IndraLab
Statements
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"We hypothesized that differential catalytic activity across species may be related to substrate affinity.53 Although the catalytic site of USP18 is well conserved between mice and humans, ISG15 sequences vary.52 54 To compare interactions between USP18 and ISG15, we performed a competitive inhibition experiment with cross-species enzyme/substrate pairs."
sparser
"The association of ISG15 with USP18 interrupts the interaction of USP18 with S-phase kinase-associated protein 2 (SKP2), inhibiting the proteasomal degradation of USP18, which is essential for negative feedback regulation of IFN signaling and prevention of autoinflammation xref , xref ."
sparser
"USP18 also has enzymatic activity in removing the covalently conjugated 15kDa protein, encoded by interferon-stimulated gene 15 ( ISG15 ), from its targets in a process called de-ISGylation. xref Finally, independent of its affinity for ISGylated proteins, USP18 also binds free ISG15, which protects USP18 against proteasomal degradation, thereby enhancing its negative regulatory capacity. xref "
reach
"ISG15 is known to promote USP18-mediated inhibition of type I 437 IFN signaling by stabilizing USP18 activity and preventing its proteasomal degradation(Zhang et 438 al., 2015), underscoring the role of ISG15 as a negative regulator of type I IFN responses when 439 co-upregulated with USP18."
| DOI
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"ISG15 appeared to act in its unconjugated free form, since silencing of UBE1L or of other ISGylation enzymes failed to reduce USP18 levels (XREF_FIG and XREF_FIG) and patients ' cells transduced with wild-type ISG15 or ISG15 (DeltaGG) exhibited attenuated levels of interferon-stimulated-gene transcripts and proteins (XREF_FIG and XREF_FIG)."
reach
"We found that ISG15 deficiency led to reduced levels of the negative regulator USP18 because of increased proteolysis due, at least in part, to SKP2 mediated ubiquitination, resulting in stronger responses to IFN-alpha and beta and an ensuing amplification of IFN-alpha and beta-induced responses."
reach
"The coexpression of either wild-type ISG15 or ISG15 (DeltaGG) with USP18 and ubiquitin resulted in markedly lower levels of USP18 ubiquitination (XREF_FIG, lanes 9-11 and XREF_FIG) and larger total amounts of USP18.Overall, these data indicate that free intracellular ISG15 antagonizes USP18 ubiquitination and degradation, thereby promoting the stability and function of this protein."
reach
"We hypothesized that differential catalytic activity across species may be related to substrate affinity.53 Although the catalytic site of USP18 is well conserved between mice and humans, ISG15 sequences vary.52 54 To compare interactions between USP18 and ISG15, we performed a competitive inhibition experiment with cross-species enzyme/substrate pairs."
sparser
"The association of ISG15 with USP18 interrupts the interaction of USP18 with S-phase kinase-associated protein 2 (SKP2), inhibiting the proteasomal degradation of USP18, which is essential for negative feedback regulation of IFN signaling and prevention of autoinflammation xref , xref ."
sparser
"USP18 also has enzymatic activity in removing the covalently conjugated 15kDa protein, encoded by interferon-stimulated gene 15 ( ISG15 ), from its targets in a process called de-ISGylation. xref Finally, independent of its affinity for ISGylated proteins, USP18 also binds free ISG15, which protects USP18 against proteasomal degradation, thereby enhancing its negative regulatory capacity. xref "
reach
"In contrast, binding this free ISG15, USP18 suppresses JAK-STAT signaling further counteracting IFN signaling.By better understanding the ISG15 pathway, it may be possible to target certain illnesses on a case-by-case basis without the need for general activation of IFN signaling with its hundreds of downstream targets."
sparser
"The IFN-mediated activation of the Jak-STAT pathway is tightly regulated by various cellular factors such as SOCS family members, USP18, the protein phosphatase 2A (PP2A), and protein inhibitors of STAT (PIAS).[ xref ] Along those lines, SOCS1 and SOCS3 transcriptional expression in hepatocytes remains detectable for only a short period of time upon alfa treatment indicating that by inhibiting Janus kinases both proteins are likely responsible for early termination of STAT activation.[ xref ] In addition, the sustained up-regulation of USP18 was associated with a long-lasting refractory state to IFN-α stimulation in hepatocytes and other primary human cells.[ xref ] The specific interaction of USP18 with IFNAR2 selectively affects IFN—induced signaling while having a marginal effect on other classes of IFNs, including type III IFNs."
IFNAR2 binds Interferon, USP18, and STAT2. 1 / 1
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"Among IFN regulated transcripts, 176 responded similarly in both IFNbeta and IFNgamma treated neurons (XREF_FIG; XREF_SUPPLEMENTARY) and included many genes with known roles in anti-viral defenses and IFN signaling such as Mx1/2, STAT1/2, ISG15, IFIT2, IRF1/7/9, Daxx, PKR, TAP1, and USP18."
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"In humans, genetic loss-of-function mutations in ubiquitin-specific peptidase 18 (USP18), a key negative regulator of type I IFN signaling, results in unrestrained type I IFN signaling in microglia and is associated with multiple and severe developmental neurological abnormalities (intracerebral hemorrhage, ventriculomegaly) along with microgliopathy (Meuwissen et al. 2016)."
reach
"It is known that IFIH1 (interferon-induced helicase-1), IFI35 (interferon-induced protein 35), and USP18 (ubiquitin-specific peptidases 18) activate the IFN signaling pathway; IFIH1 induces pro-inflammatory cytokines, and type I IFNs respond to viral infections in which they act as innate immune receptors [36,37]."
reach
"Although distinct reductions in adaptive immunity-related genes were observed, no differences were observed in the mRNA levels of the more general inflammatory cytokines C-C motif chemokine ligand 2 (Ccl2) and C-C motif chemokine ligand 3 (Ccl3) or ubiquitin-specific peptidase 18 (Usp18), which mediates the regulation of the inflammatory response to type 1 interferon (Fig. 3D)."
reach
"Further investigation with the KEGG pathway enrichment analysis showed those up-regulated genes could cause the activation of the IFN-induced pathway, type II interferon signaling pathway, and regulation of protein ISGylation by the ISG15 deconjugating enzyme USP18 pathway (Figure 4B)."
reach
"Influenza B has evolved a mechanism to directly neutralize ISG15 with its NS1 protein24 and coronaviruses have a papain‐like protease that has deISGylase activity as a strategy to overcome ISG15,25, 26 indicating the importance of ISG15 in the antiviral response.In addition to its enzymatic activity, USP18 negatively regulates T1 IFN signaling.27 USP18 is recruited by STAT2 to the type I IFN receptor subunit, IFNAR2, where it binds to IFNAR2 and prevents phosphorylation of JAK1 by blocking the interaction of JAK1 and the IFNAR2 subunit.27, 28, 29 USP18 expression also plays a role in limiting TRAIL‐induced apoptosis and has also been shown to regulate the susceptibility of certain cancer cells to IFN‐α and drug‐induced apoptosis.30, 31
Macrophages play an important role in HIV‐1 as reservoirs and can contribute directly to HIV‐1 pathogenesis.32 HIV‐1 in the ART era can be seen as a chronic disease characterized by chronic immune activation and chronic inflammation with a higher risk of non‐AIDS‐related morbidities and mortalities."
USP18 binds Interferon.
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"Interestingly, USP18 in humans (but not in mice) can also interfere with the anti-viral outcome of IFN signaling by an additional mechanism: USP18 can bind the interferon receptor 2 (IFNAR2), block the association of JAK, and possibly limit IFNAR2-IFNAR1 dimerization, thereby interfering with the JAK-STAT signaling pathway [89]."
IFNAR2 binds Interferon, USP18, and STAT2. 1 / 1
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"Two siblings with early onset autoinflammatory disease with neurological features and elevated IFN signature were additionally described with a homozygous missense mutation in STAT2 resulting in gain of activity due to the inability of mutant STAT2 to interact with the STAT2-dependent negative regulator of interferon activity, USP18 [ xref ]."
USP18 decreases the amount of Interferon.
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USP18 decreases the amount of Interferon. 6 / 6
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"We identified that nuclear USP18 diminishes binding of IFN regulated transcription factors to their corresponding DNA motifs in cooperation with NF-κB. Consequently, the suppression of USP18 not only enhances the expression of canonical IFN-stimulated genes (ISGs) but also activates a set of atypical ISGs and NF-κB target genes that induce cancer pyroptosis."
reach
"The authors have demonstrated that: (i) infection of iMphs with HIV-1 induces USP18; (ii) depletion of USP18 with CRISPR/Cas9 increases iMph reactivity to IFNI, the phosphorylation of STAT1 and STAT2, the expression of IFN-stimulated genes and ultimately results in a significant restriction of HIV replication in iMphs."
USP18 increases the amount of Interferon.
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USP18 deubiquitinates Interferon.
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USP18 deubiquitinates Interferon. 1 / 1
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"The IFN-mediated activation of the Jak-STAT pathway is tightly regulated by various cellular factors such as SOCS family members, USP18, the protein phosphatase 2A (PP2A), and protein inhibitors of STAT (PIAS).[ xref ] Along those lines, SOCS1 and SOCS3 transcriptional expression in hepatocytes remains detectable for only a short period of time upon alfa treatment indicating that by inhibiting Janus kinases both proteins are likely responsible for early termination of STAT activation.[ xref ] In addition, the sustained up-regulation of USP18 was associated with a long-lasting refractory state to IFN-α stimulation in hepatocytes and other primary human cells.[ xref ] The specific interaction of USP18 with IFNAR2 selectively affects IFN—induced signaling while having a marginal effect on other classes of IFNs, including type III IFNs."
IFNAR2 binds Interferon, USP18, and STAT2. 1 / 1
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"3D modelling of the STAT2-USP18 heterodimer showed both the amino acid residues, A219 and R148, to localize to the interface between STAT2 and USP18 (Fig. xref c), suggesting that the A219, like the R148, residue might play an essential role in mediating a STAT2-USP18 protein interaction."
