 polyubiquitin chain of TRAF2,TRAF6 and NEMO (Figure xref ), which leads to inactivation of IKK and suppression of downstream of NF‐κB pathway. xref , xref Similarly, the ubiquitination of TRAF‐binding protein (TRIP) is required for the activation of TNFα‐induced NF‐κB. This signalling pathway is controlled by CYLD‐dependent removal of K63‐linked ubiquitination chains of TRIP, which leads to attenuation of TNFα‐dependent NF‐κB signalling. xref CYLD‐Nrf2 axis plays a key role in the cardiac remodelling."
BTK inhibitor affects CYLD
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5
MiR-362-5p affects CYLD
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4
MiR-362-5p decreases the amount of CYLD.
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2
reach
"Because NF-kappaB has been proven to play critical roles in the regulation of NK cell activity and cytokine production XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR, we hypothesized that miR-362-5p might inhibit CYLD expression to induce downstream NF-kappaB signaling, thereby regulating NK cell function."
reach
"Studies found that miR-362-5p reduces the expression of tumor suppressor protein CYLD, which leads to activate the NF-kB pathway to promote the proliferation, migration, and invasion of hepatocellular carcinoma cells and human breast cancer cells (Ni et al., 2015; Ni et al., 2016)."
MiR-362-5p activates CYLD.
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2
MiR-19 affects CYLD
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1
3
eidos
"Much efforts have been devoted to detect miRNA-TF FFLs , which were used to dissect potential regulatory mechanisms underlying human diseases.12 , 13 On the one hand , started from disease-related molecules and different regulatory relationships amongst miRNAs , genes and TFs , Ye et al14 revealed that miR-19 inhibited CYLD through the identified disrupted FFLs in T-cell acute lymphoblastic leukaemia ."
MiR-130b affects CYLD
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4
reach
"Thus, the present study revealed that, in bladder cancer, NF-kappaB can maintain its activity by establishing a feedback loop, in which NF-kappaB induced the expression of miR-130b, which consequently inhibited the expression of CYLD, which in turn was an endogenous inhibitor of NF-kappaB activation."
Hsa-miR-362-5p affects CYLD
4
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sparser
"However, the phospho(Ser418)-CYLD immunoreactive band was still present in CRISPR/Cas9 generated IKKε/TBK1 double knockout cell lines, where it could still be prevented by MRT67307, indicating that the initially observed inhibitory effect of MRT67307 on TCR-induced CYLD phosphorylation is IKKε/TBK1-independent."
Snail1 affects CYLD
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4
SPATA2 affects PUB domain
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4
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [32]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [ xref ]."
PUB domain affects SPATA2
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4
sparser
"CYLD physically interacts with polo-like kinase 1 (Plk1), a serine/threonine kinase with a key regulatory role in mitotic cell division. xref It was proposed that CYLD positively regulates the function of Plk1, probably by deconjugating K63-linked ubiquitin chains on Plk1 or its upstream regulators. xref However, as the role of K63 ubiquitination in Plk1 regulation has not been established, further studies are required to understand how CYLD regulates mitosis."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [32]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [ xref ]."
N-methyl-D-aspartic acid affects CYLD
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3
1
N-methyl-D-aspartic acid phosphorylates CYLD.
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1
1
N-methyl-D-aspartic acid activates CYLD.
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2
N-[3-[[5-cyclopropyl-2-[3-(4-morpholinylmethyl)anilino]-4-pyrimidinyl]amino]propyl]cyclobutanecarboxamide affects CYLD
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4
N-[3-[[5-cyclopropyl-2-[3-(4-morpholinylmethyl)anilino]-4-pyrimidinyl]amino]propyl]cyclobutanecarboxamide leads to the dephosphorylation of CYLD. 4 / 4
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sparser
"To test whether Cyld cleaves K48- or K63-linked ubiquitination, we coexpressed Flag—NLRP6, Myc—Cyld and HA—UbK48 (in which all of the lysine residues within Ub except K48 were mutated to arginine) or HA—UbK63 (in which all of the lysine residues within Ub except K63 were mutated to arginine)."
