IndraLab

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ISG15 affects USP18
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ISG15 binds USP18.
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USP18 binds ISG15. 10 / 181
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"Finally,Structure of free and ISG15-bound USP18 (A) Overall structure of USP18 (pdb code 5cht) showing the three-domain architecture with finger, thumb and palm domains."
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No evidence text available
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"Since the interaction surfaces in the USP18–ISG15 complex are well conserved between human and murine proteins, we tested whether the ISG15-PA active site probes label USP18 across species."
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"There are two USP18–ISG15 complexes in the asymmetric unit."
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"In both molecules of unbound USP18 the imidazole of His314 is slightly shifted away from Cys61 weakening the interaction of the two side chains.Figure 2: (a) Structural alignment of both USP18–ISG15 complexes present in the asymmetric unit."
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"Therefore, the α-helix must unwind and the loop needs to change its conformation to allow for ISG15 binding.Finally, the catalytic triad in ISG15-bound USP18 is formed by small movements of all three residues (His314, Asn331, Cys61) involved (Fig. 1b-d)."
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"For the structure of the USP18–ISG15 complex the structures of unbound USP18 and murine ISG15 were used as search model in molecular replacement trials with Phaser."
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"(a) Structure of the USP18-ISG15 complex."
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"As such, the USP18:ISG15 interaction is a potentially attractive target for small molecule-based short-term treatments to boost endogenous IFN activity."
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"In human cells, binding of ISG15 to USP18 increases USP18 levels by preventing its degradation [29] , further reinforcing the inhibition of IFN receptor signaling."
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USP18 binds ISG15 and UBL. 4 / 4
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"Structural data demonstrated that only the ISG15 C-terminal but not the N-terminal UBL domain binds USP18."
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"The crystal structure of mouse USP18 in complex with mouse ISG15 displayed extensive interaction between the ISG15 C-terminal Ubl domain and the palm and thumb domain of USP18 (Basters et al., 2017)."
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"However, only the C-terminal Ubl domain of ISG15 interacts with USP18 whereas no interaction between the N-terminal Ubl domain and USP18 was detected and the presence of the N-terminal domain of ISG15 is dispensable for the deISGylation activity of USP18."
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"The crystal structure of mouse USP18 in complex with mouse ISG15 displayed extensive interaction between the ISG15 C-terminal Ubl domain and the palm and thumb domain of USP18 (Basters et al., xref )."
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USP18 binds ISG15 and Arg151. 2 / 2
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"A structural overlay of unbound USP18 and the USP18–ISG15 complex reveals that residues Arg151 and Arg153 of the LRLRGG motif clash with this short α-helix of unbound USP18 (Fig. 3b)."
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"A structural overlay of unbound USP18 and the USP18 and ISG15 complex reveals that residues Arg151 and Arg153 of the LRLRGG motif clash with this short alpha-helix of unbound USP18 (XREF_FIG)."
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FASLG binds USP18 and ISG15. 1 / 1
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"To confirm that the expected complex between ISG15 and UBP43 formed in APL cells, NB4-S1 cell lysates were immunoprecipitated with an anti-HA antibody, before immunoblotting independently with an anti-HA or the anti-UBP43-1 antibody."
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UBA7 binds USP18 and ISG15. 1 / 1
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"Interactions between UBE1L-ISG15-UBP43 pathway members may prove important."
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USP18 binds ISG15 and 129-135. 1 / 1
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"In ISG15 bound USP18, residues 129-135 of the thumb domain form an extended loop."
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USP18 binds RSAD2 and ISG15. 1 / 1
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"IRF7 was the main regulator that changed in both the liver and kidney and was found to interact with other target genes such as USP18, RSAD2, and ISG15."
| PMC
ISG15 activates USP18.
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ISG15 activates USP18. 10 / 18
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"Decreasing ISGylation by knockdown of the ISG15 E1 enzyme, Ube1L, in primary USP18(+/+) and USP18(−/−) hepatocytes led to increased MHV-3 replication."
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"USP18 exerts a negative regulatory effect on type I interferon signalling by competing with JAK1 for IFNAR2 binding, and mutations in USP18 and ISG15, which directly regulates USP18 stability, result in aberrant type I interferon induction in humans ."
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"ISG15 prevents the degradation of USP18 by sphingosine kinase 2 (SPK2) [XREF_BIBR, XREF_BIBR]."
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"Recently, we found that prolonged exposure to IFN-λ up-regulates U-ISGF3 and U-ISGs, including ISG15, and that ISG15 causes the refractoriness to exogenous IFN-α treatment by stabilizing USP18 protein [60]."
