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Statements

RNF31 binds OTULIN. 117 / 166
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"Aiming to find a mechanistic explanation for the unexpected absence of OTULIN from SCs, we first turned our attention to phosphorylation, as phosphorylation of OTULIN Tyr56 was previously reported to be capable of disrupting the interaction between HOIP and OTULIN."
26670046
sparser
"Loss of HOIP–OTULIN interaction reduces OTULIN capacity to restrict LUBAC-induced NF-kB activation ( xref )."
28469620
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"It will be interesting to determine how OTULIN 's interaction with HOIP prevents its recruitment to SCs, e.g., whether OTULIN binding could interfere with HOIP 's ability to bind ubiquitin chains, a requirement for LUBAC recruitment to SCs."
26670046
sparser
"Although HOIP is able to interact with the AAA ATPase p97/valosin-containing protein (VCP) [ xref , xref ], which has recently been implicated in the recruitment of LUBAC to misfolded Huntingtin species [ xref ], the HOIP PUB domain binds OTULIN with a 40-fold higher affinity compared to p97/VCP and NMR-based in vitro studies indicate a more stable interaction between HOIP and OTULIN compared to p97/VCP [ xref ]."
33288901
sparser
"Altogether, these data indicate that the direct binding of OTULIN to HOIP is important for its ability to limit NF-κB signaling activation."
24726327
sparser
"Since both SPATA2 and OTULIN recognize the same binding motif in the PUB of HOIP, interaction of HOIP with SPATA2/CYLD and OTULIN is mutually exclusive [ xref , xref , xref , xref ]."
33288901
sparser
"The OTULIN–HOIP interaction is also modulated by ubiquitination of OTULIN by the E3 ligase tripartite motif-containing protein 32 (TRIM32)."
33288901
sparser
"This is also the case when OTULIN is phosphorylated at Tyr56 and in cells expressing the binding mutant OTULIN Y56F, both of which disrupt the OTULIN–HOIP interaction [ xref , xref ]."
33288901
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"While OTULIN binds HOIP directly through its PUB interacting motif (PIM), CYLD is recruited via a PIM in the bridging factor SPATA2."
28919039
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"The N-terminal region of OTULIN binds to the PUB domain of HOIP ( xref ; xref ; xref ); therefore, we confirmed that the patient-derived OTULIN variants bound to LUBAC as effectively as WT by performing coimmunoprecipitation experiments; the results were consistent with the fact that the P152 and R306 residues do not reside in the N-terminal region of OTULIN ( xref and xref )."
38652464
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"In addition, OTULIN selectively interacts with the LUBAC HOIP PUB domain via the N-terminal PIM, which covers Asp54–Met55–Tyr56–Arg57–Ala58 residues ( xref , xref ) and serves as the sole site of interaction between OTULIN and HOIP, whereas the OTU domain’s presence is unnecessary for binding to HOIP ( xref , xref )."
38774872
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"HOIP interacts with both CYLD and OTULIN even in unstimulated cells."
24461064
sparser
"We provide here the first demonstration that HOIP-OTULIN interact through the HOIP PUB domain and act as a bimolecular editing pair to regulate the NF-κB activation upon TNF stimulation."
24726327
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"Moreover, immunoprecipitation of SHARPIN copurified HOIP, HOIL-1 and OTULIN, and OTULIN interacted with HOIP in proteomic experiments, indicating that OTULIN may associate with HOIP and/or LUBAC."
24726323
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"Importantly, the OTULIN peptide bound HOIP with 180nM affinity, a> 40-fold increase in comparison to p97 (XREF_FIG D)."
24726323
reach
"Importantly, even conservative mutation of the aforementioned cornerstone residue Asn102 to Asp (N102D) or Gln (N102Q) abolished HOIP binding to OTULIN (XREF_FIG I)."
24726323
sparser
"Loss of HOIP-OTULIN interaction reduces the capacity of OTULIN to restrict LUBAC-induced NF-κB activation ( xref )."
34797715
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"Despite the high-affinity, and seemingly more stable, interaction between HOIP and OTULIN, the interaction between HOIP and p97 was still significant and similar to other PUB-p97 interactions (XREF_FIG E)."
24726323
sparser
"Both DUBs interact with the LUBAC complex - OTULIN directly binds the PUB domain of the catalytic subunit HOIP, which then recruits it to the TNFR complex."
38712244
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"We wondered whether this depended on the formation of the OTULIN and HOIP complex or whether OTULIN would act in trans on the complex."
24726323
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"OTULIN interaction with LUBAC through HOIP was normal for 1 over-expressed frameshift variant (G174Dfs*2) and 2 missense (Y244C and L272P) variants [Row 6] [ xref ]."