CYLD affects production
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4
sparser
"The study results showed that 1) EAC inhibited the macrophage NO production in vivo and reprogrammed macrophages towards the M2 phenotype; 2) ascitic fluid of mice with EAC inhibited the macrophage NO production in vitro and reprogrammed macrophages towards the M2 phenotype; and 3) injection of in vitro reprogrammed M1 macrophages into mice with EAC significantly increased the lifespan of mice."
CYLD affects polyubiquitination
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3
CYLD affects miR-362-5p
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4
CYLD affects function
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4
eidos
"Moreover , since CYLD can act as a negative regulator of NF-kappaB pathways [ 48 ] , depressed CYLD expression resulted in aberrant activation of NF-kappaB , thereby inducing HCC cells to express abundantly a neutrophilic chemokine , CXCL5 , which can attract a large number of neutrophils [ 47 ] ."
CYLD affects cell growth
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4
sparser
"Together, these results show that SPATA2 contains two distinct domains that are responsible for mediating the interaction with CYLD and HOIP, respectively; while the N terminus of SPATA2 binds to the USP domain of CYLD, the interaction with HOIP is mediated via a highly conserved PIM located in the central portion of SPATA2, which is recognized by the PUB domain of HOIP."
reach
"Mouse RIP3, RIP1, MLKL, and CYLD siRNAs were synthesized by GenePharma : RIP3-1 (cccgacgaugucuucugucaa), RIP3-2 (cuccuuaaagucaauaaacau), RIP1-1 (ccacuagucugacugauga), RIP1-2 (ucaccaauguugcaggaua), CYLD-1 (uccauugaggauguaaauaaa), CYLD-2 (aaggguugaaccauuguuaaa), MLKL-1 (gagauccaguucaacgaua), and MLKL-2 (uaccaucaaaguauucaacaa)."
sparser
"CYLD physically interacts with polo-like kinase 1 (Plk1), a serine/threonine kinase with a key regulatory role in mitotic cell division. xref It was proposed that CYLD positively regulates the function of Plk1, probably by deconjugating K63-linked ubiquitin chains on Plk1 or its upstream regulators. xref However, as the role of K63 ubiquitination in Plk1 regulation has not been established, further studies are required to understand how CYLD regulates mitosis."
CYLD affects PD-L1
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4
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [32]."
sparser
"The mechanisms regulating the interaction of LUBAC with OTULIN and SPATA2-CYLD in cells are not well-understood but in vitro studies show that phosphorylation of the tyrosine (Y56) in the OTULIN PIM abrogates its interaction with HOIP, suggesting that this may be a mechanism to regulate the LUBAC–OTULIN complex [ xref ]."
CYLD affects Multiple Myeloma
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4
CYLD affects Fibroblasts
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4
CYLD inhibits Fibroblasts.
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2
CYLD activates Fibroblasts.
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2
CYLD affects CAMK2_complex
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4
Trichostatin A affects CYLD
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2
Selenite(2-) affects CYLD
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3
Protein phosphatase affects TNFAIP3
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3
Oncogene IKKepsilon affects CYLD
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3
MiR-99b-3p affects CYLD
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3
MiR-454 affects CYLD
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3
Doxorubicin affects CYLD
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2
Cadmium atom affects CYLD
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Cadmium atom inhibits CYLD. 3 / 3
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1
2
eidos
"In addition to aggregation , Cd induced CYLD inactivation , as shown by an increase in high molecular weight ( likely ubiquitinated ) forms of CYLD and the cleavage of CYLD into several inactive fragments of ~ 72 , 50 , and 40 kDa [ 67 ] , two events that were not recapitulated by proteasomal inhibition ( data not shown , Chargui A. IRCAN , Nice , France , 2021 ) ."
| PMC
USP affects Trim14
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3
USP domain affects SPATA2
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3
sparser
"Recent structural characterization of CYLD bound to Lys63-linked diubiquitin in the catalytic state and Met1-linked diubiquitin in both the pre-catalytic and catalytic states revealed that the His side chain is arranged in a catalytically competent orientation with either diubiquitin xref ."
sparser
"Structural comparison with the USP7-ubiquitin complex (PDB 5JTJ) and with the CYLD-diubiquitin K63 complex (PDB 3WXG) xref indicates that the IL-loop and the “distal” ubiquitin share a similar binding surface (Fig. xref and Supplementary Figure xref ), thus preventing substrate binding in the tetramer assembly."
