TBK1-METTL3 axis facilitates antiviral immunity.

mRNA m⁶A modification is heavily involved in modulation of immune responses. However, its function in antiviral immunity is controversial, and how immune responses regulate m⁶A modification remains elusive. We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m⁶A methyltransferase METTL3 at serine 67. The phosphorylated METTL3 interacts with the translational complex, which is required for enhancing protein translation, thus facilitating antiviral responses. TBK1 also promotes METTL3 activation and m⁶A modification to stabilize IRF3 mRNA. Type I interferon (IFN) induction is severely impaired in METTL3-deficient cells. Mettl3 ^fl/fl-lyz2-Cre mice are more susceptible to influenza A virus (IAV)-induced lethality than control mice. Consistently, Ythdf1 ^−/− mice show higher mortality than wild-type mice due to decreased IRF3 expression and subsequently attenuated IFN production. Together, we demonstrate that innate signals activate METTL3 via TBK1, and METTL3-mediated m⁶A modification secures antiviral immunity by promoting mRNA stability and protein translation. [Display omitted] • TBK1 directly phosphorylates METTL3 at serine 67 upon VSV infection • TBK1 promotes catalytic activity of METTL3 • S67 phosphorylation enhances METTL3 function in promoting translation Chen et al. report that TBK1 promotes METTL3-related translation and m⁶A modification in a kinase-activity-dependent and -independent manner. This study therefore advances our understanding of how innate signals interplay with METTL3 in host defense against virus. [ABSTRACT FROM AUTHOR]