title: Autoimmune disorders associated with gain of function of the intracellular sensor MDA5.
abstract: MDA5 is an essential intracellular sensor for several viruses, including picornaviruses, and elicits antiviral interferon (IFN) responses by recognizing viral dsRNAs. MDA5 has been implicated in autoimmunity. However, the mechanisms of how MDA5 contributes to autoimmunity remain unclear. Here we provide direct evidence that dysregulation of MDA5 caused autoimmune disorders. We established a mutant mouse line bearing MDA5 mutation by ENU mutagenesis, which spontaneously developed lupus-like autoimmune symptoms without viral infection. Inflammation was dependent on an adaptor molecule, MAVS indicating the importance of MDA5-signaling. In addition, intercrossing the mutant mice with type I IFN receptor-deficient mice ameliorated clinical manifestations. This MDA5 mutant could activate signaling in the absence of its ligand but was paradoxically defective for ligand- and virus-induced signaling, suggesting that the mutation induces a conformational change in MDA5. These findings provide insight into the association between disorders of the innate immune system and autoimmunity.
authors: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan; Department of Dermatology, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan.
authors: Masahide
authors: M
authors: Funabiki
authors: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan; Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan; PRESTO, Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
authors: Hiroki
authors: H
authors: Kato
authors: Department of Dermatology, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan.
authors: Yoshiki
authors: Y
authors: Miyachi
authors: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors: Hideaki
authors: H
authors: Toki
authors: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors: Hiromi
authors: H
authors: Motegi
authors: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors: Maki
authors: M
authors: Inoue
authors: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors: Osamu
authors: O
authors: Minowa
authors: Laboratory of Plasma Membrane and Nuclear Signaling, Graduate School of Biostudies, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Aiko
authors: A
authors: Yoshida
authors: Laboratory of Plasma Membrane and Nuclear Signaling, Graduate School of Biostudies, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Katashi
authors: K
authors: Deguchi
authors: Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences and Faculty of Pharmaceutical Sciences, 6-3 Aramaki-aza-aoba, Aoba-ku, Sendai 980-8578, Japan.
authors: Hiroshi
authors: H
authors: Sato
authors: Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8574, Japan.
authors: Sadayoshi
authors: S
authors: Ito
authors: Division of Mammalian Genetics Laboratory, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
authors: Toshihiko
authors: T
authors: Shiroishi
authors: Laboratory of Plasma Membrane and Nuclear Signaling, Graduate School of Biostudies, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Kunio
authors: K
authors: Takeyasu
authors: Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan; Department of Cell Biology, Cancer Institute, The Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto, Tokyo 135-8550, Japan.
authors: Tetsuo
authors: T
authors: Noda
authors: Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan; Laboratory of Molecular Cell Biology, Graduate School of Biostudies, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan. Electronic address: tfujita@virus.kyoto-u.ac.jp.
authors: Takashi
authors: T
authors: Fujita
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000503:physiopathology*; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation
chemical_list: C554329:Ifna1 protein, mouse; D016898:Interferon-alpha; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1