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.
Highlights
Interferons (IFNs) are a group of secreted proteins that play key roles in host antiviral immunity.IFNs are typically induced by the activation of host pattern-recognition receptors (PRRs), mainly retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLR) and Toll-like receptors (TLR) during viral infection [1,2]
When a STAT3-Y705F mutant is overexpressed in STAT3-null cells, some well-known oncoproteins, such as MRAS and MET, are upregulated by U-STAT3, but not by activated STAT3 dimers [59]. These results suggest that U-STAT3 activates gene expression by a novel mechanism distinct from canonical STAT3 dimers [59]
This observation is consistent with recent research demonstrating that U-STAT3, during Interleukin (IL)-6 stimulation, drives a second wave of gene expression that does not respond directly to STAT3 containing phosphorylated tyrosine [60]. It appears that U-STAT3-responsive genes contain nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) response elements that are activated by a novel transcription factor complex formed when U-STAT3 binds to unphosphorylated NF-κB
Summary
Interferons (IFNs) are a group of secreted proteins that play key roles in host antiviral immunity. The JAK/STAT pathway was initially characterized based on its role in type I IFN-mediated responses [16]. It has been proposed that JAK/STAT pathway antagonism is a virulence factor that could be exploited as a novel strategy to achieve virus attenuation for modified live virus (MLV) vaccine development [20] This is consistent with observations that mice lacking intact JAK/STAT signaling (IFN receptor or STAT1 knockout mice) are more susceptible to virus infection than wild-type mice [21,22,23,24]. Several topics are discussed: the discovery of the JAK/STAT pathway, including the canonical JAK/STAT pathway activated by IFNs, tyrosine phosphorylation-independent non-canonical STAT activation, virus-induced serine monophosphorylation of STATs, as well as the role of monophosphorylation of STATs during inflammation triggered by viral infection.
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