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TBK1-METTL3 axis facilitates antiviral immunity.

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机构： [1]Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor SystemsBiology, NHC Key Laboratory of Medical Immunology, Peking University Health Science Center, Beijing 100191, China [2]College of Acupuncture & Massage, Shaanxi University of Chinese Medicine, Xixian New Area, Shaanxi Province 712046, China [3]College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China [4]Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China [5]Institute of Systems Biomedicine, Department of Biochemistry and Biophysics, Beijing Key Laboratory of Tumor Systems Biology, School ofBasic Medical Sciences, Peking University Health Science Center, Beijing 100191, China [6]National Key Laboratory of Crop Genetic Improvement and National Centre of Plant Gene Research, Huazhong Agricultural University,Wuhan 430070, China [7]Department of Dental Materials, National Engineering Laboratory for Digital and Material Technology of Stomatology & NMPA KeyLaboratory for Dental Materials, Peking University School and Hospital of Stomatology, Beijing 100081, China [8]Departments of Parasitology and Public Health and Preventive Medicine, School of Medicine, Jinan University, No. 601, Huangpu AvenueWest, Guangzhou, Guangdong 510632, China [9]Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan University, Zhuhai, Guangdong519000, China [10]The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, Guangdong 510632, China

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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.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

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出版当年[2021]版：

大类 | 1 区

生物学

小类 | 2 区细胞生物学

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大类 | 1 区

生物学

小类 | 2 区细胞生物学

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第一作者机构： [1]Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor SystemsBiology, NHC Key Laboratory of Medical Immunology, Peking University Health Science Center, Beijing 100191, China [2]College of Acupuncture & Massage, Shaanxi University of Chinese Medicine, Xixian New Area, Shaanxi Province 712046, China

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