N6-methyladenosine modification of FZR1 mRNA positively regulates antiviral innate immunity by targeting the MAVS–TRAF3/6 axis
Abstract
Activation of retinoic acid-inducible gene-I-like receptors (RLRs) is important for type I interferon (IFN-I) production and antiviral innate immunity initiation. However, the epigenetic mechanisms that regulate RLR signaling remain poorly understood and require further investigation. Here, we demonstrate that Fizzy-related protein 1 (FZR1), which is essential for mitotic exit and G1/S transition, potentiates antiviral innate immune responses against RNA viruses. Mechanistically, vesicular stomatitis virus infection increases N6-methyladenosine (m 6 A) modification of FZR1 mRNA, which enhances FZR1 translation and elevates intracellular FZR1 protein levels. Upregulated FZR1 attenuates mitochondrial antiviral-signaling protein (MAVS) binding to 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3, a glycolytic rate-limiting enzyme, thereby promoting MAVS aggregation. Furthermore, FZR1 facilitates tumor necrosis factor receptor-associated factor 3/6 (TRAF3/6) autoubiquitination independently of the anaphase-promoting complex/cyclosome, subsequently activating interferon regulatory factor 3 and P65 of nuclear factor κB to drive the production of IFN-I and proinflammatory cytokines. Consequently, FZR1 deficiency impairs antiviral responses and increases viral titer in vitro and in vivo. Pharmacological inhibition of FZR1 significantly attenuates MAVS activation and TRAF3/6 ubiquitination, thereby abolishing FZR1-mediated antiviral immunity both in vitro and in vivo. Collectively, these findings reveal a molecular mechanism by which m 6 A modification of FZR1 activates the MAVS–TRAF3/6 signaling axis to potentiate IFN-I-dependent antiviral innate immunity.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Kaiwen Dou
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University
Yiyi Hu
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University
Mingyang Li
Jiale Xu
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University
Weihao Zhang
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University
Hui Wang
Qi Cheng
Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering
Zihao Jiang
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University
Liangjun Chen
College of Materials Science and Engineering and College of Mechanical Engineering
Shi Liu
Department of Chemistry, School of Science and Research Center for Industries of the Future
Ke Chen
Yuanyuan Liu
Hairong Xiong
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University
Fan Luo
New Cornerstone Science Laboratory, State Key Laboratory for Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, and National & Local Joint Engineering Research Center of Preparation Technology of Nanomaterials, College of Chemistry and Chemical Engineering
Wei Hou
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University
Shuliang Chen
State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University