IFNAR2 binds Interferon, USP18, and STAT2. 1 / 1
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USP18 binds Interferon and STAT2. 1 / 1
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sparser
"Two siblings with early onset autoinflammatory disease with neurological features and elevated IFN signature were additionally described with a homozygous missense mutation in STAT2 resulting in gain of activity due to the inability of mutant STAT2 to interact with the STAT2-dependent negative regulator of interferon activity, USP18 [ xref ]."
reach
"XREF_BIBR, XREF_BIBR To asses whether STAT1 or STAT2, which are both upregulated by USP18 inhibition (XREF_FIG), are implicated in the upregulation of Bim, DP5 and PUMA mRNA expression in USP18 silenced cells, we inhibited in parallel USP18 and STAT1 or STAT2 in INS-1E cells by use of specific siRNAs."
reach
"The authors have demonstrated that: (i) infection of iMphs with HIV-1 induces USP18; (ii) depletion of USP18 with CRISPR/Cas9 increases iMph reactivity to IFNI, the phosphorylation of STAT1 and STAT2, the expression of IFN-stimulated genes and ultimately results in a significant restriction of HIV replication in iMphs."
sparser
"3D modelling of the STAT2-USP18 heterodimer showed both the amino acid residues, A219 and R148, to localize to the interface between STAT2 and USP18 (Fig. xref c), suggesting that the A219, like the R148, residue might play an essential role in mediating a STAT2-USP18 protein interaction."
IFNAR2 binds Interferon, USP18, and STAT2. 1 / 1
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"Two siblings with early onset autoinflammatory disease with neurological features and elevated IFN signature were additionally described with a homozygous missense mutation in STAT2 resulting in gain of activity due to the inability of mutant STAT2 to interact with the STAT2-dependent negative regulator of interferon activity, USP18 [ xref ]."
Interferon affects USP18
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Interferon activates USP18.
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"Several reports by our group and others have supported the observation that RNase L modulates the stability of certain cellular mRNAs in the absence of viral infections, such as the RNA binding protein ELAVL1 (HuR), the double-strand RNA (dsRNA)-dependent protein kinase (PKR), the muscle differentiation transcriptional factor (MyoD), and the IFN stimulated genes 43 (ISG43) transcript."
Interferon increases the amount of USP18.
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"Forty of the 71 interferon-stimulated genes, including myxovirus resistance (Mx) 1, Mx2, 2’−5’-oligoadenylate synthase-like protein 1 (Oasl1), Rsad2, nicotinamide phosphoribosyltransferase (Nampt), interferon-stimulated gene (Isg) 15, Isg20, and ubiquitin specific peptidase 18 (Usp18), were expressed at higher levels in Mkp-1 mice than in Mkp-1 mice following E. coli infection."
Interferon binds USP18.
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"Interestingly, USP18 in humans (but not in mice) can also interfere with the anti-viral outcome of IFN signaling by an additional mechanism: USP18 can bind the interferon receptor 2 (IFNAR2), block the association of JAK, and possibly limit IFNAR2-IFNAR1 dimerization, thereby interfering with the JAK-STAT signaling pathway [89]."
IFNAR2 binds Interferon, USP18, and STAT2. 1 / 1
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sparser
"Two siblings with early onset autoinflammatory disease with neurological features and elevated IFN signature were additionally described with a homozygous missense mutation in STAT2 resulting in gain of activity due to the inability of mutant STAT2 to interact with the STAT2-dependent negative regulator of interferon activity, USP18 [ xref ]."
Interferon inhibits USP18.
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USP18 affects apoptotic process
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USP18 inhibits apoptotic process.
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USP18 activates apoptotic process.
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"To further investigate whether deubiquitination of TAK1 by USP18 is required for USP18 protease activity, we generated protease inactive USP18 mutants by substituting a serine residue for cysteine within the catalytic domain (C64S), and by further substituting the conserved histidine residue with alanine at position 318 (C64S H318A)."
"<span class="match term0">USP18</span> negatively regulates NF-kappaB signaling by targeting <span class="match term1">TAK1</span> and NEMO for deubiquitination"
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"Furthermore, USP18 was described to negatively regulate TLR-mediated NF-κB signalling: Yang et al. [60] suggested that USP18 inhibits ubiquitination of the TAK/TAB complex and the IKKα/β-NEMO (IκB kinase/NF-κB essential modulator) complex in a protease-dependent or independent manner, respectively."
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"In a transverse aortic constriction (TAC) mouse model, USP18 is found to be associated with myocardial hypertrophy through TAK1/p38/JNK1/2 pathway, USP18 deficiency enhances TAK1 activity in response to pressure overload [73], whereas USP18 overexpression attenuates pathological cardiac remodeling [157]."
reach
"Recent work has demonstrated that USP18 has the ability to deubiquitinate the transforming growth factor activated kinase 1 (TAK1) complexes required for NF-kappaB activation in T cells and that overexpression of USP18 leads to decreased nuclear activation and impaired formation of TAK1 complexes."
sparser
"The exacerbation of cardiac remodelling in mice with USP18 deficiency further confirmed the protective role of USP18 against cardiac dysfunction caused by pathological hypertrophy. xref A molecular study found that USP18 inactivates TAK1 by deubiquitinating K63‐linked polyubiquitination and it subsequently suppresses the downstream NF‐κB and JNK1/2 signalling pathways, which plays critical role in NAFLD progression. xref USP14 also contributes to suppress the development of cardiac hypertrophy by increasing phosphorylation of GSK‐3β (Table xref ). xref Together, these findings indicate that the most of the DUBs protect the cardiac structure and function against pathological cardiac modelling caused by various stimulus."
USP18 affects cell population proliferation
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USP18 activates cell population proliferation.
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USP18 inhibits cell population proliferation.
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"The association of ISG15 with USP18 interrupts the interaction of USP18 with S-phase kinase-associated protein 2 (SKP2), inhibiting the proteasomal degradation of USP18, which is essential for negative feedback regulation of IFN signaling and prevention of autoinflammation xref , xref ."
sparser
"Several studies have reported that SAMHD1 interacts with cyclin/CDK complexes [ xref ], USP18 and S-phase kinase-associated protein 2 [ xref , xref ], which are involved in the regulation of cell proliferation [ xref , xref ] and SAMHD1 is also recruited to DNA repair foci in response to DNA damage [ xref ]."
sparser
"While these data do not rule out the possibility that indirect interactions between ISG15 (via Trp123) and an unknown partner are responsible for USP18 stability, which may be consistent with previous reports showing that ISG15 can abrogate the USP18‐SKP2 complex and rescue USP18 from proteasomal degradation independently of its ability to bind USP18 [ xref ]."
sparser
"Mechanistically, the association of USP18 with free intracellular ISG15 prevents SCF SKP2 -mediated USP18 ubiquitination and subsequently its proteasomal degradation, thereby leading to the prevention of autoinflammation and over-amplification of IFN, which suggests that the long-term stabilization of USP18 by free intracellular ISG15 is essential for the negative feedback regulation of IFN signaling [ xref ]."
reach
"Overexpression of USP18 promoted DENV-2 replication, while its silencing abrogated the replication and increased the anti-DENV-2 specific IFN-α through the activation of the IFN-α-mediated Jak/STAT signaling pathway, as shown by the increased expression of p-STAT1/p-STAT2 and the elevated expression of some ISGs."
sparser
"The IFN-mediated activation of the Jak-STAT pathway is tightly regulated by various cellular factors such as SOCS family members, USP18, the protein phosphatase 2A (PP2A), and protein inhibitors of STAT (PIAS).[ xref ] Along those lines, SOCS1 and SOCS3 transcriptional expression in hepatocytes remains detectable for only a short period of time upon alfa treatment indicating that by inhibiting Janus kinases both proteins are likely responsible for early termination of STAT activation.[ xref ] In addition, the sustained up-regulation of USP18 was associated with a long-lasting refractory state to IFN-α stimulation in hepatocytes and other primary human cells.[ xref ] The specific interaction of USP18 with IFNAR2 selectively affects IFN—induced signaling while having a marginal effect on other classes of IFNs, including type III IFNs."
sparser
"The association of ISG15 with USP18 interrupts the interaction of USP18 with S-phase kinase-associated protein 2 (SKP2), inhibiting the proteasomal degradation of USP18, which is essential for negative feedback regulation of IFN signaling and prevention of autoinflammation xref , xref ."
sparser
"Several studies have reported that SAMHD1 interacts with cyclin/CDK complexes [ xref ], USP18 and S-phase kinase-associated protein 2 [ xref , xref ], which are involved in the regulation of cell proliferation [ xref , xref ] and SAMHD1 is also recruited to DNA repair foci in response to DNA damage [ xref ]."
sparser
"While these data do not rule out the possibility that indirect interactions between ISG15 (via Trp123) and an unknown partner are responsible for USP18 stability, which may be consistent with previous reports showing that ISG15 can abrogate the USP18‐SKP2 complex and rescue USP18 from proteasomal degradation independently of its ability to bind USP18 [ xref ]."
reach
"XREF_BIBR, XREF_BIBR To asses whether STAT1 or STAT2, which are both upregulated by USP18 inhibition (XREF_FIG), are implicated in the upregulation of Bim, DP5 and PUMA mRNA expression in USP18 silenced cells, we inhibited in parallel USP18 and STAT1 or STAT2 in INS-1E cells by use of specific siRNAs."
reach
"The authors have demonstrated that: (i) infection of iMphs with HIV-1 induces USP18; (ii) depletion of USP18 with CRISPR/Cas9 increases iMph reactivity to IFNI, the phosphorylation of STAT1 and STAT2, the expression of IFN-stimulated genes and ultimately results in a significant restriction of HIV replication in iMphs."
reach
"Specifically, IFN-alpha induced the phosphorylation of STAT1 and USP18 silencing enhanced the STAT1 activation and phosphorylation for a longer periods of time compared to the control group (XREF_FIG), leading to increased expression of ISGs, and thus enhanced the antiviral activity against HBV in Hepg2.2.15 cells."
reach
"To examine the potential role of MIB2 in regulating USP18-mediated GSDMD ubiquitination and degradation, we performed siRNA-mediated knockdown of MIB2 in HEK293T cells, and observed that MIB2 knockdown resulted in the abrogation of USP18-mediated ubiquitination of GSDMD (Fig. 5A and B) as well as USP18-mediated GSDMD degradation (Fig. 5C and D)."
reach
"USP18 deficiency or knockdown of USP20 resulted in enhanced K48 linked ubiquitination and accelerated degradation of STING, and impaired activation of IRF3 and NF-kappaB as well as induction of downstream genes after infection with DNA virus HSV-1 or transfection of various DNA ligands."
eidos
"The LPS-mediated TLR4 activation in human macrophages upregulates USP18 , which in turn inhibits NF-kappaB activation , and thus the secretion of pro-inflammatory cytokines ( TNF-alpha , IL-6 , and IL-1beta ) via interacting with TAK1-TAB1 and IKKalpha / beta-NEMO complexes ( Table 2 ) [ 193 ] ."
