IndraLab
Statements
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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"However, by de-conjugating ISG15, the virus also creates free ISG15, which in turn may affect the immune response in two opposite pathways: free ISG15 negatively regulates IFN signaling in humans by binding non-catalytically to USP18, yet at the same time free ISG15 can be secreted from the cell and induce the IFN pathway of the neighboring cells."
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"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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"This lack of intracellular free ISG15 prevents the accumulation of USP18, a known negative regulator of IFN-alpha and beta, resulting in enhanced IFN-alpha and beta immunity and autoinflammation, resembling Aicardi-Goutieres syndrome and spondyloenchondromatosis [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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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)."
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"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."
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"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."
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"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)."
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"Notably, PBMCs infected with moderate EV-A71 showed a stronger response than the mild and severe isolates, specifically interferon-stimulated gene 15 (ISG15), viperin (RSAD2), ubiquitin specific peptidase 18 (USP18), interferon alpha inducible protein 27 (IFI27), and guanosine monophosphate reductase (GMPR) (Fig. 3c)."
sparser
"Furthermore, Usp18 functions in the type I IFN pathway by down-regulating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway independently of its isopeptidase activity through an interaction between Usp18 and the IFNAR2 subunit of the type I IFN receptor complex, while neither IFNAR1 nor IFNGR1 (type II IFN) receptor subunits were able to interact with Usp18 ( xref )."
Interferon binds STAT2, USP18, and IFNAR2. 1 / 1
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USP18 affects Interferon
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USP18 inhibits Interferon.
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"Influenza B has evolved a mechanism to directly neutralize ISG15 with its NS1 protein 24 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."
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"Given that USP18 suppresses type I IFN signaling and that the mutation in Usp18 Ity9 mice lies within the IFNAR2 binding region of USP18, as well as the importance of type I IFN signaling in bacterial infection, we sought to determine if the IFNAR regulatory function of USP18 is compromised in Usp18 Ity9 mice and whether hyperactivation of type I IFN signaling contributes to the pathogenesis of infection."
USP18 bound to IFNAR2 inhibits Interferon. 2 / 2
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USP18 bound to JAK1 inhibits Interferon. 2 / 2
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USP18 bound to IFNA inhibits Interferon. 1 / 1
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USP18 activates Interferon.
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"ISG15 has also been shown to regulate type I interferon signalling by stabilizing USP18 (ref.4) and by interacting with leucine-rich repeat-containing protein 25 (LRRC25) to mediate the autophagic degradation of retinoic acid-inducible gene I protein (RIG-I; also known as DDX58)41."
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"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)."
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"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, 31Macrophages 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 bound to Interferon activates Interferon. 1 / 1
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USP18 bound to IFN receptor activates Interferon. 1 / 1
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USP18 binds Interferon.
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Interferon binds STAT2 and USP18. 2 / 2
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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 [107]."
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 binds STAT2, USP18, and IFNAR2. 1 / 1
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USP18 increases the amount of Interferon.
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sparser
"Consistent with our suspicion that this might impair the STAT2:USP18 interaction through electrostatic or steric hindrance, co-immunoprecipitation experiments in U6A cells stably expressing WT or STAT2 R148W demonstrated a significant reduction of USP18 pull-down with STAT2 R148W compared to WT ( xref ), providing a molecular mechanism for the USP18 insensitivity of patient cells."
Interferon binds STAT2 and USP18. 2 / 2
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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 [107]."
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 binds STAT2, USP18, and IFNAR2. 1 / 1
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"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."
sparser
"Consistent with our suspicion that this might impair the STAT2:USP18 interaction through electrostatic or steric hindrance, co-immunoprecipitation experiments in U6A cells stably expressing WT or STAT2 R148W demonstrated a significant reduction of USP18 pull-down with STAT2 R148W compared to WT ( xref ), providing a molecular mechanism for the USP18 insensitivity of patient cells."
Interferon binds STAT2 and USP18. 2 / 2
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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 [107]."