Trim14 affects USP
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3
TNFAIP3 affects protein phosphatase
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3
sparser
"DUB-E3 interactions are used for mutual ubiquitin-dependent regulation (e.g., to control each other’s stability, see above) or for editing ubiquitin chain architecture on particular substrates (as shown for the hybrid DUB/E3 enzyme A20 and CYLD-ITCH complexes during inflammatory signaling [ xref , xref ])."
SPATA2 affects USP domain
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3
SNAIL1 affects CYLD
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3
sparser
"MFT has been associated with mutations in the CYLD gene on a chromosome.[ xref ] Mutations in this gene have also been linked to familial cylindromatosis and Brooke–Spiegler syndrome, in which the patients develop trichoepitheliomas and cylindromas.[ xref ] CYLD gene has tumor suppressor properties and influences cell survival and proliferation."
Proteasome affects CYLD
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3
PSDs affects CYLD
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3
PPP2 affects protein phosphatase
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3
reach
"As shown in XREF_FIG and XREF_SUPPLEMENTARY, inhibition of PDE4 using Rolipram still enhanced NTHi induced upregulation of CYLD in JNK1 depleted cells but not in JNK2 depleted cells, confirming the selective requirement of JNK2 in mediating PDE4B-depenent negative regulation of CYLD expression."
reach
"Having demonstrated that inhibition of PDE4 enhanced upregulation of CYLD and suppressed NTHi induced inflammation, it is still unclear whether inhibition of PDE4 suppresses inflammation via upregulating the expression of CYLD, a key negative regulator of inflammation, or via inhibiting key positive regulators of inflammation, for example, IKKbeta."
LUBAC affects CYLD
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3
sparser
"DUB-E3 interactions are used for mutual ubiquitin-dependent regulation (e.g., to control each other’s stability, see above) or for editing ubiquitin chain architecture on particular substrates (as shown for the hybrid DUB/E3 enzyme A20 and CYLD-ITCH complexes during inflammatory signaling [ xref , xref ])."
ITCH affects E3_Ub_ligase
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3
E3_Ub_ligase binds ITCH and CYLD. 3 / 3
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3
sparser
"E3 ligase Itch and deubiquitinase CYLD form a complex that cleaves lysine (Lys) 63-linked ubiquitin chains and catalyze Lys48-linked ubiquitination on the kinase Tak1, which is a common substrate for these two proteins, thereby contributing to decreased inflammatory signalling [ xref ]."
sparser
"Recently, it has been demonstrated that E3 ligase ITCH and CYLD formed a complex which can sequentially cleave K63-linked ubiquitin-chain and catalyzes K48-linked ubiquitination to deactivate TAK1 and terminate NF-κB signaling (Ahmed et al., xref ), providing an example of how K48 and K63-linked ubiquitinations are closely linked and can be differentially utilized to control kinase activation and deactivation."
E3_Ub_ligase affects ITCH
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3
E3_Ub_ligase binds ITCH and CYLD. 3 / 3
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3
sparser
"E3 ligase Itch and deubiquitinase CYLD form a complex that cleaves lysine (Lys) 63-linked ubiquitin chains and catalyze Lys48-linked ubiquitination on the kinase Tak1, which is a common substrate for these two proteins, thereby contributing to decreased inflammatory signalling [ xref ]."
sparser
"Recently, it has been demonstrated that E3 ligase ITCH and CYLD formed a complex which can sequentially cleave K63-linked ubiquitin-chain and catalyzes K48-linked ubiquitination to deactivate TAK1 and terminate NF-κB signaling (Ahmed et al., xref ), providing an example of how K48 and K63-linked ubiquitinations are closely linked and can be differentially utilized to control kinase activation and deactivation."
reach
"We also checked in both lines of transgenic mice, that, as expected, the CYLD C/S mutant was catalytically inactive and inhibited the DUB function of the endogenous CYLD, as we previously described that occurred in the epidermal HaCaT-CYLD C/S and PDVC57-CYLD C/S cells [XREF_BIBR, XREF_BIBR] (XREF_SUPPLEMENTARY)."
