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ISG15 activates USP18. 16 / 16
| 16

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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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"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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"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."
| DOI

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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 ."
| PMC

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"Recently, we found that prolonged exposure to IFN- up-regulates U-ISGF3 and U-ISGs, including ISG15, and that ISG15 causes the refractoriness to exogenous IFN- treatment by stabilizing USP18 protein [60] ."

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"ISG15 prevents the degradation of USP18 by sphingosine kinase 2 (SPK2) [XREF_BIBR, XREF_BIBR]."
| PMC

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"9 This phenotype cannot be explained by the delSGylation activity of USP18, because deleting ISG15 or the ISGylation-activating Functions of USP18 N Honke et al enzyme UBE1L in mice did not reverse the phenotype in Usp18-deficient mice."

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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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"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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"ISG15 was shown to bind to and prevent uSP18 degradation mediated by S-phase kinase-associated protein 2 (SKP2)-dependent ubiquitylation 4,114 ."

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"In humans, binding of free ISG15 prevents proteasomal degradation of USP18 by SKP2 (Tokarz et al., 2004) and is critical to ensure negative regulation of IFN-α/β immunity by stabilizing USP18 (Zhang et al., 2015)."

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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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"In humans, binding of free ISG15 prevents proteasomal degradation of USP18 by the S-phase kinase-associated protein 2 (SKP2) and thus is critical to ensure negative regulation of IFN-α/β immunity by stabilizing USP18 (Tokarz et al., 2004; Zhang et al., 2015)."

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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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"Interestingly, in human cells, ISG15 directly regulates USP18 stability 24."