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 binds STAT2, USP18, and IFNAR2. 1 / 1
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"The increased expression of dsRNA receptor TLR3 and IFN induced genes ISG56, ISG43, Mx1 and IFIT3 after stimulation with poly I : C mimicking a viral infection indicates that these cell lines can be used as effective in vitro models to study the bat 's innate immune responses to virus infection XREF_BIBR, XREF_BIBR."
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"These IFN system genes include the dsRNA signal sensing factor TLR3, IFN, IFN signal transduction factor STAT1, IFN regulatory factor IRF7, putative IFN antiviral effectors Mx1, Mx2, PKR like, Viperin, IFI56, and other IFN stimulated genes (ISGs) IFI58, ISG15-1, ISG15-2, USP18, Gig1 and Gig2."
Interferon increases the amount of USP18.
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Interferon increases the amount of USP18. 8 / 10
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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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Interferon binds STAT2 and USP18. 2 / 2
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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 [107]."
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 binds STAT2, USP18, and IFNAR2. 1 / 1
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Interferon inhibits USP18.
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"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)."
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"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."
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"Recent work has demonstrated that USP18 has the ability to deubiquitinate the transforming growth factor-activated kinase 1 (TAK1) complexes required for NF-κB activation in T cells and that overexpression of USP18 leads to decreased nuclear activation and impaired formation of TAK1 complexes (47)."
USP18 affects apoptotic process
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USP18 inhibits apoptotic process.
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USP18 activates apoptotic process.
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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."
Lipopolysaccharide affects USP18
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Lipopolysaccharide activates USP18.
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Lipopolysaccharide inhibits USP18.
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"As seen in Fig. 6B, HIRI led to a significant increase in LCMV viral titers in USP18+/+ mice, an effect that was not observed in USP18−/− mice.Having shown that LPS/TNF-α stimulation increases hepatocyte USP18 expression, we then sought to determine whether we could pharmacologically inhibit the induction of USP18 by LPS and TNF-α."
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"Since the UBAN domain of NEMO contains all five K63 linked ubiquitination sites (Lys 285, Lys 321, Lys 325, Lys 326, and Lys 399) XREF_BIBR and two linear ubiquitination sites for NEMO (Lys 285 and Lys 309) XREF_BIBR, USP18 may prevent NEMO ubiquitination by masking these ubiquitination sites through direct binding."
"USP18 negatively regulates NF-κB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms"
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 ]."
eidos
"These data suggest that the induction of USP18 by TNF - and LPS , and pos-sibly other inflammatory stimuli , is promoted by NF - > signaling and that hepatocyte USP18 expression in particular-compared to IL-1 - may be an attractive target for pharmacologic manipulation in the setting of liver inflammation ."
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"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."
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 ."
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"These data suggest that the induction of USP18 by TNF-α and LPS, and possibly other inflammatory stimuli, is promoted by NF-κΒ signaling and that hepatocyte USP18 expression in particular—compared to IL-1β—may be an attractive target for pharmacologic manipulation in the setting of liver inflammation.In this study we examined the role of various inflammatory stimuli in the induction of USP18 and the downstream establishment of an IFN-α refractory state."
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"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 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
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"Thus, the induction of ISGs by LPS and TNF-α is very unlikely to reflect the induction of hepatocyte type 1 or type 2 IFN, which suggests that the observed USP18 induction is not due to type 1 or type 2 IFN secretion and autocrine stimulation of the IFN-α receptor.We then assessed whether tissue-wide hepatic inflammatory stress increases liver USP18 expression, as an in vivo confirmation of our in vitro findings."
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."
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"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)."
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"The IFN-α signal-blocking activity of USP18 is mediated by the binding of USP18 to the intracellular domain of IFNAR2, which prevents the binding of JAK1 to IFNAR227.Our group recently found that prolonged stimulation of IFN-λ3 induces the robust and sustained upregulation of ISG15 that stabilizes the USP18 protein and causes the unresponsiveness to exogenous IFN-α treatment10."
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 cell population proliferation
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USP18 activates cell population proliferation.
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"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."
USP18 inhibits cell population proliferation.
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"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."
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"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."
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"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)."
