title: TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity.
abstract: MDA5 plays a critical role in antiviral innate immunity by functioning as a cytoplasmic double-stranded RNA sensor that can activate type I interferon signaling pathways, but the mechanism for the activation of MDA5 is poorly understood. Here, we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743, which is critical for MDA5 oligomerization and activation. Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus (EMCV)-induced interferon regulatory factor 3 (IRF3) activation and type I interferon production but has no effect on retinoic acid-inducible I (RIG-I), Toll-like receptor 3 (TLR3), or cyclic GMP-AMP synthase signaling pathways. Importantly, Trim65-/-mice are more susceptible to EMCV infection than controls and cannot produce type I interferon in vivo. Collectively, our results identify TRIM65 as an essential component for the MDA5 signaling pathway and provide physiological evidence showing that ubiquitination is important for MDA5 oligomerization and activation.
authors.affiliation: Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.|Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Xueting
authors.identifier: 0000-0002-6491-5280
authors.initials: X
authors.lastname: Lang
authors.affiliation: Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Tiantian
authors.identifier: 0000-0002-0516-6363
authors.initials: T
authors.lastname: Tang
authors.affiliation: Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Tengchuan
authors.initials: T
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Fudan University, Shanghai 200433, China ustcjw@ustc.edu.cn zrb1980@ustc.edu.cn chend@fudan.edu.cn.|State Key Laboratory of Proteomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 102206, China.
authors.forename: Chen
authors.identifier: 0000-0001-8673-3464
authors.initials: C
authors.lastname: Ding
authors.affiliation: Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China ustcjw@ustc.edu.cn zrb1980@ustc.edu.cn chend@fudan.edu.cn.|Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei 230027, China.|Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Rongbin
authors.identifier: 0000-0002-3351-6420
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China ustcjw@ustc.edu.cn zrb1980@ustc.edu.cn chend@fudan.edu.cn.|Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000818:Animals; D018188:Cardiovirus Infections / Q000276:immunology*; D004686:Encephalomyocarditis virus; D006801:Humans; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1 / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055503:Protein Multimerization; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D000070584:Tripartite Motif Proteins; C000621862:Trim65 protein, mouse; D044767:Ubiquitin-Protein Ligases; C510592:Ifih1 protein, mouse; D000072640:Interferon-Induced Helicase, IFIH1