title: RNF122 suppresses antiviral type I interferon production by targeting RIG-I CARDs to mediate RIG-I degradation.
abstract: The activation of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic innate sensor for viral RNA, is tightly regulated to maintain immune homeostasis properly and prevent excessive inflammatory reactions other than initiation of antiviral innate response to eliminate RNA virus effectively. Posttranslational modifications, particularly ubiquitination, are crucial for regulation of RIG-I activity. Increasing evidence suggests that E3 ligases play important roles in various cellular processes, including cell proliferation and antiviral innate signaling. Here we identify that E3 ubiquitin ligase RING finger protein 122 (RNF122) directly interacts with mouse RIG-I through MS screening of RIG-I-interacting proteins in RNA virus-infected cells. The transmembrane domain of RNF122 associates with the caspase activation and recruitment domains (CARDs) of RIG-I; this interaction effectively triggers RING finger domain of RNF122 to deliver the Lys-48-linked ubiquitin to the Lys115 and Lys146 residues of RIG-I CARDs and promotes RIG-I degradation, resulting in a marked inhibition of RIG-I downstream signaling. RNF122 is widely expressed in various immune cells, with preferential expression in macrophages. Deficiency of RNF122 selectively increases RIG-I-triggered production of type I IFNs and proinflammatory cytokines in macrophages. RNF122-deficient mice exhibit more resistance against lethal RNA virus infection, with increased production of type I IFNs. Thus, we demonstrate that RNF122 acts as a selective negative regulator of RIG-I-triggered antiviral innate response by targeting CARDs of RIG-I and mediating proteasomal degradation of RIG-I. Our study outlines a way for E3 ligase to regulate innate sensor RIG-I for the control of antiviral innate immunity.
authors: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors: Wendie
authors: W
authors: Wang
authors: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors: Minghong
authors: M
authors: Jiang
authors: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors: Shuo
authors: S
authors: Liu
authors: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors: Shikun
authors: S
authors: Zhang
authors: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China;
authors: Wei
authors: W
authors: Liu
authors: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing 100021, China;
authors: Yuanwu
authors: Y
authors: Ma
authors: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing 100021, China;
authors: Lianfeng
authors: L
authors: Zhang
authors: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, China; caoxt@immunol.org zhangjy@nic.bmi.ac.cn.
authors: Jiyan
authors: J
authors: Zhang
authors: National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China caoxt@immunol.org zhangjy@nic.bmi.ac.cn.
authors: Xuetao
authors: X
authors: Cao
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D029082:Sendai virus / Q000254:growth & development / Q000276:immunology; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D018116:Vesiculovirus / Q000254:growth & development / Q000276:immunology; D000097905:Roundabout Proteins
chemical_list: D007370:Interferon Type I; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D044767:Ubiquitin-Protein Ligases; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins
keywords: E3 ligase; RIG-I; RNF122; innate immunity; type I interferon