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"After 24 h, genomic DNA was collected and a qPCR assay developed to measure integrated proviral genomes showed that there were on average 3800 genomes per 10,000 cells in USP18 +/+ iMacs and on average 4900F I G U R E 4 siRNA knockdown of USP18 enhances STAT activation and expression of ISGs in IFN--treated MDMs.MDMs from 6 donors were transfected with nontargeting (NT) control or USP18 siRNA for 3 h followed by IFN-treatment for 18 h. (A) Expression of p-STAT1, p-STAT2, and USP18 was measured by Western blot."
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"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)."
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
"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)."
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 JAK-STAT
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USP18 inhibits JAK-STAT.
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"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."
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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"In the initial experiments demonstrating IFN desensitization, ISGF3 gel shift assays and STAT1 phosphorylation levels indicated that the presence of IFN-β failed to result in prolonged JAK-STAT signaling in USP18-expressing cells; in contrast, signaling was maintained in Usp18 −/− cells (105) ."
USP18 affects ubiquitination
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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."
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."
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."
rlimsp
"We used antibodies against STAT2 (EMD Millipore), phosphorylated Tyr689 STAT2 (EMD Millipore), USP18 (Cell Signaling Technology), β-tubulin (Takara Bio Inc.), ISG15 (gift from E.C. Borden, Cleveland Clinic, Cleveland, OH), IFIT1 (gift from G. Sen, Cleveland Clinic, Cleveland, OH), and Mx1 (MxA; gift from O. Haller, University of Freiburg, Freiburg, Germany)."
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."
USP18 affects cell growth
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USP18 activates cell growth.
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USP18 inhibits cell growth.
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USP18 affects IFN receptor
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USP18 inhibits IFN receptor.
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"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."
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"Whereas ISG15 conjugation has been widely recognized to act antivirally13, unconjugated ISG15 serves a proviral role by promoting USP18 mediated suppression of type I IFN receptor (IFNAR) signaling14, 15, 16; 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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USP18 activates IFN receptor.
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USP18 affects signaling
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"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."
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"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."
USP18 affects IFN-I
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USP18 inhibits IFN-I.
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"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."
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"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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"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)."
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
"2 In addition, USP18 has been found to inhibit TRAIL-induced apoptosis independently of the deISGylation pathway.91 Furthermore, the depletion of USP18 leads to a strong increase in the levels and activity of miR-7, and this activity in turn decreases the expression of EGFR, leading to apoptosis and control of cancer cells.92Hong et al.93 found that IFN-γ can induce USP18 in tumor cells and that this protein plays an important role in inhibiting tumorigenesis and maintaining antitumor immunity."
USP18 affects signal transduction
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USP18 activates signal transduction.
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USP18 activates signal transduction. 5 / 5
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"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)."
USP18 inhibits signal transduction.
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USP18 affects cell cycle
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USP18 activates cell cycle.
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USP18 inhibits cell cycle.
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"CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages.The IFN-stimulated gene ubiquitin-specific proteinase 18 (USP18) encodes a protein that negatively regulates T1 IFN signaling via stearic inhibition of JAK1 recruitment to the IFN-receptor 2 subunit (IFNAR2)."
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"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."
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"CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV‐1 infection in macrophages.It is well established that type I IFNs (T1 IFNs) can restrict acute HIV‐1 infection in vitro.1, 2, 3, 4, 5 In clinical trials treating human patients with recombinant IFN‐α2a, T1 IFNs can suppress viral replication in the absence of antiretroviral therapy (ART) in some patients.6, 7 However, this approach failed in long‐term treatment when study subjects became refractory to IFN treatment and viral loads returned to previous levels."
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"ISG15 has also been shown to regulate type I interferon signalling by stabilizing USP18 (ref.4) and by interacting with leucine-rich repeat-containing protein 25 (LRRC25) to mediate the autophagic degradation of retinoic acid-inducible gene I protein (RIG-I; also known as DDX58)41."
USP18 affects Neoplasm Metastasis
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USP18 activates Neoplasm Metastasis.
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USP18 inhibits Neoplasm Metastasis.
