RNA helicase DDX5 suppresses IFN-I antiviral innate immune response by interacting with PP2A-Cβ to deactivate IRF3.

DEAD-box (DDX) helicases are critical for recognizing viral nucleic acids to regulate antiviral innate immunity. Although DDX5 has been reported to participate in various virus infection, whether DDX5 regulates innate immune responses and its underlying mechanisms are still unknown. Here, we report that DDX5 is a negative regulator of type I IFN (IFN-I) production in antiviral responses. DDX5 knockdown significantly promoted DNA or RNA virus infection-induced IFN-I production and IFN-stimulated genes (ISGs) expression, while ectopic expression of DDX5 inhibited IFN-I production and promoted viral replication. Furthermore, we found that DDX5 specifically interacted with serine/threonine-protein phosphatase 2 A catalytic subunit beta (PP2A-Cβ) and viral infection enhanced the interaction between DDX5 and PP2A-Cβ. Besides, PP2A-Cβ interacted with IFN regulatory factor 3 (IRF3), and PP2A-Cβ knockdown promoted viral infection-induced IRF3 phosphorylation and IFN-I production. In addition, DDX5 knockdown rendered the mice more resistant to viral infection and enhanced antiviral innate immunity in vivo. Thus, DDX5 suppresses IFN-I antiviral innate immune response by interacting with PP2A-Cβ to deactivate IRF3. Together, these findings identify a negative role of DDX5 on regulating IFN-I signaling in innate immune responses.

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