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Immunity. 2014 Feb 20;40(2):199-212. doi: 10.1016/j.immuni.2013.12.014. Epub 2014 Feb 13.

Autoimmune disorders associated with gain of function of the intracellular sensor MDA5.

Author information

1
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.
2
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.
3
Department of Dermatology, Graduate School of Medicine, Kyoto University, 53 Shogoin-Kawaharacho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan.
4
Team for Advanced Development and Evaluation of Human Disease Models, Riken BioResource Center (BRC), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
5
Laboratory of Plasma Membrane and Nuclear Signaling, Graduate School of Biostudies, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
6
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.
7
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aoba-ku, Sendai 980-8574, Japan.
8
Division of Mammalian Genetics Laboratory, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
9
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.
10
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.

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.

PMID:
24530055
DOI:
10.1016/j.immuni.2013.12.014
[Indexed for MEDLINE]
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