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"Lacking of USP18 leads to an increase signaling of IFN-I, IFN-III, TNF-α and high levels of conjugated ISG15Figure 3: Role of USP18-dependent enforced viral replication in activation of the adaptive immune system and onset of diabetes mellitus type I. (a) USP18 inhibits IFNAR signaling, which leads to enforced viral replication in CD169+ macrophages."
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"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."
USP18 affects inflammatory response
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USP18 affects activation
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USP18 affects Neoplasm Invasiveness
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USP18 inhibits Neoplasm Invasiveness.
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USP18 activates Neoplasm Invasiveness.
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USP18 activates Neoplasm Invasiveness. 3 / 3
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"At necropsy 6 weeks post-infection, Usp18 Ity9 mutant mice showed large infected foci with extensive necrotic centre and increased lymphohistiocytic inflammatory cell infiltration in the lung compared to littermate control mice with a greater percentage of the lung affected by inflammation (XREF_SUPPLEMENTARY, left and middle panels)."
USP18 affects Infections
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USP18 inhibits Infections.
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USP18 inhibits Infections. 4 / 4
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"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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USP18 affects ISG
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USP18 increases the amount of ISG.
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"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."
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"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) [41]."
USP18 decreases the amount of ISG.
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"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."
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"(b) In case of enforced viral replication in dendritic cells of a virus resembling an autoantigen, autoreactive CD8 + T cells will be primed, which leads to autoimmune diseases such as type I diabetes, whereas USP18 deficiency reduces the priming of autoreactive CD8 + T cells and onset of autoimmune diabetes owing to inhibition of enforced viral replication Functions of USP18 N Honke et al recognized as essential player for the development of MS."
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"Further temporal regulation of the ISG15 system by expression of the type I IFN-induced cellular deconjugase (human Usp18/mouse Ubp43), as well the role of free intracellular ISG15 in downregulating signaling at the type I IFN receptor in human cells, remains to be explored.We have shown that ISG15 is secreted from both lymphocytes and epithelial cells, suggesting that the ISG15 secretion mechanism is operational in a wide range of cell types."
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"The cloning of USP18 was also independently reported by 3 other groups in various species, and all confirmed the induction of USP18 by Type 1 IFN (Zhang and others 1999; Li and others 2000; Kang and others 2001) , consistent with the finding of highly conserved ISREs in the UBP43 promoter (Malakhova and others 2002) ."
IFN-I affects USP18
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IFN-I increases the amount of USP18.
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"Further studies show that the expression of USP18 by beta islet cells themselves is important for inhibiting diabetes.75, 76 On the one hand, the upregulation of USP18 expression by IFN-I in beta islet cells prevents the activity of proinflammatory chemokines such as CCL5, CXCL10, and IL-15 and consequently inhibits insulitis."
IFN-I inhibits USP18.
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IFN-I activates USP18.
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HIRI affects USP18
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"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."
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"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."
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2,3,7,8-tetrachlorodibenzodioxine increases the amount of USP18.
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2,3,7,8-tetrachlorodibenzodioxine decreases the amount of USP18.
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Input affects USP18
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"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 ."
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"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 ."
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"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]."
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"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."
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"53 In addition to ISG15, USP18 also specifically inhibits K63-linked ubiquitination of NEMO, leading to the negative regulation of NF-κB activation induced by the TAK1-TAB complex.16, 23 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.54The innate immune system reduces viral replication via IFN-I; this reduction is essential for inhibiting the spread of virus to other organs."
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"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 ."
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 ) ."
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"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 ) ."
Infections affects USP18
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Infections increases the amount of USP18.
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Infections activates USP18.
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All-trans-retinoic acid affects USP18
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All-trans-retinoic acid increases the amount of USP18.
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All-trans-retinoic acid decreases the amount of USP18.
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"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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"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."
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USP18 affects isopeptidase
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USP18 affects activity
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USP18 activates USP18.
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"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."