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Lipopolysaccharide affects USP18
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Lipopolysaccharide activates USP18.
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Lipopolysaccharide increases the amount of USP18.
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Lipopolysaccharide inhibits USP18.
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"Through IFNAR1/2 receptors and
the JAK/STAT signaling
pathway, IFN-I has a further impact on the next important component of the
development of the inflammatory response: the ISG15/USP18 axis, which regulates
the activity of the immune system [36]
and reduces the inflammatory response intensity by inhibiting the JAK/STAT
signaling pathway, indicating that there possibly exists a negative feedback
loop between USP18, IFN-I, and, therefore, TNF-α [43, 44]."
reach
"Suppression of USP18 activated the JAK and STAT signaling pathway as shown by the increased and prolonged expression of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) in combination with enhanced expression of several interferon stimulated genes (ISGs)."
reach
"22
,
23
With the establishment of BV2 microglial cells under oxygen and glucose deprivation (OGD) and middle cerebral artery occlusion (MCAO) in mice as models of ischemia, the results from Xiang and his partners suggested that the ubiquitin‐specific protease 18 (USP18) reduced HI injury via the suppression of microglial activation by negatively inhibiting the JAK‐STAT pathway."
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"PLX3397 abrogated USP18 deficiency-induced reduction in pro-tumor/immunosuppressive macrophages (Figure 4C), supporting that USP18-mediated downregulation of CSF1R expression contributes to macrophage polarization.In addition to the changes in TAM population, there were significant changes in T cell population."
reach
"These results suggest that USP18 deletion leads to CSF1R downregulation in TAMs and a decrease in pro-tumor/immunosuppressive macrophages, contributing to enhanced anti-tumor macrophage polarization, consequently promoting a Th1-dominant TME and enhancing CD8 T cell-mediated anti-tumor immunity, in agreement with previous reports."
reach
"However, according to research by Hong et al., increased USP18 expression in tumor cells would in turn inhibit carcinogenesis, whereas decreased USP18 promotes tumor growth and lowers immunosurveillance by decreasing the exogenous synthesis of IFN-γ and the survival of cytotoxic T lymphocytes (CTLs) in TME [178]."
USP18 is modified
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"Specifically, IFN-α induced the phosphorylation of STAT1 and USP18 silencing enhanced the STAT1 activation and phosphorylation for a longer periods of time compared to the control group (Fig 6C), leading to increased expression of ISGs, and thus enhanced the antiviral activity against HBV in Hepg2.2.15 cells."
USP18 is phosphorylated. 3 / 3
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"(C) Protein lysates from PMA-differentiated SAMHD1KO THP-1 cells expressing pEV, USP18, and its active-site mutant C64A were immunoblotted for p21, RNR2, TYMS, E2F1, total and phosphorylated CDK2, p53, USP18, and GAPDH using the respective antibodies after SDS-mediated denaturing gel electrophoresis."
USP18 is methylated.
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"For example, a recent study indicated that USP18 methylation is predominantly downregulated, whereas its expression is upregulated in breast cancer, which is positively associated with increasing TNM stage, worse disease-free survival rate and HER2 + patients, but negatively associated with apoptosis ( xref )."
reach
"22
,
23
With the establishment of BV2 microglial cells under oxygen and glucose deprivation (OGD) and middle cerebral artery occlusion (MCAO) in mice as models of ischemia, the results from Xiang and his partners suggested that the ubiquitin‐specific protease 18 (USP18) reduced HI injury via the suppression of microglial activation by negatively inhibiting the JAK‐STAT pathway."
reach
"Through IFNAR1/2 receptors and
the JAK/STAT signaling
pathway, IFN-I has a further impact on the next important component of the
development of the inflammatory response: the ISG15/USP18 axis, which regulates
the activity of the immune system [36]
and reduces the inflammatory response intensity by inhibiting the JAK/STAT
signaling pathway, indicating that there possibly exists a negative feedback
loop between USP18, IFN-I, and, therefore, TNF-α [43, 44]."
reach
"Suppression of USP18 activated the JAK and STAT signaling pathway as shown by the increased and prolonged expression of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) in combination with enhanced expression of several interferon stimulated genes (ISGs)."
reach
"Interestingly, USP18 in humans (but not in mice) can also interfere with the anti-viral outcome of IFN signaling by an additional mechanism: USP18 can bind the interferon receptor 2 (IFNAR2), block the association of JAK, and possibly limit IFNAR2-IFNAR1 dimerization, thereby interfering with the JAK-STAT signaling pathway [89]."
sparser
"USP18 C64S , the mutation of cysteine residues in the enzymatic center of USP18, can interact with MAVS and enhances the ubiquitination as well as aggregation of MAVS comparable to the wild-type USP18, suggesting USP18 is involved in MAVS-mediated signaling pathway independent of its enzymatic activity."
reach
"Previous studies have shown that ubiquitin specific peptidase 18 (Usp18) is involved in the negative regulation of IFN-induced inflammation and is enriched in the mitochondria of virus-infected cells to promote the polyubiquitination and aggregation of mitochondrial antiviral signaling protein (MAVS) [33]."
reach
"Interestingly, unlike the results shown in XREF_FIG for ISG15, ISG56 and ISG12, we observed little or no IFN-alpha induction of the ISG43 mRNA by northern blotting in A. 2 Akata cells (which exhibited high and prolonged ISG expression), whereas induction of ISG43 expression was easily detectable in A. 15 cells (data not shown)."
sparser
"The defect in the UBP43-mediated negative feedback control of IFN signaling that we have uncovered is in the IFN-α-induced expression of UBP43, either in the transcriptional activation of the UBP43 gene by IFN-α, or in a co- or post-transcriptional event that results in a specific reduction in UBP43 mRNA production."
sparser
"The IFN-mediated activation of the Jak-STAT pathway is tightly regulated by various cellular factors such as SOCS family members, USP18, the protein phosphatase 2A (PP2A), and protein inhibitors of STAT (PIAS).[ xref ] Along those lines, SOCS1 and SOCS3 transcriptional expression in hepatocytes remains detectable for only a short period of time upon alfa treatment indicating that by inhibiting Janus kinases both proteins are likely responsible for early termination of STAT activation.[ xref ] In addition, the sustained up-regulation of USP18 was associated with a long-lasting refractory state to IFN-α stimulation in hepatocytes and other primary human cells.[ xref ] The specific interaction of USP18 with IFNAR2 selectively affects IFN—induced signaling while having a marginal effect on other classes of IFNs, including type III IFNs."
USP18 affects inflammatory response
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"Through IFNAR1/2 receptors and
the JAK/STAT signaling
pathway, IFN-I has a further impact on the next important component of the
development of the inflammatory response: the ISG15/USP18 axis, which regulates
the activity of the immune system [36]
and reduces the inflammatory response intensity by inhibiting the JAK/STAT
signaling pathway, indicating that there possibly exists a negative feedback
loop between USP18, IFN-I, and, therefore, TNF-α [43, 44]."
USP18 activates inflammatory response.
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USP18 activates inflammatory response. 5 / 5
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"The natural flavonoid cardamonin (CAR), a specific USP18 agonist, significantly improves cardiac function in TAC mice by enhancing USP18-mediated anti-hypertrophic effects, as evidenced by increased ejection fraction (EF%), reduced B-type natriuretic peptide (BNP) levels, and attenuated myocardial inflammation/fibrosis [157]."
reach
"Although distinct reductions in adaptive immunity-related genes were observed, no differences were observed in the mRNA levels of the more general inflammatory cytokines C-C motif chemokine ligand 2 (Ccl2) and C-C motif chemokine ligand 3 (Ccl3) or ubiquitin-specific peptidase 18 (Usp18), which mediates the regulation of the inflammatory response to type 1 interferon (Fig. 3D)."
sparser
"Our above results demonstrated that (1) USP18 and USP20 correlate with limited oHSV-1 T1012G virus yields in SCC9 cells; (2) USP18 and USP20 interact with STING and alter the levels of STING proteins in SCC9 cells; and (3) altered STING accumulation regulates viral replication in SCC9 and SCC25 cells, while we need to further examine whether the DUB activity of USP18 or USP20 is crucial for the regulation of STING stabilization and oHSV-1 T1012G virus replication."
reach
"Inactivation of CRL E3 ligase through neddylation blockage (by MLN4924) would, therefore, cause the accumulation of SLC7A11 at the transcriptional levels by the Keap1-NRF2-SLC7A11 and β-TrCP-ATF4-SLC7A11 axes through increased transcription, and at the posttranslational level by the KCTD10–SLC7A11 axis through reduced degradation.In this study, we also characterized USP18 as a deubiquitylase that stabilizes SLC7A11 with the following lines of supporting evidence: 1) USP18 binds to SLC7A11 through its intermediate domain (AA 51-150) and SLC7A11 interacts with USP18 through its N-terminal domain; 2) USP18 overexpression or knockdown increases or decreases SLC7A11 levels, by extending or shortening the SLC7A11 protein half-life, respectively; 3) USP18 decreases the levels of SLC7A11 polyubiquitylation.Whether or under what physiological and pathological conditions that SLC7A11 is subjected to KCTD10 and USP18 regulation?"
sparser
"In this study, we also characterized USP18 as a deubiquitylase that stabilizes SLC7A11 with the following lines of supporting evidence: 1) USP18 binds to SLC7A11 through its intermediate domain (AA 51-150) and SLC7A11 interacts with USP18 through its N-terminal domain; 2) USP18 overexpression or knockdown increases or decreases SLC7A11 levels, by extending or shortening the SLC7A11 protein half-life, respectively; 3) USP18 decreases the levels of SLC7A11 polyubiquitylation."
sparser
"Here we showed a dynamic regulation of the SLC7A11 stability by KCTD10 and USP18 in response to cystine levels in the culture, as evidenced by 1) cystine deprivation decreases the levels of KCTD10, but increases the levels of USP18, which is reversed/rescued by cystine resupply, and 2) cystine deprivations disrupts the SLC7A11–KCTD10 interaction to reduce SLC7A11 ubiquitylation, whereas increases the SLC7A11–USP18 interaction to enhance SLC7A11 deubiquitylation."