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"ISG15 silencing decreased the amount of USP18 protein in recombinant IFN-lambda4-treated cells, and the protein level of USP18 was restored not only by transfection of wild type (WT) ISG15 gene but also by transfection of conjugation defective ISG15 AA mutant gene."
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"Stronger association of human USP18 and ISG15 enhances the stability of USP18, prolonging this inhibitory effect in humans, but not in mice."
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"Indeed, individuals lacking ISG15 expressed lower levels of Ubl carboxy-terminal hydrolase 18 (USP18), which was rescued by complementation with either wild-type or a non-conjugatable form of ISG15 (ref."
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"Interestingly, Speer et al. have demonstrated that ISG15-mediated USP18 stabilization occurs in humans but not mice, and mice can regulate the IFN response in the absence of ISG15."
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"Moreover, we confirm that ISG15 promotes USP18 accumulation independently of conjugation 8."
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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."
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ISG15 inhibits USP18.
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ISG15 inhibits USP18. 10 / 14
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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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"In a follow-up report, Zhang et al. show that the absence of intracellular ISG15 in patients ' cells also prevents the accumulation of USP18, a potent negative regulator of type I IFN [XREF_BIBR]."
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"We further show that an absence of intracellular ISG15 in the patients ' cells prevents the accumulation of USP18 XREF_BIBR, XREF_BIBR, a potent negative regulator of IFN-alpha and beta signalling, resulting in the enhancement and amplification of IFN-alpha and beta responses."
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"Recently, human ISG15 deficiency was found to cause a decrease in USP18 accumulation and this was hypothesized to cause the loss of negative feedback of type I interferon signaling in these patients leading to auto-inflammation [XREF_BIBR]."
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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
eidos
"In turn , ISG15 prevents USP18 from being degraded by the proteasome ."
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"ISG15 prevents degradation of IFNAR’s negative regulator USP18, and as a result, type I IFN signaling is strongly enhanced in the absence of ISG15 (119, 120)."
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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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"We therefore analysed the impact of ISG15 on SKP2 mediated USP18 degradation."
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"The authors also showed that intracellular ISG15 deficiency prevented ubiquitin specific peptidase 18 (USP18) accumulation."
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ISG15 inhibits USP18-I60N. 1 / 1
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"However, this is unlikely since ISG15 abrogates a complex of SKP2 and USP18 I60N, this latter unable to bind ISG15."
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ISG15 decreases the amount of USP18.
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ISG15 decreases the amount of USP18. 3 / 3
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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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"These data indicate that intracellular free ISG15 downregulates the IFN-alpha and beta response by maintaining levels of the negative-feedback regulator USP18."
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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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Modified ISG15 decreases the amount of USP18. 2 / 2
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"As expected from the previous study 10, silencing ISG15 expression decreased the protein level of USP18 in IFN-lambda4-transfected cells."
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"As expected from the previous study10, silencing ISG15 expression decreased the protein level of USP18 in IFN-λ4-transfected cells (Fig. 5C)."
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ISG15 increases the amount of USP18.
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ISG15 increases the amount of USP18. 3 / 3
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"Here we studied the role of ISG15-specific ubiquitin-like protease 43 (USP18) in HIV-1 innate immune sensing.HIV-1 infection induces the expression of USP18 in PMA-differentiated THP-1 cells."
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"ISG15 silencing decreased the amount of USP18 protein in recombinant IFN-λ4-treated cells, and the protein level of USP18 was restored not only by transfection of wild type (WT) ISG15 gene but also by transfection of conjugation-defective ISG15 AA mutant gene (Supplementary Fig. 8A)."
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"ISG15 silencing decreased the amount of USP18 protein in recombinant IFN-lambda4-treated cells, and the protein level of USP18 was restored not only by transfection of wild type (WT) ISG15 gene but also by transfection of conjugation defective ISG15 AA mutant gene."
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Modified ISG15 increases the amount of USP18. 1 / 1
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"As expected from the previous study10, silencing ISG15 expression decreased the protein level of USP18 in IFN-λ4-transfected cells (Fig. 5C)."
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ISG15 deubiquitinates USP18.
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ISG15 leads to the deubiquitination of USP18. 2 / 2
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"The non-covalent interactions of ISG15 and USP18 prevent the ubiquitination of USP18 by S-phase kinase-associated protein two and stabilize the downregulation of the IFN signaling pathway by USP18 (Tokarz et al., 2004; Zhang et al., 2015)."