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"Usp18 (-/-) BM cells were rescued by exogenous expression of either wild-type or deconjugation-inactive Usp18, and superimposition of an IFN-alpha and beta receptor knockout returned in vivo DC populations to normal, clearly showing that the defect seen is due solely to Usp18 's effect on IFN signaling."
USP18 inhibits USP18.
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USP18 affects UBL
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"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."
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"53 In addition to ISG15, USP18 also specifically inhibits K63-linked ubiquitination of NEMO, leading to the negative regulation of NF-κB activation induced by the TAK1-TAB complex.16, 23 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.54The innate immune system reduces viral replication via IFN-I; this reduction is essential for inhibiting the spread of virus to other organs."
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"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."
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"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."
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"53 In addition to ISG15, USP18 also specifically inhibits K63-linked ubiquitination of NEMO, leading to the negative regulation of NF-κB activation induced by the TAK1-TAB complex.16, 23 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.54The innate immune system reduces viral replication via IFN-I; this reduction is essential for inhibiting the spread of virus to other organs."
USP18 affects PC
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USP18 affects IKK_complex
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USP18 dephosphorylates IKK_complex.
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USP18 leads to the dephosphorylation of IKK_complex. 2 / 2
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"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 phosphorylates IKK_complex.
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USP18 leads to the phosphorylation of IKK_complex. 1 / 1
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USP18 binds IKK_complex.
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USP18 affects IFN-lambda
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"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."
UBL affects USP18
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"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."
IFN-λ4 affects USP18
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IFN-λ4 inhibits USP18.
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"Moreover, we identified ISG15 as a critical regulator for increased USP18 protein levels in IFN-λ4-expressing or -treated cells and demonstrated for the first time that DAAs can restore IFN-α responsiveness by decreasing the production of endogenous IFN-λs, including IFN-λ4, in HCV-infected cells.Taken together, our data clearly demonstrate that virus-induced IFN-λ4 potently blocked IFN-α signalling via upregulation of ISG15 and USP18 in HCV infection and that DAA therapy restored the IFN-α responsiveness The cells were harvested, and protein expression was analysed by immunoblotting."
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"Moreover, we identified ISG15 as a critical regulator for increased USP18 protein levels in IFN-λ4-expressing or -treated cells and demonstrated for the first time that DAAs can restore IFN-α responsiveness by decreasing the production of endogenous IFN-λs, including IFN-λ4, in HCV-infected cells.Taken together, our data clearly demonstrate that virus-induced IFN-λ4 potently blocked IFN-α signalling via upregulation of ISG15 and USP18 in HCV infection and that DAA therapy restored the IFN-α responsiveness of HCV-infected cells."
IFN-λ4 decreases the amount of USP18.
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Viral process affects USP18
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Type I IFNs affects USP18
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Inflammatory affects USP18
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USP18 affects interaction
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"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 ."
USP18 affects immune response
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USP18 affects defense response to virus
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USP18 activates defense response to virus. 3 / 3
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"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."
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"The average RQ of the USP18 −/− clones divided by the average RQ of the USP18 +/+ clones are expressed as fold change The strategy used by HIV-1 for transcription from its LTR promoter utilizes transcription factors such as NF B, 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 cellular senescence
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USP18 affects cell differentiation
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USP18 affects breast cancer growth
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"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]."
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"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 (USP18C61A/C61A) are healthy and display a normal lifespan [27]."
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"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 Pancreatic Neoplasms
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"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."
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"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 ISGs
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USP18 affects Cell Survival
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"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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Interferon binds STAT2 and USP18. 2 / 2
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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 [107]."
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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 binds STAT2, USP18, and IFNAR2. 1 / 1
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"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)."
