Interferon Independent Non-Canonical STAT Activation and Virus Induced Inflammation

Abstract

Interferons (IFNs) are a group of secreted proteins that play critical roles in antiviral immunity, antitumor activity, activation of cytotoxic T cells, and modulation of host immune responses. IFNs are cytokines, and bind receptors on cell surfaces to trigger signal transduction. The major signaling pathway activated by IFNs is the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, a complex pathway involved in both viral and host survival strategies. On the one hand, viruses have evolved strategies to escape from antiviral host defenses evoked by IFN-activated JAK/STAT signaling. On the other hand, viruses have also evolved to exploit the JAK/STAT pathway to evoke activation of certain STATs that somehow promote viral pathogenesis. In this review, recent progress in our understanding of the virus-induced IFN-independent STAT signaling and its potential roles in viral induced inflammation and pathogenesis are summarized in detail, and perspectives are provided.

Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

“…In addition to the contribution of U-STAT2 to U-ISGF3 formation, U-STAT2 could also bind constitutively to a considerable number of IFN-activated promoters, even in the absence of exogenous IFN stimulation [45]. Those findings corroborated earlier studies, which demonstrated that STAT2 could mediate innate immune responses in the absence of STAT1 [37].…”

“…Although tyrosine phosphorylation is critical for STAT activation; unphosphorylated STAT proteins continue to perform integral functions that activate ISGs [37]. In recent studies, unphosphorylated STATs (U-STATs; i.e., those with unphosphorylated tyrosine residues) were observed in the nucleus, where they bound to the upstream regulatory regions and initiated the expression of a set of ISGs [10,11,31,[38][39][40].…”

“…Excessive IFN stimulation is prevented through the close regulation of STAT activation by ubiquitin carboxy-terminal hydrolase 18 (USP18) and inhibitory regulators of STAT activities, including the family of protein inhibitors of activated STAT (PIAS) and suppressors of cytokine signaling (SOCS) [30,37]. USP18 is a 368-amino acid protein that typically functions as an ISG15 isopeptidase.…”

“…The PIAS family also includes negative regulators of IFN signaling. PIAS proteins function as small ubiquitin-like modifier (SUMO) E3 ligases, which interfere with STAT signaling functions [37,53]. Phosphorylation of the proximal tyrosine residue on STAT1 is prevented by PIAS-induced STAT1 SUMOylation, which results in the generation of partially phosphorylated STAT dimers.…”

Manipulation of the Innate Immune Response by Varicella Zoster Virus

“…These patients had VZV infection but did not experience severe complications, which questions the importance of type I IFN in controlling VZV infection (104). Interferon independent pathways have also been shown to play a critical role in the control of viral infection and may be able to compensate for the lack of type I IFN response in these patients (106).…”