38712244
reach
"OTULIN interacts with disheveled 2 (DVL2) to promote Wnt signaling and binds to the HOIP to antagonize LUBAC-mediated inhibition of Wnt signaling (Rivkin et al. 2013; Takiuchi et al. 2014)."
39281196
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"TNF stimulation, however, did not abolish the interaction between HOIP and OTULIN ( xref C and xref A)."
26670046
sparser
"Intriguingly, although the interaction of OTULIN with HOIP has been shown to be direct and was structurally characterized ( xref , xref ), we were not able to detect direct binding of CYLD to HOIP."
27545878
sparser
"Unlike these DUBs, which do not have a strict ubiquitin chain specificity, OTULIN (OTU deubiquitinase with linear specificity, also known as FAM105B or Gumby) binds the PUB domain of HOIP and selectively removes linear ubiquitin chains on LUBAC components thereby keeping uncontrolled TNF-associated inflammation in check ( xref ; xref ; xref ; xref ; xref )."
32671059
sparser
"The HOIP-OTULIN interaction can be disrupted by mutation of a critical residue (N102) in HOIP’s PUB domain ( xref )."
26670046
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"This is in stark contrast to the interaction of HOIP with OTULIN, which was substantially increased by OTULIN overexpression ( xref C)."
27545878
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"OTULIN directly binds the PUB domain of HOIP to protect LUBAC from autoubiquitination, while CYLD associates with HOIP through Spermatogenesis-associated 2 (SPATA2) without affecting HOIP autoubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34157307
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"Intriguingly, although OTULIN binds to HOIP, only HOIP is readily detected within TNFR1 complex I [43]."
35608338
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"Why the CYLD-SPATA2-HOIP complex associates with complex I, but the OTULIN-HOIP complex does not remains unknown."
35608338
sparser
"OTULIN also interacts with HOIP via its PUB-interacting motif and inhibits LUBAC activity [ xref , xref ]."
33498196
sparser
"Recently, we found that TRIM32 conjugates nonproteolytic polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN, thereby activating NF-κB signaling [ xref ]."
33498196
sparser
"OTULIN binds directly to the LUBAC subunit HOIP [ xref – xref ] and regulates LUBAC signalling, autoubiquitination, and stability [ xref , xref – xref ]."
32231246
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"LUBAC seems to be constantly active in cells, but the accumulation of Met1-Ub is continuously counterbalanced by OTULIN bound to HOIP."
25060092
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"An interaction between HOIP and OTULIN or CYLD at first inspection would seem contradictory, as a futile energy consuming cycle would exist."
27913667
sparser
"OTULIN interacts with HOIP via its PUB‐interacting motif (PIM), which binds to the N‐terminal PUB domain of HOIP."
26085216
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"Here, we show that SPATA2 can attenuate M1-linked receptor complex ubiquitylation independently of CYLD by preventing the interaction of OTULIN and HOIP."
36640323
sparser
"These results implied that SC recruited HOIP was not associated with OTULIN, despite the fact that OTULIN and HOIP interacted prior to stimulation."
26670046
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"Whilst CYLD was recruited to TRAIL complex I and to the TRAIL‐induced necroptosis‐mediating complex in a HOIP‐dependent manner, OTULIN did not form part of these complexes (Fig  xref B and C)."
28258062
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"It will be interesting to determine how OTULIN’s interaction with HOIP prevents its recruitment to SCs, e.g., whether OTULIN binding could interfere with HOIP’s ability to bind ubiquitin chains, a requirement for LUBAC recruitment to SCs ( xref , xref )."
26670046
sparser
"Interestingly, OTULIN binds to the N-terminal PUB domain of HOIP through the PUB domain-interacting motif (PIM), and the phosphorylation of Tyr56 in the PIM of OTULIN abrogated the HOIP binding [ xref , xref , xref ]."
32403254
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"Finally, ubiquitination of OTULIN on K64 and K66 by tripartite motif-containing protein 32 (TRIM32) disrupted the interaction between OTULIN and HOIP, promoting NF-κB signaling in HEK293 cells [ 33 ]."
34074601
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"The OTULIN PIM binds HOIP with 40-fold greater affinity than a similar PIM from p97."
27913667
reach
"OTULIN binds directly to HOIP, and CYLD interacts with HOIP through the adaptor protein, SPATA2 (Elliott et al., 2014; 2016; Kupka et al., 2016; Schaeffer et al., 2014; Takiuchi et al., 2014; Wagner et al., 2016)."