reach
"To further confirm the role of USP18 in regulating SLC7A11 turnover, we generated USP18 knockout MDA-MB-231 cells through the CRISPR-Cas9 approach, and found that USP18 deletion decreased SLC7A11 levels (SI Appendix, Fig. S5J), shortened its protein half-life (SI Appendix, Fig. S5 K and L), and increased the polyubiquitylation of SLC7A11 (SI Appendix, Fig. S5M)."
sparser
"USP18 C64S , the mutation of cysteine residues in the enzymatic center of USP18, can interact with MAVS and enhances the ubiquitination as well as aggregation of MAVS comparable to the wild-type USP18, suggesting USP18 is involved in MAVS-mediated signaling pathway independent of its enzymatic activity."
eidos
"These data suggest that the induction of USP18 by TNF-alpha and LPS , and possibly other inflammatory stimuli , is promoted by NF-kappaBeta signaling and that hepatocyte USP18 expression in particular - - compared to IL-1beta - - may be an attractive target for pharmacologic manipulation in the setting of liver inflammation ."
reach
"These data suggest that the induction of USP18 by TNF-alpha and LPS, and possibly other inflammatory stimuli, is promoted by NF-kappaBeta signaling and that hepatocyte USP18 expression in particular -- compared to IL-1beta -- may be an attractive target for pharmacologic manipulation in the setting of liver inflammation."
USP18 affects signal transduction
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USP18 inhibits signal transduction.
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USP18 inhibits signal transduction. 10 / 11
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"Through IFNAR1/2 receptors and
the JAK/STAT signaling
pathway, IFN-I has a further impact on the next important component of the
development of the inflammatory response: the ISG15/USP18 axis, which regulates
the activity of the immune system [36]
and reduces the inflammatory response intensity by inhibiting the JAK/STAT
signaling pathway, indicating that there possibly exists a negative feedback
loop between USP18, IFN-I, and, therefore, TNF-α [43, 44]."
USP18 activates signal transduction.
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5
USP18 activates signal transduction. 5 / 5
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reach
"It is known that IFIH1 (interferon-induced helicase-1), IFI35 (interferon-induced protein 35), and USP18 (ubiquitin-specific peptidases 18) activate the IFN signaling pathway; IFIH1 induces pro-inflammatory cytokines, and type I IFNs respond to viral infections in which they act as innate immune receptors [36,37]."
reach
"Further investigation with the KEGG pathway enrichment analysis showed those up-regulated genes could cause the activation of the IFN-induced pathway, type II interferon signaling pathway, and regulation of protein ISGylation by the ISG15 deconjugating enzyme USP18 pathway (Figure 4B)."
Infections affects USP18
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15
Infections increases the amount of USP18.
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7
Infections activates USP18.
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reach
"Postactivation silencing of IFNAR signaling is achieved quickly after IFN exposure and is mediated by at least two proteins that are ISGs themselves and therefore accumulate in response to IFN: Suppressor of cytokine signaling 1 (SOCS1) binds and inhibits TYK2, whereas USP18 (UBP43) occupies IFNAR2 and hence blocks JAK1 activation (83, 84)."
reach
"The results indicated that USP18 interacted with TAK1, TAB1, and TAB2 without stimulation and PMA and ion stimulation reduced but did not totally abolish their association, whereas USP18 interacted with CARMA1 weakly in unstimulated cells and PMA and ion stimulation first enhanced their interaction and then resulted in their disassociation (XREF_FIG)."
USP18 affects Neoplasm Metastasis
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USP18 activates Neoplasm Metastasis.
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USP18 activates Neoplasm Metastasis. 10 / 12
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2
10
reach
"In the tumor, this signaling drives expression of angiogenic and immunosuppressive myeloid chemokines CXCL1, CXCL10, and CCL5; protumor interferon-stimulated genes ISG15 and IFIT3; and oncoprotein USP18, all of which promote tumor growth and metastases, and are selectively blocked by nciLT but not by ciLT."
USP18 inhibits Neoplasm Metastasis.
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2
USP18 affects JAK-STAT
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12
USP18 inhibits JAK-STAT.
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2
9
reach
"In contrast, binding this free ISG15, USP18 suppresses JAK-STAT signaling further counteracting IFN signaling.By better understanding the ISG15 pathway, it may be possible to target certain illnesses on a case-by-case basis without the need for general activation of IFN signaling with its hundreds of downstream targets."
eidos
"Recent data by Zhang and coworkers ( Malakhova et al ., 2006 ) revealed , however , that USP18 attenuates JAK-STAT signaling , and thereby the type 1 IFN response , in a non-enzymatic manner , i.e ., by directly competing with JAK1 for binding to the IFNAR2 subunit of the type 1 IFN receptor ."
USP18 activates JAK-STAT.
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3
USP18 affects IFN-I
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14
USP18 inhibits IFN-I.
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12
reach
"Therefore, under the circumstances of enhanced IFN-I signaling caused by USP18 deletion, IFN-I-inducible E2 enzyme UBCH5 likely enhances the activity of E3 ligase NEDD4, leading to degradation of CSF1R via the ubiquitin-proteasome system.Since NEDD4 is frequently overexpressed in cancers, including prostate, bladder, and colon cancers, NEDD4 was originally thought to be an oncogene."
reach
"The mechanism by which MARCH1 regulates IFN-I remains obscure and several factors may include increased expression of genes encoding SOCS1, SOCS3, SIKE1, CACTIN, TRIM24, IL-10RA, USP18, and mir-21 that are known to suppress IFN-I responses and changes in DCs, Macs, and other cell populations can may also affect the levels of proteins critical for IFN-I production."
reach
"During systemic infection with the vesicular stomatitis virus (VSV), CD169 + macrophages of the splenic marginal zone and the lymph node sinusoid can express the endogenous IFN-I blocker Usp18, thereby promoting virus replication and enhancing the antiviral immune response [XREF_BIBR, XREF_BIBR]."
| PMC
USP18 activates IFN-I.
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2
USP18 affects ubiquitination
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13
USP18 affects pyroptosis
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USP18 inhibits pyroptosis.
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USP18 inhibits pyroptosis. 8 / 8
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"Since pyroptosis was induced by USP18 depletion but has not been well described upon interferon treatment, and Caspase-3-mediated GSDME cleavage is not involved in canonical inflammasome-Caspase-1-mediated GSDMD cleavage, we hypothesized that atypical ISGs may contribute to cleaved GSDME-mediated pyroptosis."
USP18 activates pyroptosis.
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5
USP18 affects immune response
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13
USP18 inhibits immune response.
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USP18 inhibits immune response. 10 / 10
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10
reach
"Based on these interesting findings, USP18 can attenuate the immune response even without dampening the type I IFN signaling.Finally, it has been reported that STAT1 transcriptional activity and NF-κB signaling activation, which regulate both the transcription and expression of ISGs, can be inhibited by SLFN5 and SLFN2, respectively [78,79]."
reach
"These results suggest that USP18 deletion leads to CSF1R downregulation in TAMs and a decrease in pro-tumor/immunosuppressive macrophages, contributing to enhanced anti-tumor macrophage polarization, consequently promoting a Th1-dominant TME and enhancing CD8 T cell-mediated anti-tumor immunity, in agreement with previous reports."
reach
"These observations suggest that residual leukemia cells may upregulate USP18 expression as a protective mechanism against chemotherapy-induced death.Taken together, these results indicate that reduction of Usp18 expression potently suppresses cancer development and induces an anti-tumor immune response in vivo by a mechanism dependent on type I IFN signaling."
USP18 activates immune response.
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3
USP18 activates USP18.
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5
reach
"In GM-CSF-supplemented culture, over-expression of Usp18 restored the development of CD11b + CD11c + cells in Usp18 deficient BM cells, but did not affect DC development in wild-type BM cells (XREF_FIG), which confirmed the notion that the development defect of BM-DCs is intrinsic to Usp18 deficient cells."
reach
"Pretreatment with IFNβ led to increased levels of IRF3 activation by dsDNA90 treatment in all cell sublines.IFNβ pretreatment but not dsDNA90 increased USP18 levels in parental FTE-194 cells and UBA7-null cells, but not in ISG15-null cells (Fig. 3), likely reflecting the importance of free ISG15 in stabilizing USP18."
USP18 inhibits USP18.
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4
USP18 increases the amount of USP18.
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2
USP18 methylates USP18.
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1
USP18 affects Neoplasm Invasiveness
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1
12
USP18 activates Neoplasm Invasiveness.
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1
8
USP18 inhibits Neoplasm Invasiveness.
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4
USP18 affects cell growth
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9
1
USP18 activates cell growth.
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7
USP18 inhibits cell growth.
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2
1
reach
"For example, USP18 is known to prevent IFNAR activation as shown by Honke et al. where USP-18 secreting CD169 macrophages displayed a lower type I IFN sensitivity upon viral infection [38], [57].4
Strategies to control innate immune activation upon conventional and self-amplifying mRNA delivery."
reach
"Inactivation of CRL E3 ligase through neddylation blockage (by MLN4924) would, therefore, cause the accumulation of SLC7A11 at the transcriptional levels by the Keap1-NRF2-SLC7A11 and β-TrCP-ATF4-SLC7A11 axes through increased transcription, and at the posttranslational level by the KCTD10–SLC7A11 axis through reduced degradation.In this study, we also characterized USP18 as a deubiquitylase that stabilizes SLC7A11 with the following lines of supporting evidence: 1) USP18 binds to SLC7A11 through its intermediate domain (AA 51-150) and SLC7A11 interacts with USP18 through its N-terminal domain; 2) USP18 overexpression or knockdown increases or decreases SLC7A11 levels, by extending or shortening the SLC7A11 protein half-life, respectively; 3) USP18 decreases the levels of SLC7A11 polyubiquitylation.Whether or under what physiological and pathological conditions that SLC7A11 is subjected to KCTD10 and USP18 regulation?"
sparser
"In this study, we also characterized USP18 as a deubiquitylase that stabilizes SLC7A11 with the following lines of supporting evidence: 1) USP18 binds to SLC7A11 through its intermediate domain (AA 51-150) and SLC7A11 interacts with USP18 through its N-terminal domain; 2) USP18 overexpression or knockdown increases or decreases SLC7A11 levels, by extending or shortening the SLC7A11 protein half-life, respectively; 3) USP18 decreases the levels of SLC7A11 polyubiquitylation."
sparser
"Here we showed a dynamic regulation of the SLC7A11 stability by KCTD10 and USP18 in response to cystine levels in the culture, as evidenced by 1) cystine deprivation decreases the levels of KCTD10, but increases the levels of USP18, which is reversed/rescued by cystine resupply, and 2) cystine deprivations disrupts the SLC7A11–KCTD10 interaction to reduce SLC7A11 ubiquitylation, whereas increases the SLC7A11–USP18 interaction to enhance SLC7A11 deubiquitylation."
sparser
"Our above results demonstrated that (1) USP18 and USP20 correlate with limited oHSV-1 T1012G virus yields in SCC9 cells; (2) USP18 and USP20 interact with STING and alter the levels of STING proteins in SCC9 cells; and (3) altered STING accumulation regulates viral replication in SCC9 and SCC25 cells, while we need to further examine whether the DUB activity of USP18 or USP20 is crucial for the regulation of STING stabilization and oHSV-1 T1012G virus replication."
