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

Masahide Funabiki, Hiroki Kato, Yoshiki Miyachi, Hideaki Toki, Hiromi Motegi, Maki Inoue, Osamu Minowa, Aiko Yoshida, Katashi Deguchi, Hiroshi Sato, Sadayoshi Ito, Toshihiko Shiroishi, Kunio Takeyasu, Tetsuo Noda, Takashi Fujita

Research output: Contribution to journalArticlepeer-review

190 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)199-212
Number of pages14
Issue number2
Publication statusPublished - 2014 Feb 20

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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