1. TBK1-METTL3 axis facilitates antiviral immunity
- Author
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Xuehui Zhang, Yujie Luo, Zhinan Yin, Jianlei Hao, Zhe Zhou, Xuhui Yan, Tong Liu, Xiao Wang, Yingchi Zhao, Fuping You, Lu Li, Hongqiang Du, Xuemei Wei, Yunfei Li, Ping Yin, Ling Liang, Luoying Chen, Zeming Zhang, Xuliang Deng, Lili Cao, Jingxuan Chen, Guang Yang, and Tongtong Liu
- Subjects
Adenosine ,Protein Serine-Threonine Kinases ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Serine ,Immune system ,TANK-binding kinase 1 ,Animals ,Humans ,Amino Acid Sequence ,Phosphorylation ,Messenger RNA ,Kinase ,Chemistry ,RNA-Binding Proteins ,Translation (biology) ,Methyltransferases ,biochemical phenomena, metabolism, and nutrition ,Immunity, Innate ,Cell biology ,Mice, Inbred C57BL ,Virus Diseases ,Protein Biosynthesis ,Interferon Type I ,Interferon Regulatory Factor-3 ,IRF3 ,Protein Binding - Abstract
mRNA m6A modification is involved in modulation of immune responses. However, its function in antiviral immunity is controversial, and how immune responses regulate m6A modification remains unknown. We here found TBK1, a key kinase of antiviral pathways, phosphorylated the core m6A methyltransferase METTL3 at Serine 67. The phosphorylated METTL3 interacted with translational complex to enhance proteins translation, including IRF3, thus facilitating antiviral responses. TBK1 also promoted METTL3 activation and m6A modification, which was required for stabilizing IRF3 mRNA. Type I IFN induction was severely impaired in METTL3 deficient cells. Mettl3fl/fl-lyz2-Cre mice were more susceptible to IAV-induced lethality than control mice. Consistently, Ythdf1—/— mice showed higher mortality than wild type mice due to decreased IRF3 expression and subsequently attenuated IFNs production. Together, we demonstrated that innate signals activated METTL3 via TBK1, then METTL3 mediated m6A modification secured antiviral immunity by promoting mRNA stability and protein translation.
- Published
- 2022