CYLD affects protein phosphatase
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3
CYLD affects protein deubiquitination
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3
CYLD affects pathway
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3
sparser
"Similarly, in HBE cells transformed with 2% cigarette smoke extract (CSE), increased levels of m 6 A and upregulated expression of METTL3 were observed after 48 hours of treatment. xref In particular, METTL3-mediated increases of m 6 A on the 3’ UTR of the tumor suppressor Zbtb4 resulted in decreased ZBTB4 expression through YTHDF2-mediated mRNA decay. xref As a result, decreased ZBTB4 expression promoted cigarette smoke (CS)-induced EMT and carcinogenesis. xref In another study, human bronchial epithelial (BEAS-2B) cells exposed to CS had downregulated expression of YTHDC2. xref Mechanistically, YTHDC2 was found to bind m 6 A sites on the transcript of the tumor suppressor Cyld and promoted Cyld mRNA stability. xref As CYLD normally inhibits the NF- κ B pathway, decreased YTHDC2 expression after CS exposure can promote cancer cell proliferation by modulating the CYLD/NF- κ B axis in CS-induced lung cancer. xref "
sparser
"Previous studies report that CYLD negatively regulates NF-κB signaling by removing K63- and M1-linked polyubiquitin chains from key signaling molecules, including NF-κB essential modulator, tumor necrosis factor (TNF)-associated factor (TRAF) 2, TRAF6, and Receptor-interacting serine/threonine-protein kinase 1, in familial cylindromatosis tumors. xref – xref Additionally, Tauriello et al xref demonstrated that CYLD inhibits the Wnt pathway by deubiquitinating disheveled in familial cylindromatosis tumors."
CYLD affects miR-500
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3
reach
"Importantly, the repressive effect of antagomiR-500 on NF-kappaB activity and BCL2L1, CCND1 expression were potently antagonised by individual silencing of CYLD, TAX1BP1, or OTUD7B (XREF_SUPPLEMENTARY), indicating that CYLD, TAX1BP1, and OTUD7B are functionally relevant effectors of miR-500 in NF-kappaB activation."
CYLD affects induction
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3
CYLD affects immune response
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3
CYLD affects homeostatic process
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3
CYLD affects growth
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3
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1
2
CYLD activates epithelial to mesenchymal transition. 3 / 3
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1
2
reach
"CYLD downregulation or inactivation induced an epithelial to mesenchymal transition of mammary epithelial cells that was dependent on the concomitant activation of the transcription factors Yes associated protein (YAP)/transcriptional coactivator with PDZ binding motif (TAZ) and transforming growth factor beta (TGF) signaling."
CYLD affects cell adhesion
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3
CYLD affects angiogenesis
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3
CYLD affects USP domain
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3
sparser
"Recent structural characterization of CYLD bound to Lys63-linked diubiquitin in the catalytic state and Met1-linked diubiquitin in both the pre-catalytic and catalytic states revealed that the His side chain is arranged in a catalytically competent orientation with either diubiquitin xref ."
sparser
"Structural comparison with the USP7-ubiquitin complex (PDB 5JTJ) and with the CYLD-diubiquitin K63 complex (PDB 3WXG) xref indicates that the IL-loop and the “distal” ubiquitin share a similar binding surface (Fig. xref and Supplementary Figure xref ), thus preventing substrate binding in the tetramer assembly."