37431163
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"Several studies have shown that OTULIN binds directly to the LUBAC subunit HOIP (Elliott et al , xref ; Schaeffer et al , xref ; Takiuchi et al , xref )."
30804083
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"OTULIN also interacts with HOIP via its PUB interacting motif and inhibits LUBAC activity [XREF_BIBR, XREF_BIBR]."
33498196
reach
"Recently, we found that TRIM32 conjugates nonproteolytic polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN, thereby activating NF-kappaB signaling [XREF_BIBR]."
33498196
sparser
"OTULIN binds to the N-terminal PUB (PNGase/UBA or UBX-containing proteins) domain of HOIP via its PUB-interacting motif (PIM) and this interaction seems to be regulated by phosphorylation (Elliott et al., xref ; Schaeffer et al., xref ; Takiuchi et al., xref )."
31998699
sparser
"OTULIN, like SPATA2, binds to the PUB domain of HOIP."
36640323
reach
"OTULIN interacts with HOIP via its PUB interacting motif (PIM), which binds to the N-terminal PUB domain of HOIP."
26085216
reach
"Phosphorylation of OTULIN 's tyrosine (Tyr) 56 prevents the binding of OTULIN to HOIP 97, 98."
26085216
sparser
"The OTULIN directly binds to the N-terminal PUB domain of HOIP via its PIM domain."
37813853
sparser
"Phosphorylation of the highly conserved Tyr56 within the PIM was shown to disrupt the interaction between OTULIN and HOIP, which abrogates OTULIN-dependent suppression of LUBAC and enables LUBAC-regulated signaling."
32770022
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"Strikingly, HA-OTULIN , which specifically cannot bind HOIP (Schaeffer et al., 2014), localized to the plasma membrane periphery but was excluded from the central cytoplasmic region of all transfected cells (Fig. 2B)."
37589075
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"OTULIN and CYLD bind HOIP in a mutually exclusive manner (71)."
35587511
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"Mutations in the OTULIN catalytic Cys129 do not affect the association between OTULIN and HOIP (15, 21)."
38774872
sparser
"Different from direct interaction between OTULIN and HOIP, CYLD binding to PUB domain of HOIP requires spermatogenesis-associated 2 (SPATA2) for bridge factor [ xref ]."
37813853
sparser
"OTULIN binding to HOIP is required to restrict LUBAC auto-ubiquitination, which is readily detected on HOIP, HOIL-1, and SHARPIN when OTULIN is depleted or mutated in its PIM ( xref , xref , xref , xref , xref )."
27591049
sparser
"OTULIN directly binds the LUBAC component HOIP, and knockdown of OTULIN in human cell lines increases M1-linked chains on LUBAC and its substrates ( xref , xref , xref , xref , xref )."
27523608
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"OTULIN directly binds the LUBAC component HOIP, and knockdown of OTULIN in human cell lines increases M1 linked chains on LUBAC and its substrates."
27523608
sparser
"Further experiments found that TRIM32 conjugates polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN, thereby activating NF-κB signaling."
31504727
reach
"Although HOIP is able to interact with the AAA ATPase p97 and valosin containing protein (VCP) [XREF_BIBR, XREF_BIBR], which has recently been implicated in the recruitment of LUBAC to misfolded Huntingtin species [XREF_BIBR], the HOIP PUB domain binds OTULIN with a 40-fold higher affinity compared to p97 and VCP and NMR based in vitro studies indicate a more stable interaction between HOIP and OTULIN compared to p97 and VCP [XREF_BIBR]."
33288901
reach
"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_BIBR] 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_BIBR]."
33288901
reach
"Several studies have shown that OTULIN binds directly to the LUBAC subunit HOIP (Elliott etal, 2014; Schaeffer etal, 2014; Takiuchi etal, 2014)."
30804083
sparser
"OTULIN binds to HOIP and thereby controls autoubiquitination of the LUBAC complex ( xref ; xref ; xref ; xref )."
38630025
sparser
"Intriguingly, although OTULIN binds to HOIP, only HOIP is readily detected within TNFR1 complex I [ xref ]."
35608338
sparser
"Why the CYLD-SPATA2-HOIP complex associates with complex I, but the OTULIN-HOIP complex does not remains unknown."
35608338
sparser
"OTULIN bound to HOIP is thought to sustain LUBAC levels by cleaving M1-linked polyubiquitin attached to LUBAC itself [ xref , xref ]."
35608338
sparser
"9 , 17 , 18 The disassembly of M1-linked chains, conjugated to the LUBAC, depends on the direct interaction of OTULIN and HOIP."
36640323
sparser
"OTULIN forms a complex with LUBAC through HOIP in unstimulated cells xref , xref , xref ."
