Cellular nucleic acid–binding protein is essential for type I interferon–mediated immunity to RNA virus infection

Abstract

Significance Infections due to RNA viruses pose a substantial threat to human health around the globe. A better understanding of how the immune system controls RNA virus infection is critical for developing new treatments and vaccines. Here, we demonstrated that CNBP was required to control RNA virus infection through regulating the production of type I IFNs. Overall, we discovered an important role for CNBP in regulating innate immune responses and defined the underlying mechanisms, which suggest that CNBP might be a therapeutic target in controlling viral infections and inflammatory diseases. Type I interferons (IFNs) are innate immune cytokines required to establish cellular host defense. Precise control of IFN gene expression is crucial to maintaining immune homeostasis. Here, we demonstrated that cellular nucleic acid–binding protein (CNBP) was required for the production of type I IFNs in response to RNA virus infection. CNBP deficiency markedly impaired IFN production in macrophages and dendritic cells that were infected with a panel of RNA viruses or stimulated with synthetic double-stranded RNA. Furthermore, CNBP-deficient mice were more susceptible to influenza virus infection than were wild-type mice. Mechanistically, CNBP was phosphorylated and translocated to the nucleus, where it directly binds to the promoter of IFNb in response to RNA virus infection. Furthermore, CNBP controlled the recruitment of IFN regulatory factor (IRF) 3 and IRF7 to IFN promoters for the maximal induction of IFNb gene expression. These studies reveal a previously unrecognized role for CNBP as a transcriptional regulator of type I IFN genes engaged downstream of RNA virus–mediated innate immune signaling, which provides an additional layer of control for IRF3- and IRF7-dependent type I IFN gene expression and the antiviral innate immune response.