TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity

• Published in: The Journal of experimental medicine Vol. 214; no. 2; pp. 459 - 473
• Main Authors: Lang, Xueting, Tang, Tiantian, Jin, Tengchuan, Ding, Chen, Zhou, Rongbin, Jiang, Wei
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.02.2017; The Rockefeller University Press
• Subjects: Activation; AMP; Animals; Cardiovirus Infections - immunology; Cyclic GMP; Double-stranded RNA; Encephalomyocarditis virus; Humans; Immunity; Immunity, Innate; Innate immunity; Interferon; Interferon regulatory factor; Interferon regulatory factor 3; Interferon-Induced Helicase, IFIH1 - chemistry; Interferon-Induced Helicase, IFIH1 - physiology; Lysine; Mice; Mice, Inbred C57BL; Oligomerization; Protein Multimerization; Retinoic acid; Ribonucleic acid; RNA; Signal Transduction; Signaling; TLR3 protein; Toll-like receptors; Tripartite Motif Proteins - physiology; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - physiology; Ubiquitination; Viruses
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20160592

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.