Cytoplasmic STAT4 Promotes Antiviral Type I IFN Production by Blocking CHIP-Mediated Degradation of RIG-I

Abstract

Retinoic acid-inducible gene I (RIG-I) signaling is critical to host innate immune response against RNA virus infection. Numerous factors use different mechanisms to regulate RIG-I signaling. In this study, we report that STAT family member STAT4 promotes RIG-I-triggered type I IFN production in antiviral innate immunity. Silencing of STAT4 impaired IFN-β production in macrophages upon RNA virus infection, whereas overexpression of STAT4 enhanced RIG-I-induced IFN-β promoter activation and IFN-stimulated response element activity. Silencing of STAT4 increased degradation of RIG-I. Interestingly, during RNA virus infection STAT4 was found to be constantly present in cytoplasm of macrophages without Tyr(693) phosphorylation, which is required for its classical activation and nuclear translocation. Mechanistically, cytoplasmic STAT4 could interact with E3 ligase CHIP and block RIG-I and CHIP association, preventing CHIP-mediated proteasomal degradation of RIG-I via K48-linked ubiquitination. Our study provides a new manner for posttranslational regulation of RIG-I signaling and identifies a previously unknown function of cytoplasm-localized STAT4 in antiviral innate immunity.