title: Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5.
abstract: Sensing of viral RNA by the cytosolic receptors RIG-I and melanoma differentiation-associated gene 5 (MDA5) leads to innate antiviral response. How RIG-I and MDA5 are dynamically regulated in innate antiviral response is not well understood. Here, we show that TRIM38 positively regulates MDA5- and RIG-I-mediated induction of downstream genes and acts as a SUMO E3 ligase for their dynamic sumoylation at K43/K865 and K96/K888, respectively, before and after viral infection. The sumoylation of MDA5 and RIG-I suppresses their K48-linked polyubiquitination and degradation in uninfected or early-infected cells. Sumoylation of the caspase recruitment domains of MDA5 and RIG-I is also required for their dephosphorylation by PP1 and activation upon viral infection. At the late phase of viral infection, both MDA5 and RIG-I are desumoylated by SENP2, resulting in their K48-linked polyubiquitination and degradation. These findings suggest that dynamic sumoylation and desumoylation of MDA5 and RIG-I modulate efficient innate immunity to RNA virus and its timely termination.
authors.affiliation: Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Ming-Ming
authors.identifier: 0000-0001-9667-7662
authors.initials: MM
authors.lastname: Hu
authors.affiliation: Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Chen-Yang
authors.identifier: 0000-0002-2898-7607
authors.initials: CY
authors.lastname: Liao
authors.affiliation: Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Xue-Qin
authors.initials: XQ
authors.lastname: Xie
authors.affiliation: Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan 430071, China shuh@whu.edu.cn.|Department of Cell Biology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Hong-Bing
authors.identifier: 0000-0001-9102-3272
authors.initials: HB
authors.lastname: Shu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D003546:Cysteine Endopeptidases / Q000502:physiology; D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D000072640:Interferon-Induced Helicase, IFIH1 / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D012328:RNA Viruses / Q000276:immunology*; D011971:Receptors, Immunologic; D058207:Sumoylation; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D011971:Receptors, Immunologic; D000070584:Tripartite Motif Proteins; C106984:TRIM38 protein, human; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D000072640:Interferon-Induced Helicase, IFIH1