TBK1-METTL3 axis facilitates antiviral immunity

Cell Rep. 2022 Feb 15;38(7):110373. doi: 10.1016/j.celrep.2022.110373.


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. Mettl3fl/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.

Keywords: METTL3; TBK1; antiviral immunity; m(6)A; protein translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Amino Acid Sequence
  • Animals
  • Antiviral Agents / immunology*
  • Cell Line
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / metabolism
  • Methyltransferases / chemistry
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Binding
  • Protein Biosynthesis
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA-Binding Proteins / metabolism
  • Virus Diseases / immunology
  • Virus Diseases / pathology


  • Antiviral Agents
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Irf3 protein, mouse
  • RNA-Binding Proteins
  • Ythdf1 protein, mouse
  • N-methyladenosine
  • Methyltransferases
  • Mettl3 protein, mouse
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Adenosine