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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."
25307056
USP18 affects ISG15
3 1 1 | 99 116
USP18 binds ISG15.
3 1 | 71 116
USP18 binds ISG15. 10 / 181
3 1 | 68 109
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"Finally,Structure of free and ISG15-bound USP18 (A) Overall structure of USP18 (pdb code 5cht) showing the three-domain architecture with finger, thumb and palm domains."
30126853
biogrid
No evidence text available
25307056
reach
"Since the interaction surfaces in the USP18–ISG15 complex are well conserved between human and murine proteins, we tested whether the ISG15-PA active site probes label USP18 across species."
28165509
sparser
"There are two USP18–ISG15 complexes in the asymmetric unit."
28165509
reach
"In both molecules of unbound USP18 the imidazole of His314 is slightly shifted away from Cys61 weakening the interaction of the two side chains.Figure 2: (a) Structural alignment of both USP18–ISG15 complexes present in the asymmetric unit."
28165509
reach
"Therefore, the α-helix must unwind and the loop needs to change its conformation to allow for ISG15 binding.Finally, the catalytic triad in ISG15-bound USP18 is formed by small movements of all three residues (His314, Asn331, Cys61) involved (Fig. 1b-d)."
28165509
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"For the structure of the USP18–ISG15 complex the structures of unbound USP18 and murine ISG15 were used as search model in molecular replacement trials with Phaser."
28165509
reach
"(a) Structure of the USP18-ISG15 complex."
28165509
sparser
"As such, the USP18:ISG15 interaction is a potentially attractive target for small molecule-based short-term treatments to boost endogenous IFN activity."
27193971
reach
"In human cells, binding of ISG15 to USP18 increases USP18 levels by preventing its degradation [29] , further reinforcing the inhibition of IFN receptor signaling."
30890331
USP18 binds ISG15 and UBL. 4 / 4
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"Structural data demonstrated that only the ISG15 C-terminal but not the N-terminal UBL domain binds USP18."
32039148
sparser
"The crystal structure of mouse USP18 in complex with mouse ISG15 displayed extensive interaction between the ISG15 C-terminal Ubl domain and the palm and thumb domain of USP18 (Basters et al., 2017)."
32039148
sparser
"However, only the C-terminal Ubl domain of ISG15 interacts with USP18 whereas no interaction between the N-terminal Ubl domain and USP18 was detected and the presence of the N-terminal domain of ISG15 is dispensable for the deISGylation activity of USP18."
30126853
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"The crystal structure of mouse USP18 in complex with mouse ISG15 displayed extensive interaction between the ISG15 C-terminal Ubl domain and the palm and thumb domain of USP18 (Basters et al., xref )."
32039148
USP18 binds ISG15 and Arg151. 2 / 2
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"A structural overlay of unbound USP18 and the USP18–ISG15 complex reveals that residues Arg151 and Arg153 of the LRLRGG motif clash with this short α-helix of unbound USP18 (Fig. 3b)."
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"A structural overlay of unbound USP18 and the USP18 and ISG15 complex reveals that residues Arg151 and Arg153 of the LRLRGG motif clash with this short alpha-helix of unbound USP18 (XREF_FIG)."
28165509
FASLG binds USP18 and ISG15. 1 / 1
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"To confirm that the expected complex between ISG15 and UBP43 formed in APL cells, NB4-S1 cell lysates were immunoprecipitated with an anti-HA antibody, before immunoblotting independently with an anti-HA or the anti-UBP43-1 antibody."
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UBA7 binds USP18 and ISG15. 1 / 1
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"Interactions between UBE1L-ISG15-UBP43 pathway members may prove important."
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USP18 binds ISG15 and 129-135. 1 / 1
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"In ISG15 bound USP18, residues 129-135 of the thumb domain form an extended loop."
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USP18 binds RSAD2 and ISG15. 1 / 1
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"IRF7 was the main regulator that changed in both the liver and kidney and was found to interact with other target genes such as USP18, RSAD2, and ISG15."
| PMC
USP18 activates ISG15.
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USP18 activates ISG15. 10 / 14
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"However divergent, ISG15 removal is nevertheless exclusively mediated by USP18 in humans, mice, and zebrafish."
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"Other key negative feedback regulators are ubiquitin-specific peptidase 18 (USP18) and interferon stimulated gene 15 (ISG15) (Figure 2)."