USP18 affects cell differentiation
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10
USP18 inhibits cell differentiation.
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6
USP18 activates cell differentiation.
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4
reach
"Previous studies demonstrated that USP18 plays a significant role in regulating autophagy: USP18 decreased paclitaxol sensitivity of triple-negative breast cancer via promoting autophagy [26]; USP18 overexpression could promote autophagy to inhibit cell apoptosis induced by spinal cord ischemia–reperfusion injury [27]; USP18 stabilizes cGAS through deubiquitination, enhancing autophagy in melanoma cells and thereby promoting resistance to vemurafenib in BRAF V600E mutant melanoma [28]."
sparser
"Our above results demonstrated that (1) USP18 and USP20 correlate with limited oHSV-1 T1012G virus yields in SCC9 cells; (2) USP18 and USP20 interact with STING and alter the levels of STING proteins in SCC9 cells; and (3) altered STING accumulation regulates viral replication in SCC9 and SCC25 cells, while we need to further examine whether the DUB activity of USP18 or USP20 is crucial for the regulation of STING stabilization and oHSV-1 T1012G virus replication."
reach
"Immune regulatory components whose downregulation improves anti-HIV responses include activated leukocyte cell adhesion molecular (ALCAM) , ubiquitin-specific proteinase 18 (USP18) which negatively regulates type I interferon responses and SAMHD1 in macrophages , and miR-146a that represses antiviral cytokine signaling ."
reach
"An interaction between USP18 and ABCG1 in THP‐1‐derived macrophage cells was further substantiated by subsequent co‐immunoprecipitation analysis using endogenous USP18 and ABCG1 antibodies, as evident in Figure 6F,G. Following the silencing of USP18, we undertook an investigation into the ubiquitin level of ABCG1 in cells."
sparser
"Our above results demonstrated that (1) USP18 and USP20 correlate with limited oHSV-1 T1012G virus yields in SCC9 cells; (2) USP18 and USP20 interact with STING and alter the levels of STING proteins in SCC9 cells; and (3) altered STING accumulation regulates viral replication in SCC9 and SCC25 cells, while we need to further examine whether the DUB activity of USP18 or USP20 is crucial for the regulation of STING stabilization and oHSV-1 T1012G virus replication."
reach
"An interaction between USP18 and ABCG1 in THP‐1‐derived macrophage cells was further substantiated by subsequent co‐immunoprecipitation analysis using endogenous USP18 and ABCG1 antibodies, as evident in Figure 6F,G. Following the silencing of USP18, we undertook an investigation into the ubiquitin level of ABCG1 in cells."
USP18 affects signaling
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9
USP18 affects cell cycle
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1
8
USP18 activates cell cycle.
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1
6
USP18 inhibits cell cycle.
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2
sparser
"To determine the mechanism of the USP18 and IKKβ interaction, we generated deletion mutants encompassing the amino-terminal kinase domain (KD), leucine zipper domain (LZ), and a C-terminal helix-loop-helix (HLH) domain of IKKβ ( xref ), and performed immunoprecipitation to test their ability to interact with USP18."
reach
"To determine the mechanism of the USP18 and IKKbeta interaction, we generated deletion mutants encompassing the amino-terminal kinase domain (KD), leucine zipper domain (LZ), and a C-terminal helix-loop-helix (HLH) domain of IKKbeta (XREF_FIG), and performed immunoprecipitation to test their ability to interact with USP18."
reach
"The results indicated that USP18 interacted with TAK1, TAB1, and TAB2 without stimulation and PMA and ion stimulation reduced but did not totally abolish their association, whereas USP18 interacted with CARMA1 weakly in unstimulated cells and PMA and ion stimulation first enhanced their interaction and then resulted in their disassociation (XREF_FIG)."
USP18 affects ISG
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8
USP18 increases the amount of ISG.
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4
reach
"However, infection did interfere with the ISG regulatory IRF-STAT1 and STAT2 pathways to inhibit IFNT induced ISG expression including ISG15, HERC5, USP18 (involved in protein modification via ISGylation), DDX58, IFIH1 (cytosolic detection of viral RNA) and IFIT3, MX2, RSAD2, and SAMD9 (immune regulators with antiviral activity) XREF_BIBR."
USP18 decreases the amount of ISG.
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2
USP18 activates ISG.
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2
USP18 affects IFN receptor
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8
USP18 inhibits IFN receptor.
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5
reach
"Whereas ISG15 conjugation has been widely recognized to act antivirally 13, unconjugated ISG15 serves a proviral role by promoting USP18 mediated suppression of type I IFN receptor (IFNAR) signaling XREF_BIBR, XREF_BIBR, XREF_BIBR; this latter function of ISG15 is responsible for over-amplified ISG induction and fortified viral resistance in humans with inherited ISG15 deficiency."
USP18 binds IFN receptor.
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3
reach
"Furthermore, in comparison to control mice, the frequency of conventional CD11b + DCs in the spleen of Usp18 -/- mice was reduced by about 50% (XREF_FIG), however, the conventional CD8 + DCs (XREF_FIG) and pDCs (CD11c int B220 + CD11b -) (data not shown) populations were observed with the same frequency in the spleens of both Usp18 -/- and control mice."
reach
"These results suggest that USP18 deletion leads to CSF1R downregulation in TAMs and a decrease in pro-tumor/immunosuppressive macrophages, contributing to enhanced anti-tumor macrophage polarization, consequently promoting a Th1-dominant TME and enhancing CD8 T cell-mediated anti-tumor immunity, in agreement with previous reports."
8
|
2,3,7,8-tetrachlorodibenzodioxine increases the amount of USP18.
5
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2,3,7,8-tetrachlorodibenzodioxine decreases the amount of USP18.
3
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USP18 affects cell death
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6
USP18 inhibits cell death.
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5
USP18 inhibits cell death. 5 / 5
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5
reach
"Our results demonstrate that I60N retains deISGylase activity, and the observed accumulation of ISGylated proteins can be decoupled from the loss of catalytic function.Partial impairments in scaffold function by the I60N mutation were correlated with intermediate levels of ISGylation and IFN sensitivity, implicating scaffold function as the primary mechanism by which USP18 loss promotes tumor intrinsic growth arrest and cell death."
USP18 activates cell death.
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USP18 activates cell death. 1 / 2
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1
reach
"Overall, our study and other studies indicate that USP18 recruits distinct E3 ubiquitin ligases to mediate different ubiquitin linkage types of targeted proteins for regulating its functions, facilitating the balance of immune responses and the maintenance of homeostasis.In summary, we identified USP18 as a negative regulator of pyroptosis by promoting the autophagic degradation of GSDMD."
USP18 affects Pancreatic Neoplasms
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4
3
eidos
"STAT1 , USP18 and IRF1 modulate CXCL10 levels in EC following IFN-alpha stimulation To validate the transcriptional regulations inferred in our multiple-output FFL regulatory subnetwork ( Fig. 2 ) , we measured CXCL10 protein levels in tissue culture media conditioned by STAT1 - , USP18 - , IFIH1 - and IRF1-silenced HUVECs , compared to HUVECs transfected with a scrambled siRNA ( siCTRL ) ."
reach
"In our current study, we revealed another mechanism of CSF1R regulation mediated by USP18 and NEDD4.Reduction of CSF1R on cell membranes has been reported by shedding with TNF-α-converting enzyme TACE and γ-secretase and by CSF1 or Toll-like receptor (TLR) agonist-stimulated internalization and lysozyme degradation."
reach
"This study, led by Miyauchi et al., found that the reduction of USP18 enhances the proteasomal degradation of colony stimulating factor 1 receptor (CSF1R) mediated by ubiquitin conjugating enzyme E2 D1 (UBCH5) and neural precursor cell expressed developmentally downregulated 4 E3 ubiquitin protein ligase (NEDD4)."
Bisphenol A affects USP18
6
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Bisphenol A increases the amount of USP18.
3
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Bisphenol A decreases the amount of USP18.
3
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All-trans-retinoic acid affects USP18
4
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All-trans-retinoic acid increases the amount of USP18.
2
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1
All-trans-retinoic acid increases the amount of USP18. 3 / 4
2
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All-trans-retinoic acid decreases the amount of USP18.
2
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USP18 affects regulation of cell cycle
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6
USP18 inhibits regulation of cell cycle.
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USP18 activates regulation of cell cycle.
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USP18 affects activation
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USP18 affects Infections
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6
USP18 inhibits Infections.
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USP18 inhibits Infections. 3 / 3
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3
reach
"Therefore, these results suggested that inhibiting the expression of IFIT3, OASL, USP18, XAF1, IFI27, and EPSTI1 may reduce the risk of SARS‐CoV‐2 infection and may also have a positive effect on antiviral therapy in patients with SARS‐CoV‐2 infection.In conclusion, this study comprehensively analyzed the blood leukocytes gene expression profile data of COVID‐19 patients by using bioinformatics methods and provided a preliminary understanding of the functions and mechanisms of DEGs in the leukocytes of COVID‐19 patients."
USP18 activates Infections.