17beta-estradiol affects USP18
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Valproic acid affects USP18
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Type-III IFNs affects USP18
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Titanium dioxide affects USP18
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Same doses affects USP18
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Progesterone affects USP18
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Plasmid transfection affects USP18
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Pentachlorophenol affects USP18
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MiR-191-5p affects USP18
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Bisphenol A affects USP18
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Bis(2-ethylhexyl) phthalate affects USP18
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Affinity IFNAR1 affects USP18
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USP18 affects translation
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USP18 affects transforming growth factor-beta-activated kinase TAK1
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USP18 affects transcription, DNA-templated
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USP18 affects signaling independent enzymatic
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"These results are consistent with there being no role for ISGylation ( and , thus , for the ability of USP18 to strip ISG15 from its protein conjugates ) in the ability of TNF-alpha and LPS to block type 1 IFN signaling in hepatocytes , and this finding is in agreement with previous data showing that USP18 blocks IFN signaling independent of its enzymatic activity ( 15 ) ."
eidos
"These results are consistent with there being no role for ISGylation ( and , thus , for the ability of USP18 to strip ISG15 from its protein conjugates ) in the ability of TNF - and LPS to block type 1 IFN signaling in hepatocytes , and this finding is in agreement with previous data showing that USP18 blocks IFN signaling independent of its enzymatic activity ( 15 ) ."
USP18 affects responses
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USP18 affects response
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USP18 affects reactive oxygen species
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USP18 inhibits reactive oxygen species. 2 / 2
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"Interestingly , USP18 inhibition promotes the antibacterial effect of TNFalpha and subsequently induces reactive oxygen species ( ROS ) , thereby controlling primary and secondary bacterial infection , which suggests the therapeutic potential of targeting USP18 in patients to ameliorate disease caused by serious bacterial infections ."
USP18 affects phosphorylation
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USP18 affects phosphorylated STAT1
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USP18 affects pSTAT1
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USP18 affects negative regulatory signaling
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"USP18 was shown to bind to IFNAR2 and attenuate the JAK-STAT pathway , thereby negatively regulating IFN signaling ( Table 1 ) .223 Reduced USP18 expression results in increased antiviral activity against many viruses , such as SINV , hepatitis B virus and VSV , in USP18 knockout mice.218 ,223,224,225 USP18 knockdown is concomitant with increased cellular protein ISGylation , prolonged STAT1 tyrosine phosphorylation and enhanced ISG expression , thus greatly enhancing the anti-HCV potency of IFN.226 All these studies suggest that USP18 disruption can impede its negative regulatory effect on IFN signaling , resulting in sustained JAK-STAT activity and antiviral activity ."
USP18 affects migration ovarian cancer cells
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USP18 affects lipid catabolic process
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USP18 affects in-membrane dissociation ternary complex
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"USP18 effectively increases the in-membrane dissociation of ternary complex , and the much weaker receptor binding strength of IFNalpha2 as compared to IFNbeta leads to a greater inhibitory effect on the IFNalpha2 response , thus generating a difference in the pSTATmax between these IFNs ( Section Long Time Deactivation via USP18 Regulates Receptor Complex Stability to Achieve Absolute Discrimination ) ."
eidos
"USP18 effectively increases the in-membrane dissociation of ternary complex , and the much weaker receptor binding strength of IFNa2 as compared to IFNb leads to a greater inhibitory effect on the IFNa2 response , thus generating a difference in the pSTAT max between these IFNs ( Section Long Time Deactivation via USP18 Regulates Receptor Complex Stability to Achieve Absolute Discrimination ) ."
USP18 affects deconjugation USP15 target proteins
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USP18 affects conjugation
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USP18 inhibits conjugation. 2 / 2
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USP18 affects cell death
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USP18 affects antiviral agent
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USP18 inhibits antiviral agent. 2 / 2
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eidos
"USP18 was shown to bind to IFNAR2 and attenuate the JAK-STAT pathway , thereby negatively regulating IFN signaling ( Table 1 ) .223 Reduced USP18 expression results in increased antiviral activity against many viruses , such as SINV , hepatitis B virus and VSV , in USP18 knockout mice.218 ,223,224,225 USP18 knockdown is concomitant with increased cellular protein ISGylation , prolonged STAT1 tyrosine phosphorylation and enhanced ISG expression , thus greatly enhancing the anti-HCV potency of IFN.226 All these studies suggest that USP18 disruption can impede its negative regulatory effect on IFN signaling , resulting in sustained JAK-STAT activity and antiviral activity ."
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"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."
