Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses

Hiroki Kato, Osamu Takeuchi, Shintaro Sato, Mitsutoshi Yoneyama, Masahiro Yamamoto, Kosuke Matsui, Satoshi Uematsu, Andreas Jung, Taro Kawai, Ken J. Ishii, Osamu Yamaguchi, Kinya Otsu, Tohru Tsujimura, Chang-Sung Koh, Caetano Reis e Sousa, Yoshiharu Matsuura, Takashi Fujita and Shizuo Akira ()
Additional contact information
Hiroki Kato: Department of Host Defense
Osamu Takeuchi: Department of Host Defense
Shintaro Sato: ERATO, Japan Science and Technology Agency
Mitsutoshi Yoneyama: Kyoto University
Masahiro Yamamoto: Department of Host Defense
Kosuke Matsui: Department of Host Defense
Satoshi Uematsu: Department of Host Defense
Andreas Jung: Department of Host Defense
Taro Kawai: ERATO, Japan Science and Technology Agency
Ken J. Ishii: ERATO, Japan Science and Technology Agency
Osamu Yamaguchi: Osaka University Graduate School of Medicine
Kinya Otsu: Osaka University Graduate School of Medicine
Tohru Tsujimura: Hyogo College of Medicine
Chang-Sung Koh: Shinshu University School of Allied Medical Sciences
Caetano Reis e Sousa: Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories
Yoshiharu Matsuura: Research Institute for Microbial Diseases, University
Takashi Fujita: Kyoto University
Shizuo Akira: Department of Host Defense

Nature, 2006, vol. 441, issue 7089, 101-105

Abstract: Abstract The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses1,2. The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition3,4,5,6,7. In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue3. Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified8, the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 (MDA5-/-) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I-/- and MDA5-/- mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.

Date: 2006
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DOI: 10.1038/nature04734

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