32770022
sparser
"Finally, ubiquitination of OTULIN on K64 and K66 by tripartite motif-containing protein 32 (TRIM32) disrupted the interaction between OTULIN and HOIP, promoting NF-κB signaling in HEK293 cells [ 33 ]."
34074601
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"The linear ubiquitin chain assembly complex (LUBAC) regulates immune signaling, and its function is regulated by the deubiquitinases OTULIN and CYLD, which associate with the catalytic subunit HOIP."
27591049
sparser
"Moreover, a phospho-mimetic mutation on Tyr56 (Y56D) also abolished the association between OTULIN and HOIP, suggesting that genotoxic treatment may induce OTULIN phosphorylation at Tyr56, which disrupts the OTULIN-HOIP association."
32770022
sparser
"Together, our data suggest that SPATA2 plays an important role for the dynamic interaction of OTULIN and HOIP, and it will be interesting to see whether and how this activity of SPATA2 is regulated."
36640323
sparser
"However, while the Y56D mutation decreased OTULIN interaction with HOIP, it enhanced OTULIN association with β-catenin (Fig.  xref and Supplementary Fig.  xref ), suggesting that OTULIN Tyr56 phosphorylation may promote OTULIN interaction with β-catenin."
32770022
sparser
"Met1-linked ubiquitin (Met1-Ub) is assembled by the linear ubiquitin assembly complex (LUBAC), and this is counteracted by the Met1-Ub-specific deubiquitinase OTULIN, which binds to the catalytic LUBAC subunit HOIP."
26997266
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"Met1 linked ubiquitin (Met1-Ub) is assembled by the linear ubiquitin assembly complex (LUBAC), and this is counteracted by the Met1-Ub-specific deubiquitinase OTULIN, which binds to the catalytic LUBAC subunit HOIP."
26997266
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"LUBAC activity is counterbalanced by the Met1 specific deubiquitinase (DUB) OTULIN, which binds to the catalytic subunit HOIP via interactions between the HOIP peptide : N-glycanase and UBA- or UBX containing proteins (PUB) domain and a PUB interacting motif (PIM) in OTULIN."
26997266
sparser
"Since SPATA2 and OTULIN bind to the same PUB domain of HOIP, their binding is mutually exclusive. xref Therefore, the OTULIN-HOIP relationship, which is disrupted as a result of genotoxicity, may increase the CYLD-SPATA2-HOIP association."
35958947
sparser
"Regulating the HOIP‐OTULIN interaction."
26503766
sparser
"Consistent with the structure, phosphorylation of Tyr56 prevents interaction between OTULIN and HOIP xref , xref (Fig. xref , bottom)."
26503766
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"Furthermore, the direct binding of OTULIN and HOIP revealed the importance of their interaction for the proper action of the NF-kappaB signaling in vivo.We investigated the interactome of LUBAC in sta[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24726327
reach
"Moreover, affinity measurements using ITC indicated that HOIP binding to OTULIN was stronger than for p97."
24726327
reach
"This posed the possibility for a very similar OTULIN binding mode to the HOIP PUB domain in comparison to p97 and the PNGase PUB domain.To further investigate the interaction between HOIP, OTULIN and [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24726327
sparser
"Phosphorylation‐dependent regulation of the interaction between OTULIN and HOIP offers an elegant additional layer of control for Met1‐signalling (Fig. xref B)."
26503766
sparser
"However, the kinases or phosphatases regulating the interaction between OTULIN and HOIP are still unknown."
26503766
sparser
"Interestingly, in AP-MS experiments, proteasomal inhibition with MG132 abrogated recovery of the OTULIN-HOIP interaction and also reduced recovery of the OTULIN-SCRIB interaction ( xref B; xref ), suggesting that other, less stable proteins can interfere with both HOIP-OTULIN and OTULIN-SCRIB complexes."
37589075
reach
"Altogether, these data indicate that the direct binding of OTULIN to HOIP is important for its ability to limit NF-kappaB signaling activation.In this study, we showed that the DUB OTULIN interacts wi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24726327
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"TNFalpha stimulation promotes the recruitment of the HOIP and OTULIN complex to the active receptor complex, indicating that they can act as a bimolecular ubiquitin editing pair (ligase and DUB) impli[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24726327
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"Thus, the activity of HOIP and OTULIN complex in the activated receptor complexes might be necessary for an efficient and precise regulation of the NF-kappaB pathway."
24726327
sparser
"OTULIN directly interacts with the PUB domain of HOIP, a component of LUBAC, via the N- or C-domain of OTULIN, which refers to the PIM [172,173] ."