USP18 affects TAK1-TAB1
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"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 Refractory
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USP18 affects PyVmT
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USP18 affects LPS-induced sepsis
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USP18 affects IFNs
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"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 IFNLR
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USP18 affects Hepatitis C
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USP18 affects DENV-2
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"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."
reach
"Further studies show that the expression of USP18 by beta islet cells themselves is important for inhibiting diabetes.75, 76 On the one hand, the upregulation of USP18 expression by IFN-I in beta islet cells prevents the activity of proinflammatory chemokines such as CCL5, CXCL10, and IL-15 and consequently inhibits insulitis."
USP18 affects Arg151
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USP18 affects 1-phenylethanol
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USP18 inhibits 1-phenylethanol. 2 / 2
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TLR4 activation human macrophages affects USP18
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"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 ] ."
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"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)."
Reperfusion Injury affects USP18
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LPS with O-antigen affects USP18
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JAK-STAT affects USP18
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Interferon affects STAT2, and USP18
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Interferon binds STAT2 and USP18. 2 / 2
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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 [107]."
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 ]."
ISG15 affects Arg151
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IFNs affects USP18
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IFNalpha/beta affects USP18
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IFN receptor affects USP18
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GRL0617 affects USP18
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"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 )."
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"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)."
Fig. affects USP18
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Experimental hepatic ischemia affects USP18
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Dietary Fats affects USP18
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DENV-2 affects USP18
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CLQ affects USP18
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"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 ."
Arg151 affects USP18
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Tumor necrosis alpha affects USP18
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Toluene 2,4-diisocyanate affects USP18
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Tetraphene affects USP18
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Specific interference RNA affects USP18
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Recombinant IFN-lambda4 protein affects USP18
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PolyI :C affects USP18
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Phenformin affects USP18
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Phage cell line affects USP18
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MiR-532-3p affects USP18
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Methylation affects USP18
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Methylation inhibits USP18. 1 / 1
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"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
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Magnetite nanoparticle affects USP18
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Linc-UR-B1 affects USP18
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Linc-DGCR6-1 affects USP18
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IncobotulinumtoxinA affects USP18
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Hsa-miR-215-5p affects USP18
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Fumonisin B1 affects USP18
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Endotoxin affects USP18
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EIFNlambda4 affects USP18
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DsRNA affects USP18
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Copper(II) sulfate affects USP18
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Cobalt dichloride affects USP18
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Clustered interspaced palindromic repeats affects USP18
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Clone affects USP18
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Clofibrate affects USP18
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Carbon nanotube affects USP18
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Candesartan affects USP18
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Candesartan activates USP18. 1 / 1
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XBP affects USP18
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USP18 affects white matter microglia
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USP18 affects susceptibility
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USP18 affects supernatant Figure 4C
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USP18 affects signal transmission
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USP18 affects resistance Hepatitis C Virus
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USP18 affects replication
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eidos
"The over-expression of porcine ubiquitin specific protease 18 ( USP18 ) is reported to reduce the in-vitro PRRSV replication by altering the cellular distribution of two subunits of NFkB heterodimers ( p56 and p50 ) ; [ 60 ] which indicates the role of USP18 as a host restriction factor during innate immune response to PRRSV ."
USP18 affects regulation IFN-I
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USP18 affects rbPept2
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"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 rbPept1
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"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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USP18 affects polyubiquitination
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"The changes in TLR3 and IRF7 would predict increased responses to poly(I:C) when conditioned with IFNβ, but expression of USP18, a key negative regulator of IFNAR was also dramatically increased, perhaps mitigating the poly(I:C) response.The effect of IFNγ conditioning on IRF and ISGF3 signaling was particularly striking."
