Autoimmune Disorders Associated with Gain of Function of the Intracellular Sensor MDA5

被引：236

作者：

Funabiki, Masahide ^{[1
,2
]}

Kato, Hiroki ^{[1
,3
,4
]}

Miyachi, Yoshiki ^{[2
]}

Toki, Hideaki ^{[5
]}

Motegi, Hiromi ^{[5
]}

Inoue, Maki ^{[5
]}

Minowa, Osamu ^{[5
]}

Yoshida, Aiko ^{[6
]}

Deguchi, Katashi ^{[6
]}

Sato, Hiroshi ^{[7
,8
]}

Ito, Sadayoshi ^{[9
]}

Shiroishi, Toshihiko ^{[10
]}

Takeyasu, Kunio ^{[6
]}

Noda, Tetsuo ^{[5
,11
]}

Fujita, Takashi ^{[1
,3
]}

机构：

[1] Kyoto Univ, Mol Genet Lab, Inst Virus Res, Sakyo Ku, Kyoto 6068507, Japan

[2] Kyoto Univ, Grad Sch Med, Dept Dermatol, Sakyo Ku, Kyoto 6068507, Japan

[3] Kyoto Univ, Mol Cell Biol Lab, Grad Sch Biostudies, Sakyo Ku, Kyoto 6068507, Japan

[4] Sci & Technol Agcy JST, PRESTO, Kawaguchi, Saitama 3320012, Japan

[5] Riken BioResource Ctr BRC, Team Adv Dev & Evaluat Human Dis Models, Tsukuba, Ibaraki 3050074, Japan

[6] Kyoto Univ, Grad Sch Biostudies, Lab Plasma Membrane & Nucl Signaling, Sakyo Ku, Kyoto 6068501, Japan

[7] Tohoku Univ, Grad Sch Pharmaceut Sci, Dept Clin Pharmacol & Therapeut, Sendai, Miyagi 9808578, Japan

[8] Fac Pharmaceut Sci, Aoba Ku, Sendai, Miyagi 9808578, Japan

[9] Tohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Aoba Ku, Sendai, Miyagi 9808574, Japan

[10] Natl Inst Genet, Div Mammalian Genet Lab, Mishima, Shizuoka 4118540, Japan

[11] Japanese Fdn Canc Res, Inst Canc, Dept Cell Biol, Koto Ku, Tokyo 1358550, Japan

来源：

IMMUNITY | 2014年 / 40卷 / 02期

基金：

日本科学技术振兴机构;

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; RIG-I HELICASE; ANTIVIRAL RESPONSES; CROHNS-DISEASE; SIGNAL-TRANSDUCTION; STRUCTURAL BASIS; ADAPTER PROTEIN; STRANDED-RNA; RECOGNITION; INTERFERON;

D O I：

10.1016/j.immuni.2013.12.014

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：199 / 212

页数：14

共 46 条

[1]

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