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3
sparser
"Interestingly, USP18 in humans (but not in mice) can also interfere with the anti-viral outcome of IFN signaling by an additional mechanism: USP18 can bind the interferon receptor 2 (IFNAR2), block the association of JAK, and possibly limit IFNAR2-IFNAR1 dimerization, thereby interfering with the JAK-STAT signaling pathway xref ."
reach
"Immunofluorescence analysis using specific dsRNA antibodies showed a significant and time-dependent accumulation of dsRNA in the USP18 KO cells after IFN treatment, indicating that USP18-dependent ISGylation under these conditions could inhibit ADAR activity.In addition to ADAR, PKR, RIG-I and MDA5, we found other proteins involved in antigen presentation and resistance to immunotherapy, such as TAP1, GBP1, STAT1, IFIT1, PSMB10, PSMB9, GBP2, MAGE and PARP14, also regulated by USP18-dependent ISGylation."
USP18 affects Cell Survival
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1
5
sparser
"To determine the mechanism of the USP18 and IKKβ interaction, we generated deletion mutants encompassing the amino-terminal kinase domain (KD), leucine zipper domain (LZ), and a C-terminal helix-loop-helix (HLH) domain of IKKβ ( xref ), and performed immunoprecipitation to test their ability to interact with USP18."
reach
"To determine the mechanism of the USP18 and IKKbeta interaction, we generated deletion mutants encompassing the amino-terminal kinase domain (KD), leucine zipper domain (LZ), and a C-terminal helix-loop-helix (HLH) domain of IKKbeta (XREF_FIG), and performed immunoprecipitation to test their ability to interact with USP18."
sparser
"Interestingly, USP18 in humans (but not in mice) can also interfere with the anti-viral outcome of IFN signaling by an additional mechanism: USP18 can bind the interferon receptor 2 (IFNAR2), block the association of JAK, and possibly limit IFNAR2-IFNAR1 dimerization, thereby interfering with the JAK-STAT signaling pathway xref ."
IFN-I affects USP18
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USP18 affects interferon receptor
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USP18 inhibits interferon receptor.
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3
USP18 binds interferon receptor.
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2
reach
"Interestingly, USP18 in humans (but not in mice) can also interfere with the anti-viral outcome of IFN signaling by an additional mechanism: USP18 can bind the interferon receptor 2 (IFNAR2), block the association of JAK, and possibly limit IFNAR2-IFNAR1 dimerization, thereby interfering with the JAK-STAT signaling pathway [89]."
USP18 affects ferroptosis
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5
USP18 activates ferroptosis.
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3
USP18 inhibits ferroptosis.
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2
reach
"The natural flavonoid cardamonin (CAR), a specific USP18 agonist, significantly improves cardiac function in TAC mice by enhancing USP18-mediated anti-hypertrophic effects, as evidenced by increased ejection fraction (EF%), reduced B-type natriuretic peptide (BNP) levels, and attenuated myocardial inflammation/fibrosis [157]."
USP18 affects DNA-templated transcription
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USP18 inhibits DNA-templated transcription. 5 / 5
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5
reach
"We identified that nuclear USP18 diminishes binding of IFN regulated transcription factors to their corresponding DNA motifs in cooperation with NF-κB. Consequently, the suppression of USP18 not only enhances the expression of canonical IFN-stimulated genes (ISGs) but also activates a set of atypical ISGs and NF-κB target genes that induce cancer pyroptosis."
USP18 affects Carcinogenesis
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USP18 activates Carcinogenesis. 5 / 5
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5
reach
"The effect of ISGylation of specific protein targets in the tumour microenvironment will also be the focus of our further research.Previous studies have shown that increased USP18 expression promotes tumorigenesis by increasing stability of critical ISG15‐conjugated oncogenic proteins (Basters et al., 2017; Liu et al., 2020; Pinto‐Fernandez et al., 2021)."
reach
"A study has indicated that USP18 contributes to controlling carcinogenesis, as loss of USP18 function increases apoptosis and decreases cell proliferation by destabilization of the cyclin D1 protein 22.It remains, however, unclear so far whether the EFP, HERC5 and USP18 genes contribute to tumourigenesis through ISG15/ISGylation or other mechanisms."
eidos
"STAT1 , USP18 and IRF1 modulate CXCL10 levels in EC following IFN-alpha stimulation To validate the transcriptional regulations inferred in our multiple-output FFL regulatory subnetwork ( Fig. 2 ) , we measured CXCL10 protein levels in tissue culture media conditioned by STAT1 - , USP18 - , IFIH1 - and IRF1-silenced HUVECs , compared to HUVECs transfected with a scrambled siRNA ( siCTRL ) ."
Lipopolysaccharides affects USP18
5
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IFNs affects USP18
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HIRI affects USP18
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17beta-estradiol affects USP18
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sparser
"Our above results demonstrated that (1) USP18 and USP20 correlate with limited oHSV-1 T1012G virus yields in SCC9 cells; (2) USP18 and USP20 interact with STING and alter the levels of STING proteins in SCC9 cells; and (3) altered STING accumulation regulates viral replication in SCC9 and SCC25 cells, while we need to further examine whether the DUB activity of USP18 or USP20 is crucial for the regulation of STING stabilization and oHSV-1 T1012G virus replication."
USP18 affects process
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2
2
sparser
"By comparing the behavior of IFNα2 mutants with different affinities for the two receptor subunits, the researchers concluded that IFNs do, in fact, recruit IFNAR1 into a ternary complex with IFNAR2, and that this process is inhibited by USP18. “Cells expressing USP18 lose the ability to bind IFNα2 because receptor dimerization isn’t as efficient,” Piehler says."
| PMC
USP18 affects isopeptidase
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4
USP18 affects activity
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sparser
"Treating Usp18 -deficient hematopoietic cells with Poly I:C decreases the number of white blood cells since apoptosis is not prevented by USP18. xref Moreover, knocking down USP18 markedly enhances the NF- κ B signaling induced by various TLR ligands. xref A study using an oncogenic cell line (E1A cells) found that USP18 activates the extrinsic TNF-related apoptosis-inducing ligand (TRAIL) pathway after IFN- α challenge. xref In human promonocytic THP-1 cells, the expression of proinflammatory cytokines such as TNF- α , interleukin-6 (IL-6), and IL-1 β is significantly higher when USP18 is silenced with siRNA. xref Interestingly, in contrast to E1A cells, Usp18 -deficient murine bone marrow cells and THP-1 cells that have been treated with IFN α / β do not experience apoptosis after treatment with TRAIL or FASL. xref However, IFN- α / β still triggers apoptosis in these cells through the mitochondrial pathway and the reactive oxygen species pathway, xref a finding indicating that USP18 influences cell survival in various pathways depending on the cell type."
USP18 affects Hypertrophy
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USP18 inhibits Hypertrophy. 4 / 4
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4
reach
"USP18 plays a well-described protective role in the development of heart failure but its role in kidney injury remains unrecognized.Both in murine experimental models and in humans, USP18 inhibits myocardial hypertrophy via the TAK1-p38-JNK1/2 axis upon an increased afterload [4]."
reach
"Conclusion
Deciphering the complex molecular interactions between FOXO3a and USP18 in fibroblasts provides a deeper understanding of IPF pathogenesis and unveils novel therapeutic avenues, offering a promising potential for not just halting but potentially reversing the progression of this debilitating disease."
sparser
"Conclusion Deciphering the complex molecular interactions between FOXO3a and USP18 in fibroblasts provides a deeper understanding of IPF pathogenesis and unveils novel therapeutic avenues, offering a promising potential for not just halting but potentially reversing the progression of this debilitating disease."
sparser
"Our above results demonstrated that (1) USP18 and USP20 correlate with limited oHSV-1 T1012G virus yields in SCC9 cells; (2) USP18 and USP20 interact with STING and alter the levels of STING proteins in SCC9 cells; and (3) altered STING accumulation regulates viral replication in SCC9 and SCC25 cells, while we need to further examine whether the DUB activity of USP18 or USP20 is crucial for the regulation of STING stabilization and oHSV-1 T1012G virus replication."
reach
"Conclusion
Deciphering the complex molecular interactions between FOXO3a and USP18 in fibroblasts provides a deeper understanding of IPF pathogenesis and unveils novel therapeutic avenues, offering a promising potential for not just halting but potentially reversing the progression of this debilitating disease."
sparser
"Conclusion Deciphering the complex molecular interactions between FOXO3a and USP18 in fibroblasts provides a deeper understanding of IPF pathogenesis and unveils novel therapeutic avenues, offering a promising potential for not just halting but potentially reversing the progression of this debilitating disease."
Type I IFNs affects USP18
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3
Input affects USP18
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3
eidos
"Computational modeling suggests a delayed negative feedback loop through USP18 Based on our experimental results , we postulated that the opposite effects induced by short versus prolonged pretreatment inputs might be caused by different expression kinetics of ISGF3 components and USP18 : a short input is sufficient to trigger ISGF3 expression and thereby the priming effect , whereas a prolonged input is required to induce USP18 expression and hence desensitization ."
Inflammatory affects USP18
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3
reach
"Here we showed a dynamic regulation of the SLC7A11 stability by KCTD10 and USP18 in response to cystine levels in the culture, as evidenced by 1) cystine deprivation decreases the levels of KCTD10, but increases the levels of USP18, which is reversed/rescued by cystine resupply, and 2) cystine deprivations disrupts the SLC7A11–KCTD10 interaction to reduce SLC7A11 ubiquitylation, whereas increases the SLC7A11–USP18 interaction to enhance SLC7A11 deubiquitylation."
Cadmium dichloride affects USP18
3
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Cadmium dichloride increases the amount of USP18.
2
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Cadmium dichloride decreases the amount of USP18.
1
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USP18 affects viral RNA genome replication
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3
USP18 inhibits viral RNA genome replication.
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2
USP18 activates viral RNA genome replication.
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1
USP18 activates viral RNA genome replication. 1 / 1
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1
reach
"XREF_BIBR, XREF_BIBR A recent study found that USP18 can enhance the cellular transport rate in Xenopus laevis oocytes by increasing the activity of PEPT1 and PEPT2; this activation was believed to be due to the reversal of ubiquitination and the subsequent degradation of carrier protein."
reach
"Warsi, et al demonstrated that transport activity of rabbit peptide transporters Pept1 and Pept2 was decreased in Xenopus laevis oocytes injected with cRNA encoding the E3 ubiquitin ligase Nedd4-2, whereas overexpression of USP18 (Ubiquitin like specific protease 18), an enzyme cleaving ubiquitin from target proteins, stimulated the transport activity of rbPept1 and rbPept2 [XREF_BIBR]."