USP18 affects phosphorylated AKT p-AKT p-mTOR protein
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USP18 affects pathogenesis
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USP18 inhibits pathogenesis. 1 / 1
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USP18 affects pancreatic tumour growth
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USP18 affects osteopenia
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USP18 affects oncogenic NF-kappaB
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USP18 affects miR-24-3p
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USP18 affects miR-122
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USP18 affects master thermoregulator
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USP18 affects maintain responsiveness cells
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USP18 affects lung tumorigenesis
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USP18 affects interferonopathy resulting perinatal death brain malformations
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USP18 affects interferon response
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USP18 affects infection.Figure 2
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USP18 affects growth PC cells
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eidos
"c-Myc is crucial for USP18-mediated pancreatic cancer progression To further validate that USP18 mediated the growth of PC cells by regulating c-Myc , we first increased the expression of c-Myc in USP18 knockdown PC cells and then measured the USP18 and c-Myc protein expression levels and cell proliferation ."
USP18 affects genotoxic stress
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USP18 affects gene expression
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USP18 activates gene expression. 1 / 1
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USP18 affects fatty acid oxidation
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USP18 activates fatty acid oxidation. 1 / 1
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USP18 affects emergence absolute discrimination
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eidos
"Most importantly , this differential effect of USP18 increases the separation in pSTATmax values between the two interferons and leads to the emergence of a region of absolute discrimination , which is expected to be apparent at long times ( 10-48 hours ) when sufficient USP18 has accumulated in the cell ."
USP18 affects differential-IFN-α
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USP18 affects desensitization
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USP18 affects desensitization IFNalpha signal transduction
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USP18 affects degradation
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USP18 affects cell sensitivity IFN-a
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USP18 affects cell migration
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USP18 inhibits cell migration. 1 / 1
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USP18 affects c-Myc mRNA
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USP18 affects antiviral mechanism
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USP18 affects acute promyelocytic leukaemia cell growth
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reach
"Because USP18 deficiency potentiated activation of molecules such as IKK, JNK, and NFAT distal from TCR, but not TCR proximal signaling complex ZAP70 or PLC-gamma, we reasoned that USP18 might target some key molecules in between the proximal and distal signaling complexes, of which TAK1 is a promising candidate."
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USP18 inhibits Triple Negative Breast Neoplasms. 1 / 1
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USP18 affects Th17
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USP18 affects Th17 cell differentiation
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"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-TAB1 complex [ 61 ] and USP25 has been regarded as a negative regulator of IL-17-mediated inflammation via TRAF5 and TRAF6 deubiquitination [ 62 ] ."
USP18 affects TAK1-TAB complexes
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USP18 affects T cell
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eidos
"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-TAB1 complex [ 61 ] and USP25 has been regarded as a negative regulator of IL-17-mediated inflammation via TRAF5 and TRAF6 deubiquitination [ 62 ] ."
USP18 affects SARS-CoV-2
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USP18 inhibits SARS-CoV-2. 1 / 1
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USP18 affects Reperfusion Injury
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USP18 inhibits Reperfusion Injury. 1 / 1
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USP18 affects PC cell growth
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USP18 affects PAMPs
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USP18 affects MHC I
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USP18 affects JAK1-IFNAR2 interaction
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USP18 affects ISG induction
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USP18 affects ISG induction anti-HCV IFN-alpha
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USP18 affects IRF1-silenced HUVECs
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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
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USP18 affects IFNA2R
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USP18 affects IFN-alpha refractory
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USP18 affects IFN responsiveness
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USP18 affects GBM cell invasion
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USP18 affects FTO protein
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1
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 E3_Ub_ligase
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USP18 affects Deconjugation
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USP18 affects DENV resistance IFN-alpha
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Treatment Huh7.5 cells TNF LPS affects USP18
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1
LPS treatment murine macrophage cell line affects USP18
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1
LC3II affects USP18
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Interferon affects IFNAR2
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Interferon Type I affects USP18
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Interferon Type I activates USP18. 1 / 1
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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 ."
IKK_complex affects USP18
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IKBKG affects IKK_complex, and USP18
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IFNAR2 affects Interferon, STAT2, and USP18
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IFNA2R affects USP18
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HIV-1 tunes affects USP18
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FIP related reasons affects USP18
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E3_Ub_ligase affects USP18
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CRISPR Cas9 editing affects USP18
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3-isobutyl-1-methyl-7H-xanthine affects USP18
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3,3',4,4',5-pentachlorobiphenyl affects USP18
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