IndraLab

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ISG15 activates USP18. 20 / 20
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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."
29769653
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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 ."
29769653
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"The U-ISGF3 target genes, Isg15 and Mx1 [31,32,33], and the ISG15-induced Usp18 [34,35] were all significantly upregulated in response to both PARP7 loss or inhibition (Figure 3K–M), and this increase was greater than that observed for the P-ISGF3 target genes."
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"Interestingly, in human cells, ISG15 directly regulates USP18 stability 24."
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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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"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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"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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"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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"Moreover, whereas ISG15 co-expression led to a stabilization and increased abundance of exogenously expressed USP18 (Figure 2E, Input panel), it had no effect on USP41 protein levels."
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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)."
32039148
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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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"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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"Notably, the interaction of USP18 with free intracellular ISG15 impairs ubiquitination and proteasomal degradation of USP18, which leads to the prevention of overamplification of IFN signaling and autoinflammation, suggesting that free ISG15-mediated stabilization of USP18 is pivotal for the negative feedback regulation of long-term IFN signaling ."
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"Notably, stabilization of USP18 by free ISG15 protects against its proteasomal degradation; thus, ISG15 supports the downregulatory function of USP18 in the control of type I IFN-JAK/STAT signaling pathway [20]."
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"ISG15 prevents the degradation of USP18 by sphingosine kinase 2 (SPK2) [XREF_BIBR, XREF_BIBR]."
| PMC
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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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"In cells with enhanced ISGylation ( usp18 ), induced by catalytic inactivation of the ISG15-specific protease USP18 (Ketscher et al., 2015) , we observed an accumulation of GML following serum starvation in cells ( Figure 1C )."
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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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"Intracellular unconjugated ISG15 prevents degradation of USP18, a negative regulator of IFNα/β signalling and thereby stops over-amplification of IFN signals and autoinflammation (55)."
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