CYLD affects TOPFlash reporter
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3
sparser
"MFT has been associated with mutations in the CYLD gene on a chromosome.[ xref ] Mutations in this gene have also been linked to familial cylindromatosis and Brooke–Spiegler syndrome, in which the patients develop trichoepitheliomas and cylindromas.[ xref ] CYLD gene has tumor suppressor properties and influences cell survival and proliferation."
reach
"The silencing of CYLD significantly inhibited AF transdifferentiation and activation as evidenced by the expression of contractile proteins, the production of the proinflammatory cytokines MCP-1 (monocyte chemotactic protein 1) and IL-6 (interleukin-6), the deposition of extracellular matrix, and cell migration."
reach
"- Cyld knockout impairs amygdala-dependent tone-cued fear memory in mice.- Cyld mice display aberrant neuronal activation in BLA in response to tone-cued fear test.- Cyld mice show decreased excitability of BLA principal neurons.- CYLD is critical for both excitatory and inhibitory synaptic neurotransmission in mouse BLA."
sparser
"Thus, CYLD inhibits MyD88, RIP1 (receptor-interacting serine/threonine-protein kinase 1), TRAF2, TRAF6, TRAF7 and NEMO downstream to TLR signaling and regulates exaggerated inflammation which can lead to the development of severe infection causing sepsis and associated organ damage."
| DOI
reach
"These results suggest that CYLD colocalizes mainly with acetylated MTs in the perinuclear region, and this localization is constitutive in CYLD transduced melanoma cells, whereas in primary mouse keratinocytes or primary human melanocytes (XREF_SUPPLEMENTARY) it is induced after TPA treatment or exposure to UV light."
CYLD affects LUBAC
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3
sparser
"DUB-E3 interactions are used for mutual ubiquitin-dependent regulation (e.g., to control each other’s stability, see above) or for editing ubiquitin chain architecture on particular substrates (as shown for the hybrid DUB/E3 enzyme A20 and CYLD-ITCH complexes during inflammatory signaling [ xref , xref ])."
CYLD affects E3_Ub_ligase, and ITCH
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3
E3_Ub_ligase binds ITCH and CYLD. 3 / 3
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3
sparser
"E3 ligase Itch and deubiquitinase CYLD form a complex that cleaves lysine (Lys) 63-linked ubiquitin chains and catalyze Lys48-linked ubiquitination on the kinase Tak1, which is a common substrate for these two proteins, thereby contributing to decreased inflammatory signalling [ xref ]."
sparser
"Recently, it has been demonstrated that E3 ligase ITCH and CYLD formed a complex which can sequentially cleave K63-linked ubiquitin-chain and catalyzes K48-linked ubiquitination to deactivate TAK1 and terminate NF-κB signaling (Ahmed et al., xref ), providing an example of how K48 and K63-linked ubiquitinations are closely linked and can be differentially utilized to control kinase activation and deactivation."
CYLD affects Cardiomyopathies
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3
Salicylate affects CYLD
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2
Multikinase inhibitor affects CYLD
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2
reach
"We have already shown that CYLD expression in HCC cells can be triggered by the multikinase inhibitor sorafenib, by inhibition of Raf-1, as well as by blockage of the pro survival kinases MEK and EGFR and identified the recovery of CYLD expression as an interesting approach for overcoming HCC resistance XREF_BIBR."
MiR-526a affects CYLD
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2
MiR-500 affects CYLD
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2
sparser
"The adverse phenotypes observed in 2-week TAC-CR-CYLD mice were reminiscent of those in CR-mTOR KO mice, including inhibited p-p70S6K, accumulated autophagic vacuoles with undegraded contents, cardiomyocyte death, and cardiac dysfunction [ xref ], supporting the axis of CYLD–mTORC1 inactivation–autolysosome efflux inhibition–cardiomyocyte death in PO-hearts."