30452908
reach
"Although further experiments will be required to address these questions, ubiquitination could play an important role in regulating the interaction between HOIP and OTULIN."
24726327
reach
"An interaction between HOIP and OTULIN or CYLD seems strange, since their highly specific yet counteracting activities would generate a futile energy consuming circle."
26503766
sparser
"TNF induces the phosphorylation of OTULIN on Y56 by an unknown kinase, inhibiting the interaction between OTULIN and HOIP to stabilize the linear ubiquitination complex [172,173] ."
30452908
reach
"Consistent with the structure, phosphorylation of Tyr56 prevents interaction between OTULIN and HOIP 60, 71."
26503766
reach
"Phosphorylation dependent regulation of the interaction between OTULIN and HOIP offers an elegant additional layer of control for Met1 signalling."
26503766
reach
"However, the kinases or phosphatases regulating the interaction between OTULIN and HOIP are still unknown."
26503766
reach
"Additionally, either expression of a constitutively active MST1 or the S1066E mutation of HOIP did not affect the binding of HOIP to OTULIN or CYLD ( Figures S4 F and S4G)."
30901564
sparser
"OTULIN binds to the PUB domain of HOIP and loss of HOIP-OTULIN interaction reduces OTULIN’s capacity to restrict LUBAC-induced immune responses [ xref ]."
27906774
sparser
"OTULIN binds directly to HOIP, and CYLD interacts with HOIP through the adaptor protein, SPATA2 ( xref ; xref ; xref ; xref ; xref ; xref )."
37431163
reach
"OTULIN binding to HOIP is required to restrict LUBAC auto-ubiquitination, which is readily detected on HOIP, HOIL-1, and SHARPIN when OTULIN is depleted or mutated in its PIM."
27591049
sparser
"The PIM is responsible for binding to the N-terminal PUB domain of HOIP; however, the Y56 phosphorylation abrogates OTULIN-HOIP interaction [ xref – xref ]."
38017534
reach
"9 , 17 , 18 The disassembly of M1-linked chains, conjugated to the LUBAC, depends on the direct interaction of OTULIN and HOIP."
36640323
sparser
"Thus, we wondered whether biotin-PD of OTULIN ABP can be used to monitor association of active substrate-bound OTULIN to HOIP, and potentially the entire LUBAC complex ( xref )."
28919039
sparser
"The polyubiquitin disrupts HOIP-OTULIN interaction, thereby enhancing TNFα-induced NF-κB activation [ xref ]."
38017534
sparser
"Furthermore, the direct binding of OTULIN and HOIP revealed the importance of their interaction for the proper action of the NF-κB signaling in vivo."
24726327
sparser
"The interaction of HOIP with OTULIN is also involved in OTULIN suppressing the canonical Wnt signaling pathway activation by LUBAC."
24461064
sparser
"In glutathione S-transferase (GST) pull-down assays OTULIN bound to HOIP, but not to HOIL-1 or Sharpin ( Figure 2 A)."
24726327
reach
"Both OTULIN and CYLD bind HOIP in the LUBAC complex, either directly (OTULIN) or indirectly via SPATA2 (CYLD)."
38630025
reach
"OTULIN binds to HOIP and thereby controls autoubiquitination of the LUBAC complex (Elliott et al., 2014; Schaeffer et al., 2014; Kelsall et al., 2019; Fuseya et al., 2020)."
38630025
sparser
"Moreover, affinity measurements using ITC indicated that HOIP binding to OTULIN was stronger than for p97 ( Table 2 )."
24726327
reach
"In line with recent reports, our data showed that prior to stimulation, both CYLD and OTULIN interacted with HOIP (XREF_SUPPLEMENTARY B-S1D)."
26670046
sparser
"To investigate the functional consequences of the HOIP-OTULIN interaction, we analyzed the recruitment of OTULIN to the TNFR upon TNFα-mediated activation."
24726327
sparser
"However, OTULIN Y56F, which cannot bind to HOIP, was reduced in its ability to block NF-κB signaling to a similar extent as the C129S catalytic mutant of OTULIN."
24726327
sparser
"The interaction of HOIP with OTULIN is also involved in OTULIN suppressing the canonical Wnt signaling pathway activation by LUBAC [ xref ]."
25972356
reach
"TNF stimulation, however, did not abolish the interaction between HOIP and OTULIN (XREF_FIG C and XREF_SUPPLEMENTARY A)."
26670046
reach
"Together, these results show that CYLD and OTULIN interact with HOIP via the same or an overlapping site and that HOIP 's interactions with CYLD and OTULIN are mutually exclusive."
26670046