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"USP18 can increase HBV susceptibility by removing isopeptidase activity of ISG15 and promoting HBV replication by downregulating the I-IFN signal transduction pathway."
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"The absence of USP18 strengthens the signaling of IFN-I and IFN-III; 1,2 and is associated with prolonged Janusactivated kinase/signal transducer and activator of In addition, absence of USP18, which cleaves ISG15 from its target protein, prolongs ISG15-mediated ISGylation."
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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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"Our data are consistent with this mechanism, since the blunting of hepatocyte IFN signaling after exposure to inflammatory stimuli is independent of USP18 mediated removal of ISG15 from its target proteins."
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"Usp18 deficient cells have enhanced IFN-alpha and beta signaling and more ISG15 modified proteins."
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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)."
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"In addition, absence of USP18, which cleaves ISG15 from its target protein, prolongs ISG15 mediated ISGylation."
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"At later stages, USP18 mediated de-ISGylation releases free ISG15, which in turn stabilizes USP18 and tunes down IFN-alpha and beta signalling and inflammation."
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USP18 inhibits ISG15.
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USP18 inhibits ISG15. 10 / 11
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"Finally, USP18 (an ISG15 specific isopeptidase enzyme) can reverse ISG15 conjugation of target proteins."
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"USP18 is the main ISG15 isopeptidase and can inhibit 593 ISG15-mediated ISGylation and can repress the establishment of an antiviral state (Honke et al., 594 2016; Ketscher et al., 2015)."
| DOI
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"Immunoprecipitation (IP) assays confirmed that ISG15 directly complexed with PTEN protein and this conjugation was attenuated by engineered overexpression of USP18."
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"In particular, replacement of the Ala138 in USP18 by a polar residue in other USPs might block the access of the bulky and hydrophobic Trp121 side chain of ISG15 (XREF_FIG)."
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"As expected, USP18 silencing dramatically decreased USP18 protein and increased the free ISG15 protein compared to the control group (XREF_FIG)."
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"Here, a clear negative feedback loop can be observed, in which Ubiquitin like protein ISG15 (G1P2) induces IFN-gamma expression while Ubl carboxyl-terminal hydrolase 18 (USP18) inhibits G1P2 activity, explaining the observed down-regulation state of IFN-gamma."
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"In particular, replacement of the Ala138 in USP18 by a polar residue in other USPs might block the access of the bulky and hydrophobic Trp121 side chain of ISG15 (Fig. 4d)."
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"ISG15 conjugation (ISGylation) can be reversed by the IFN-a/b-induced isopeptidase (USP18) that cleaves ISG15 from target proteins 4 ."
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"USP18 activity reduces ISG15 protein conjugation and promotes tumorigenesis if an oncogenic substrate is stabilized by USP18."
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"Inhibiting USP18, the negative regulator of ISGylation, has been shown in both cell line and invivo systems to enhance ISG15 conjugation (Ketscher et al., 2015)."
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USP18 decreases the amount of ISG15.
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USP18 decreases the amount of ISG15. 3 / 3
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"As expected, incubation with purified USP18 decreased ISG15 conjugates and increased levels of free ISG15 [88]."
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"We demonstrated that USP18 deficient cells have increased expression of IFIT1, IFIT2, IFIT3, IFITM1, IFITM2, CXCL9, CXCL10, ISG15, and MX2 after treatment with exogenous IFN-. Many of these genes have been previously shown to restrict HIV-1 replication."
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"We demonstrated that USP18 deficient cells have increased expression of IFIT1, IFIT2, IFIT3, IFITM1, IFITM2, CXCL9, CXCL10, ISG15, and MX2 after treatment with exogenous IFN‐β."
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USP18 deubiquitinates ISG15.
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USP18 deubiquitinates ISG15. 1 / 1
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"Prior work implicated the IFN-stimulated gene 15 (ISG15) deubiquitinase (DUB) USP18 as having antineoplastic activity by regulating lung cancer growth and oncoprotein stability."
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DICER1 affects IFIH1, IRF7, ISG15, MAVS, MX1, OASL, RSAD2, and USP18
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USP18 binds DICER1, IFIH1, MAVS, RSAD2, ISG15, IRF7, MX1, and OASL. 1 / 1
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"DHX58 is further found to interact with IFIH1, ISG15, RSAD2, IRF7, MX1, MAVS, DICER1, USP18 and OASL."
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129-135 affects USP18
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USP18 binds ISG15 and 129-135. 1 / 1
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"In ISG15 bound USP18, residues 129-135 of the thumb domain form an extended loop."
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