Protein ISGylation modulates the JAK-STAT signaling pathway

Abstract

ISG15 is one of the most strongly induced genes upon viral infection, type I interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation. Here we report that mice lacking UBP43, a protease that removes ISG15 from ISGylated proteins, are hypersensitive to type I IFN. Most importantly, in UBP43-deficient cells, IFN-β induces a prolonged Stat1 tyrosine phosphorylation, DNA binding, and IFN-mediated gene activation. Furthermore, restoration of ISG15 conjugation in protein ISGylation-defective K562 cells increases IFN-stimulated promoter activity. These findings identify UBP43 as a novel negative regulator of IFN signaling and suggest the involvement of protein ISGylation in the regulation of the JAK-STAT pathway.

Identification and characterization of two homologues of interferon-stimulated gene ISG15 in crucian carp

“…However, the biological consequences of ISGylation are still uncertain. For example, a study on mice lacking UBP43, an IFN-inducible ISG15 deconjugating enzyme, showed that ISGylation of STAT1 by ISG15 was required for the JAK-STAT signalling pathway [15], but recent reports revealed that lack of ISG15 or lack of Ubel did not influence IFN signalling and formation of antiviral state [35,36], and UBP43 downregulated JAK-STAT signalling pathway independent of its isopeptidase activity towards ISG15, just by specifically binding to the IFNAR2 receptor subunit and blocking the interaction between JAK and the IFN receptor [37]. With regard to the role of ISGylation in protein degradation, an increased expression of ISG15 was detected in tumour cells and could interfere with protein polyubiquitination/degradation [38].…”

“…Several recent reports have provided indirect and direct evidence for involvement of ISG15 and protein ISGylation in innate antiviral response. Loss of mouse UBP43 (USP18), a protease specifically removed ISG15 from conjugated proteins [13], resulted in decreased life span, brain cell injury [14], hypersensitivity to type I IFN stimulation [15], and more resistant to both LCMV and VSV infection [16]. More recently, the antiviral role of ISG15 has been revealed in IFNa/breceptor deficient mice in which ISG15 expression protected against Sindbis virus-induced lethality and decreased sindbis virus replication in multiple organs [17].…”

Enhanced Antibacterial Potential in UBP43-Deficient Mice against Salmonella typhimurium Infection by Up-Regulating Type I IFN Signaling

“…Recently, we have demonstrated that UBP43, a deconjugating protease of ISG15, is a new negative regulator of the type I IFN signaling pathway (6). ISG15 is an IFN-inducible ubiquitin-like protein and its expression and conjugation to target proteins are highly induced upon viral or bacterial infection (7,8).…”

Expression characterization, genomic structure and function analysis of fish ubiquitin-specific protease 18 (USP18) genes

“…Therefore, host cells develop stringent mechanisms of signal attenuation, for example, termination of IFN signaling, to ensure an appropriate IFN response (Ivashkiv and Donlin, 2014;Schneider et al, 2014). Among the inhibitors, USP18 (ubiquitinspecific protease) impedes the expression of IFN-induced downstream genes by negative regulation of Jak-Stat signaling pathway Malakhova et al, 2003;Sarasin-Filipowicz et al, 2009;Schneider et al, 2014).…”

“…Indeed USP18-deleted mice are hypersensitive to IFN treatment and show enhanced resistance to viral infection (Malakhova et al, 2003;Ritchie and Zhang, 2004); USP18−/− cells treated with type I IFNs have enhanced and prolonged STAT1 phosphorylation, increased the expression of ISG (Malakhova et al, 2003;Murray et al, 2011;Sarasin-Filipowicz et al, 2009). Interestingly, USP18 is a major ISG15-specific protease for maintaining a proper balance of ISG15-conjugated proteins in cells; however, the antiviral roles of USP18 are independent of its ISG15 isopeptidase activity Malakhova et al, 2006;Osiak et al, 2005), and seem to be mediated by specific binding of USP18 to the IFN receptor IFNAR2 and subsequently disrupting IFNAR2-JAK1 interaction, thus negatively regulating IFN signaling cascade (Malakhova et al, 2006).…”