USP18 affects macrophage activation
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3
USP18 affects interaction
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1
2
sparser
"The isopeptidase activity of UBP43 responsible for deconjugation of ISG15ylated proteins, however, is not required for the inhibition of STAT1 phosphorylation, which appears to be mediated instead through direct inhibition by UBP43 of the interaction of JAK1 with the type I IFN receptor xref ."
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3
USP18 affects cleaved-caspase-3
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3
USP18 affects cellular senescence
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1
2
USP18 affects breast cancer growth
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3
USP18 affects biosynthetic process
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3
USP18 activates biosynthetic process. 3 / 3
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3
reach
"However, according to research by Hong et al., increased USP18 expression in tumor cells would in turn inhibit carcinogenesis, whereas decreased USP18 promotes tumor growth and lowers immunosurveillance by decreasing the exogenous synthesis of IFN-γ and the survival of cytotoxic T lymphocytes (CTLs) in TME [178]."
USP18 affects UBL
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3
reach
"As these two signals have been thought to have counter-regulatory roles in psoriasis (39), lower USP18 might promote higher IFN response and thus lower TNF dependence, and vice versa, agreeing with the positive correlation with PASI improvement we observed during the course of etanercept treatment."
reach
"In GM-CSF-supplemented culture, over-expression of Usp18 restored the development of CD11b + CD11c + cells in Usp18 deficient BM cells, but did not affect DC development in wild-type BM cells (XREF_FIG), which confirmed the notion that the development defect of BM-DCs is intrinsic to Usp18 deficient cells."
USP18 affects IKK_complex
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2
1
USP18 dephosphorylates IKK_complex.
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2
USP18 leads to the dephosphorylation of IKK_complex. 2 / 2
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2
reach
"Conversely, knockdown of USP18 in THP-1 and THP-1-derived macrophages enhanced the phosphorylation of IKK, the degradation of IKBalpha and expression of proinflammatory cytokines, such as IL-6, TNF-alpha and IL-1beta in response to LPS treatment These results suggest that USP18 is a novel negative regulator of NF-kappaB signaling."
USP18 binds IKK_complex.
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1
USP18 affects IFN-lambda
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2
1
USP18 affects GSDMD-N
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3
USP18 affects DENV-2
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3
reach
"Overexpression of USP18 promoted DENV-2 replication, while its silencing abrogated the replication and increased the anti-DENV-2 specific IFN-α through the activation of the IFN-α-mediated Jak/STAT signaling pathway, as shown by the increased expression of p-STAT1/p-STAT2 and the elevated expression of some ISGs."
sparser
"Moreover, an exhaustive analysis of amino acid residue contacts within both complexes was conducted, with particular attention to the number of contacts between charged polar residues and nonpolar residues, with the ISG15-PD-L1 and USP18-PD-L1 complexes having contact counts of 12 and 24 and 20 and 18, respectively."
reach
"The results indicated that USP18 interacted with TAK1, TAB1, and TAB2 without stimulation and PMA and ion stimulation reduced but did not totally abolish their association, whereas USP18 interacted with CARMA1 weakly in unstimulated cells and PMA and ion stimulation first enhanced their interaction and then resulted in their disassociation (XREF_FIG)."
UBL affects USP18
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3
IFN receptor affects USP18
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3
sparser
"Moreover, an exhaustive analysis of amino acid residue contacts within both complexes was conducted, with particular attention to the number of contacts between charged polar residues and nonpolar residues, with the ISG15-PD-L1 and USP18-PD-L1 complexes having contact counts of 12 and 24 and 20 and 18, respectively."
reach
"The results indicated that USP18 interacted with TAK1, TAB1, and TAB2 without stimulation and PMA and ion stimulation reduced but did not totally abolish their association, whereas USP18 interacted with CARMA1 weakly in unstimulated cells and PMA and ion stimulation first enhanced their interaction and then resulted in their disassociation (XREF_FIG)."
Valproic acid affects USP18
2
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Trichloroethene affects USP18
2
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Titanium dioxide affects USP18
2
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Plasmid transfection affects USP18
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2
Pentachlorophenol affects USP18
2
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MiR-191-5p affects USP18
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2
Interferon receptor affects USP18
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2
reach
"Interestingly, USP18 in humans (but not in mice) can also interfere with the anti-viral outcome of IFN signaling by an additional mechanism: USP18 can bind the interferon receptor 2 (IFNAR2), block the association of JAK, and possibly limit IFNAR2-IFNAR1 dimerization, thereby interfering with the JAK-STAT signaling pathway [89]."
Bis(2-ethylhexyl) phthalate affects USP18
2
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Benzo[a]pyrene affects USP18
2
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Acetaldehyde affects USP18
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1
Acetaldehyde activates USP18. 1 / 2
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1
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1
1
sparser
"Although the precise molecular mechanisms underlying the non-catalytic function of USP18 remain incompletely understood, data suggest that there is a direct interaction between USP18 and STAT2, which is crucial for recruiting USP18 to the plasma membrane, where it competes with janus kinase 1 (JAK1) for binding to IFNAR2."
reach
"Although the precise molecular mechanisms underlying the non-catalytic function of USP18 remain incompletely understood, data suggest that there is a direct interaction between USP18 and STAT2, which is crucial for recruiting USP18 to the plasma membrane, where it competes with janus kinase 1 (JAK1) for binding to IFNAR2."
USP18 affects vemurafenib
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2
USP18 affects translation
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1
1
USP18 affects transforming growth factor-beta-activated kinase TAK1
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2
USP18 affects responses
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1
1
USP18 affects protein stabilization
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2
USP18 affects phosphorylation
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2
USP18 affects osteoclast differentiation
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2
USP18 activates osteoclast differentiation. 2 / 2
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2
USP18 affects muscle cell differentiation
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2
USP18 affects migration ovarian cancer cells
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2
USP18 affects malonaldehyde
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2
USP18 inhibits malonaldehyde. 2 / 2
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2
USP18 affects lipid catabolic process
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2
USP18 affects fatty acid metabolic process
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2
USP18 affects defense response to virus
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2
USP18 activates defense response to virus. 2 / 2
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2
reach
"By providing exogenous IFN‐β, we were able to demonstrate that lack of USP18 makes cells more sensitive to the effects of IFN.The strategy used by HIV‐1 for transcription from its LTR promoter utilizes transcription factors such as NFκB, NFAT, and IRFs,73, 74 that would normally be present in a cell that has detected a viral infection and has initiated an antiviral response."
USP18 affects cell migration
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2
USP18 inhibits cell migration.
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1
USP18 inhibits cell migration. 1 / 1
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1
USP18 activates cell migration.
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1
USP18 activates cell migration. 1 / 1
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1
USP18 affects cGAS-STING
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2
USP18 affects autophagy of mitochondrion
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2
reach
"In addition, USP18-mediated deISGylation in vitro is approximately 40-fold faster than deISGylation by the cross-reactive deubiquitinating enzymes (DUB) USP21 [15] raising the question whether deISGylation by Ub/ISG15 cross-reactive DUBs is relevant in vivo.Despite enhanced ISGylation, mice homozygous for USP18-C61A (USP18 ) are healthy and display a normal lifespan [27]."
reach
"Moreover, USP17 is a positive regulator of RORgammat in Th17 cells, whereas USP18 has been reported to modulate T cell activation and Th17 cell differentiation by deubiquitinating of the TAK1 and TAB1 complex [XREF_BIBR] and USP25 has been regarded as a negative regulator of IL-17-mediated inflammation via TRAF5 and TRAF6 deubiquitination [XREF_BIBR]."
USP18 affects TAK1-TAB1
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1
reach
"The results indicated that USP18 interacted with TAK1, TAB1, and TAB2 without stimulation and PMA and ion stimulation reduced but did not totally abolish their association, whereas USP18 interacted with CARMA1 weakly in unstimulated cells and PMA and ion stimulation first enhanced their interaction and then resulted in their disassociation (XREF_FIG)."
USP18 affects PyVmT
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2
USP18 affects Pertussis_toxin
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2
USP18 affects Parkinson Disease
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2
USP18 affects NS2B
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2
reach
"To further address the mechanisms by which USP18 regulated DENV replication, we generated usp18-knockout (KO) A549 cells with the CRISPR technique, which eliminated USP18 in both the cytosol and mitochondrial fractions Fig. 6A,B. Transfection and induced overexpression of USP18-flag upregulated DENV NS2B expression in usp18-KO cells in a dose-dependent manner (Fig. 6C)."
USP18 affects NF-κB.
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2
reach
"We identified that nuclear USP18 diminishes binding of IFN regulated transcription factors to their corresponding DNA motifs in cooperation with NF-κB. Consequently, the suppression of USP18 not only enhances the expression of canonical IFN-stimulated genes (ISGs) but also activates a set of atypical ISGs and NF-κB target genes that induce cancer pyroptosis."
USP18 affects LPS-induced sepsis
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2
USP18 affects LC3-II
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2
reach
"In GM-CSF-supplemented culture, over-expression of Usp18 restored the development of CD11b + CD11c + cells in Usp18 deficient BM cells, but did not affect DC development in wild-type BM cells (XREF_FIG), which confirmed the notion that the development defect of BM-DCs is intrinsic to Usp18 deficient cells."
USP18 affects IFNs
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2
reach
"Therapeutically, USP18 represents an attractive target, with agonists being of use in clinical settings where there is overabundance of type I IFNs and USP18 antagonists acting to prolong the beneficial effects of therapeutic IFNs, as in multiple sclerosis, hairy cell leukemia, and melanoma."
USP18 affects Endoplasmic Reticulum Stress
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2
USP18 affects E3_Ub_ligase
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1
1
USP18 deubiquitinates E3_Ub_ligase.
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1
USP18 leads to the deubiquitination of E3_Ub_ligase. 1 / 1
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1
USP18 binds E3_Ub_ligase.
