Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.
The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses. 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 recognition. In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue. Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified, 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.
Kato
Hiroki
H
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Takeuchi
Osamu
O
Sato
Shintaro
S
Yoneyama
Mitsutoshi
M
Yamamoto
Masahiro
M
Matsui
Kosuke
K
Uematsu
Satoshi
S
Jung
Andreas
A
Kawai
Taro
T
Ishii
Ken J
KJ
Yamaguchi
Osamu
O
Otsu
Kinya
K
Tsujimura
Tohru
T
Koh
Chang-Sung
CS
Reis e Sousa
Caetano
C
Matsuura
Yoshiharu
Y
Fujita
Takashi
T
Akira
Shizuo
S
D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D004664:Encephalitis Virus, Japanese / Q000276:immunology; D004686:Encephalomyocarditis virus / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D020365:RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012328:RNA Viruses / Q000145:classification / Q000235:genetics / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000235:genetics / Q000276:immunology; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology
D012330:RNA, Double-Stranded; D012367:RNA, Viral; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D020365:RNA Helicases