title: Negative regulation of melanoma differentiation-associated gene 5 (MDA5)-dependent antiviral innate immune responses by Arf-like protein 5B.
abstract: RIG-I-like receptors (RLRs), including retinoic acid-inducible gene-I (RIG-I) and MDA5, constitute a family of cytoplasmic RNA helicases that senses viral RNA and mounts antiviral innate immunity by producing type I interferons and inflammatory cytokines. Despite their essential roles in antiviral host defense, RLR signaling is negatively regulated to protect the host from excessive inflammation and autoimmunity. Here, we identified ADP-ribosylation factor-like protein 5B (Arl5B), an Arl family small GTPase, as a regulator of RLR signaling through MDA5 but not RIG-I. Overexpression of Arl5B repressed interferon β promoter activation by MDA5 but not RIG-I, and its knockdown enhanced MDA5-mediated responses. Furthermore, Arl5B-deficient mouse embryonic fibroblast cells exhibited increased type I interferon expression in response to MDA5 agonists such as poly(I:C) and encephalomyocarditis virus. Arl5B-mediated negative regulation of MDA5 signaling does not require its GTP binding ability but requires Arl5B binding to the C-terminal domain of MDA5, which prevents interaction between MDA5 and poly(I:C). Our results, therefore, suggest that Arl5B is a negative regulator for MDA5.
authors.affiliation: From the Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan, the Laboratory of Host Defense, Immunology Frontier Research Center (IFReC) and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, and.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kitai
authors.affiliation: the Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.affiliation: From the Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawasaki
authors.affiliation: the Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ori
authors.affiliation: From the Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Sueyoshi
authors.affiliation: From the Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan.
authors.forename: Motoya
authors.initials: M
authors.lastname: Murase
authors.affiliation: the Laboratory of Host Defense, Immunology Frontier Research Center (IFReC) and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, and.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: From the Laboratory of Molecular Immunobiology, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan, tarokawai@bs.naist.jp.
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007370:Interferon Type I / Q000096:biosynthesis*; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D020365:RNA Helicases / Q000276:immunology; D012367:RNA, Viral / Q000276:immunology; D011971:Receptors, Immunologic; D015398:Signal Transduction
chemical_list: D007370:Interferon Type I; D012367:RNA, Viral; D011971:Receptors, Immunologic; D016899:Interferon-beta; C452820:RIGI protein, human; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D020365:RNA Helicases; D020727:ADP-Ribosylation Factors; C475880:Arl5a protein, mouse
keywords: Interferon; RIG-I-like Receptor (RLR); Signal Transduction; Small GTPase; Virus