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1
USP18 affects BCCE4
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2
USP18 affects Atherosclerosis
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2
USP18 affects 1-phenylethanol
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2
USP18 inhibits 1-phenylethanol. 2 / 2
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2
TLR4 activation human macrophages affects USP18
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2
eidos
"The LPS-mediated TLR4 activation in human macrophages upregulates USP18 , which in turn inhibits NF-kappaB activation , and thus the secretion of proinflammatory cytokines ( TNF-alpha , IL-6 , and IL-1beta ) via interacting with TAK1-TAB1 and IKKalpha / beta-NEMO complexes ( Table 2 ) [ 193 ] ."
| DOI
eidos
"The LPS-mediated TLR4 activation in human macrophages upregulates USP18 , which in turn inhibits NF-kappaB activation , and thus the secretion of pro-inflammatory cytokines ( TNF-alpha , IL-6 , and IL-1beta ) via interacting with TAK1-TAB1 and IKKalpha / beta-NEMO complexes ( Table 2 ) [ 193 ] ."
| PMC
reach
"The results indicated that USP18 interacted with TAK1, TAB1, and TAB2 without stimulation and PMA and ion stimulation reduced but did not totally abolish their association, whereas USP18 interacted with CARMA1 weakly in unstimulated cells and PMA and ion stimulation first enhanced their interaction and then resulted in their disassociation (XREF_FIG)."
STAT2 affects Interferon
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2
IFNAR2 binds Interferon, USP18, and STAT2. 1 / 1
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1
USP18 binds Interferon and STAT2. 1 / 1
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1
sparser
"Two siblings with early onset autoinflammatory disease with neurological features and elevated IFN signature were additionally described with a homozygous missense mutation in STAT2 resulting in gain of activity due to the inability of mutant STAT2 to interact with the STAT2-dependent negative regulator of interferon activity, USP18 [ xref ]."
reach
"We observed that OPN silencing significantly (p<0.05) decreased USP18 mRNA levels (
Figure 4F
) in fibrotic stiffness gel-attached HepG2.2.15 cells, whereas rOPN treatment did not increase the USP18 mRNA expression in soft gel-attached HepG2.2.15 cells when compared to IFNα-treated group (
Figure 4G
)."
JAK-STAT affects USP18
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2
Interferon affects STAT2
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2
IFNAR2 binds Interferon, USP18, and STAT2. 1 / 1
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1
USP18 binds Interferon and STAT2. 1 / 1
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1
sparser
"Two siblings with early onset autoinflammatory disease with neurological features and elevated IFN signature were additionally described with a homozygous missense mutation in STAT2 resulting in gain of activity due to the inability of mutant STAT2 to interact with the STAT2-dependent negative regulator of interferon activity, USP18 [ xref ]."
GRL0617 affects USP18
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2
sparser
"Moreover, upstream analysis using ingenuity pathway analysis (IPA) showed that GATA3 modulated the transcription of several innate lymphocyte related genes including activation of CCL5, IL1B, IL-27, IRF7, MAVS, and TNF, whereas GATA3 inhibited BTK, USP18, CNOT7, and SOCS1 ( xref )."
reach
"Moreover, upstream analysis using ingenuity pathway analysis (IPA) showed that GATA3 modulated the transcription of several innate lymphocyte related genes including activation of CCL5, IL1B, IL-27, IRF7, MAVS, and TNF, whereas GATA3 inhibited BTK, USP18, CNOT7, and SOCS1 (Figure 3E)."
E3_Ub_ligase affects USP18
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1
1
E3_Ub_ligase ubiquitinates USP18.
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1
E3_Ub_ligase leads to the ubiquitination of USP18. 1 / 1
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1
E3_Ub_ligase binds USP18.
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1
Dietary Fats affects USP18
2
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DENV-2 affects USP18
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2
CLQ affects USP18
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2
reach
"BMP-6, upregulated in iLCs only after incubation with poly(I:C)-EVs, induces interferon-stimulated genes, down-regulates USP18 (a suppressor of interferon signaling) and induces an immediate exit from the cell cycle in epithelial stem cells, all favorable conditions during viral challenge ."
eidos
"BMP-6 , upregulated in iLCs only after incubation with poly ( I :C ) - EVs , induces interferon-stimulated genes , down-regulates USP18 ( a suppressor of interferon signaling ) and induces an immediate exit from the cell cycle in epithelial stem cells , all favorable conditions during viral challenge33 , 36 ."
(+)-JQ1 compound affects USP18
2
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Testosterone affects USP18
1
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Temozolomide affects USP18
1
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Same doses affects USP18
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1
1
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NciLT affects USP18
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1
reach
"In addition, protumor interferon-stimulated genes ISG15 and IFIT3 (interferon-induced protein with tetratricopeptide repeats 3), and oncoprotein USP18 (Ubiquitin Specific Peptidase 18), which suppresses IFN responses, were also driven by LTβR-nonclassical signaling, downregulated by nciLT, and diminished in NIK-deficient B16F10 cells (Fig. 5a)."
Mitomycin C affects USP18
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1
Mitomycin C activates USP18. 1 / 1
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1
MiR-532-3p affects USP18
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1
Methylation affects USP18
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1
Methylation inhibits USP18. 1 / 1
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1
eidos
"We observed that the decitabine treatment reduced the fraction of cells with prolonged delay times in USP18 induction , which is in part due to earlier USP18 upregulation ( Figure 5 - - figure supplement 4 ) , supporting that the promoter methylation inhibits USP18 induction ( Figure 5D ) ."
Manganese atom affects USP18
1
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Linc-UR-B1 affects USP18
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1
Endotoxin affects USP18
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1
DsDNA90 affects USP18
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1
reach
"Pretreatment with IFNβ led to increased levels of IRF3 activation by dsDNA90 treatment in all cell sublines.IFNβ pretreatment but not dsDNA90 increased USP18 levels in parental FTE-194 cells and UBA7-null cells, but not in ISG15-null cells (Fig. 3), likely reflecting the importance of free ISG15 in stabilizing USP18."
Clone affects USP18
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1
USP18 affects tunicamycin
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1
USP18 inhibits tunicamycin. 1 / 1
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1
USP18 affects susceptibility
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1
USP18 affects rbPept2
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1
reach
"Warsi, et al demonstrated that transport activity of rabbit peptide transporters Pept1 and Pept2 was decreased in Xenopus laevis oocytes injected with cRNA encoding the E3 ubiquitin ligase Nedd4-2, whereas overexpression of USP18 (Ubiquitin like specific protease 18), an enzyme cleaving ubiquitin from target proteins, stimulated the transport activity of rbPept1 and rbPept2 [XREF_BIBR]."
USP18 affects protein is expressed tumor tissues cells
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1
USP18 affects pGL3-1790/+22bp
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1
USP18 affects miR-122
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1
USP18 affects maintain responsiveness cells
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1
USP18 affects innate immune response
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1
USP18 activates innate immune response. 1 / 1
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1
USP18 affects glycolytic process
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1
USP18 inhibits glycolytic process. 1 / 1
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1
USP18 affects gene expression
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1
USP18 activates gene expression. 1 / 1
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1
USP18 affects desensitization IFNalpha signal transduction
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1
USP18 affects degradation
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1
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1
USP18 inhibits Triple Negative Breast Neoplasms. 1 / 1
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1
reach
"Previous studies demonstrated that USP18 plays a significant role in regulating autophagy: USP18 decreased paclitaxol sensitivity of triple-negative breast cancer via promoting autophagy [26]; USP18 overexpression could promote autophagy to inhibit cell apoptosis induced by spinal cord ischemia–reperfusion injury [27]; USP18 stabilizes cGAS through deubiquitination, enhancing autophagy in melanoma cells and thereby promoting resistance to vemurafenib in BRAF V600E mutant melanoma [28]."
USP18 affects RNA biosynthetic process
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1
USP18 inhibits RNA biosynthetic process. 1 / 1
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1
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1
USP18 activates Pulmonary Disease, Chronic Obstructive. 1 / 1
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1
USP18 affects Pseudomonas aeruginosa
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1
USP18 affects PERK-eIF2alpha-ATF4
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1
USP18 affects PAMPs
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1
USP18 affects JAK1-IFNAR2 interaction
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1
USP18 affects IRF1-silenced HUVECs
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1
eidos
"STAT1 , USP18 and IRF1 modulate CXCL10 levels in EC following IFN-alpha stimulation To validate the transcriptional regulations inferred in our multiple-output FFL regulatory subnetwork ( Fig. 2 ) , we measured CXCL10 protein levels in tissue culture media conditioned by STAT1 - , USP18 - , IFIH1 - and IRF1-silenced HUVECs , compared to HUVECs transfected with a scrambled siRNA ( siCTRL ) ."
USP18 affects IFNAR1 recruitment
|
1
USP18 affects IFNA2R
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1
USP18 affects IFN-α/β receptor 2 complex
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1
USP18 affects IFN responsiveness
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1
USP18 affects HOAX10 gene
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1
USP18 affects FTO protein
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1
USP18 affects Communicable Diseases
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1
USP18 activates Communicable Diseases. 1 / 1
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1
Pseudomonas aeruginosa affects USP18
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1
Interferon affects STAT2, and USP18
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1
USP18 binds Interferon and STAT2. 1 / 1
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1
sparser
"Two siblings with early onset autoinflammatory disease with neurological features and elevated IFN signature were additionally described with a homozygous missense mutation in STAT2 resulting in gain of activity due to the inability of mutant STAT2 to interact with the STAT2-dependent negative regulator of interferon activity, USP18 [ xref ]."
Interferon affects IFNAR2
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1
Interferon Type I affects USP18
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1
Interferon Type I activates USP18. 1 / 1
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1
eidos
"b | Intracellular functions : Ubl carboxy-terminal hydrolase 18 ( USP18 ) and S-phase kinase-associated protein 2 ( SKP2 ) : USP18 , which is induced by type I interferons , mediates the negative feedback regulation of interferon signalling independent of its deISGylase activity ."
ILI27 affects USP18
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1
IKK_complex affects USP18
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1
IKBKG affects IKK_complex, and USP18
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1
IFNAR2 affects Interferon, STAT2, and USP18
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1
IFNA2R affects USP18
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1
IFN1 affects USP18
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1
IFN-α/β receptor 2 complex affects USP18
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1
IBB1 affects USP18
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1
E3_Ub_ligase affects UBA7
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1
1,2-dimethylhydrazine affects USP18
1
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3,3',4,4',5-pentachlorobiphenyl affects USP18
1
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