Hsa-miR-181b-5p affects CYLD
2
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Factor 2 affects CYLD
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2
reach
"Later work studying signaling through the toll like receptor 2 (TLR2) performed cell based experiments to demonstrate that CYLD binds to TRAF6 and TRAF7 and that depletion of CYLD increases the ability of transfected TRAF6 or TRAF7 to activate an NFkappaB dependent reporter gene [XREF_BIBR]."
sparser
"Several DUBs, including A20, CYLD and USP7, have been reported to downregulate NF- κ B. Co-IP assays were thus carried out to examine the interactions between these enzymes and HSCARG, and the results showed that HSCARG interacts weakly with A20 or CYLD but strongly interacts with USP7 ( xref , xref )."
TNF-RSC affects CYLD
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2
Radiation, Ionizing affects CYLD
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2
sparser
"Several DUBs, including A20, CYLD and USP7, have been reported to downregulate NF- κ B. Co-IP assays were thus carried out to examine the interactions between these enzymes and HSCARG, and the results showed that HSCARG interacts weakly with A20 or CYLD but strongly interacts with USP7 ( xref , xref )."
MicroRNA-301b affects CYLD
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2
K63 affects DDX58
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2
DDX58 affects K63
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2
CYLD affects recovery
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2
CYLD affects polyubiquitin chains
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2
CYLD affects p38 mitogen-activated protein kinase
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2
sparser
"The adverse phenotypes observed in 2-week TAC-CR-CYLD mice were reminiscent of those in CR-mTOR KO mice, including inhibited p-p70S6K, accumulated autophagic vacuoles with undegraded contents, cardiomyocyte death, and cardiac dysfunction [ xref ], supporting the axis of CYLD–mTORC1 inactivation–autolysosome efflux inhibition–cardiomyocyte death in PO-hearts."
CYLD affects initiation necroptosis
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2
CYLD affects factor 2
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2
CYLD affects TNF-RSC
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2
CYLD affects Proteasome
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1
CYLD inhibits Proteasome. 1 / 2
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1
sparser
"Several DUBs, including A20, CYLD and USP7, have been reported to downregulate NF- κ B. Co-IP assays were thus carried out to examine the interactions between these enzymes and HSCARG, and the results showed that HSCARG interacts weakly with A20 or CYLD but strongly interacts with USP7 ( xref , xref )."
CYLD affects K63-
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2
reach
"CYLD, another DUB, is reported to limit NF-kappaB activation by removing K63- and M1 linked poly-ubiquitin chains on several complex I components (including TRAF2, NEMO and RIPK1), thereby disrupting the ubiquitin scaffold required for the recruitment and activation of the TAB2/3-TAK 1 and NEMO-IKKalpha-IKKbeta complexes [XREF_BIBR, XREF_BIBR - XREF_BIBR]."
reach
"Previous studies report that CYLD negatively regulates NF-kappaB signaling by removing K63- and M1 linked polyubiquitin chains from key signaling molecules, including NF-kappaB essential modulator, tumor necrosis factor (TNF)-associated factor (TRAF) 2, TRAF6, and Receptor interacting serine/threonine protein kinase 1, in familial cylindromatosis tumors."
CYLD affects K63
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2
CYLD affects HES1
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2
sparser
"Using a conventional ChIP assay in human Hes1 + T-ALL cells and a Hes1 antibody followed by PCR with specific primers flanking the identified putative N-box sites, we were able to show that endogenous Hes1 binds to the predicted PRO2 site in the CYLD 5’UTR ( xref ) and this association was lost following Hes1 knock-down ( xref ) as measured by qPCR."
reach
"However, the parasite load in the CD8 + T cell depleted Cyld -/- mice was always lower compared to CD8 + T cell depleted WT mice, indicating that in addition to the contribution of CD8 + T cells the enhanced parasite control in the Cyld -/- mice is also mediated by other cell types, likely Cyld -/- macrophages and granulocytes."
reach
"Although our CD8 + T cell depletion experiments show the importance of CD8 + T cells in the control of PbA blood parasites, CD8 + T cell depleted Cyld -/- mice harbored lower parasite loads compared to CD8 + T cell depleted WT mice, indicating that the enhanced parasite control in the Cyld -/- mice is also mediated by other immune cells in addition to CD8 + T cells."
BTK inhibitors affects CYLD
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2