Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses (original) (raw)

Nature volume 441, pages 101–105 (2006) Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 52 print issues and online access

$199.00 per year

only $3.83 per issue

Buy this article

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006)
    Article CAS Google Scholar
  2. Katze, M. G., He, Y. & Gale, M. Jr. Viruses and interferon: A fight for supremacy. Nature Rev. Immunol. 2, 675–687 (2002)
    Article CAS Google Scholar
  3. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nature Immunol. 5, 730–737 (2004)
    Article CAS Google Scholar
  4. Kang, D. C. et al. mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc. Natl Acad. Sci. USA 99, 637–642 (2002)
    Article ADS CAS Google Scholar
  5. Andrejeva, J. et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the _IFN_-β promoter. Proc. Natl Acad. Sci. USA 101, 17264–17269 (2004)
    Article ADS CAS Google Scholar
  6. Yoneyama, M. et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175, 2851–2858 (2005)
    Article CAS Google Scholar
  7. Rothenfusser, S. et al. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J. Immunol. 175, 5260–5268 (2005)
    Article CAS Google Scholar
  8. Kato, H. et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005)
    Article CAS Google Scholar
  9. Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature Immunol. 5, 987–995 (2004)
    Article CAS Google Scholar
  10. Beutler, B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430, 257–263 (2004)
    Article ADS CAS Google Scholar
  11. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001)
    Article ADS CAS Google Scholar
  12. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003)
    Article ADS CAS Google Scholar
  13. Kovacsovics, M. et al. Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr. Biol. 12, 838–843 (2002)
    Article CAS Google Scholar
  14. Kawai, T. et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nature Immunol. 6, 981–988 (2005)
    Article CAS Google Scholar
  15. Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122, 669–682 (2005)
    Article CAS Google Scholar
  16. Xu, L. G. et al. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell 19, 727–740 (2005)
    Article CAS Google Scholar
  17. Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005)
    Article ADS CAS Google Scholar
  18. Fitzgerald, K. A. et al. IKKɛ and TBK1 are essential components of the IRF3 signaling pathway. Nature Immunol. 4, 491–496 (2003)
    Article CAS Google Scholar
  19. Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148–1151 (2003)
    Article ADS CAS Google Scholar
  20. Hemmi, H. et al. The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199, 1641–1650 (2004)
    Article CAS Google Scholar
  21. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13, 539–548 (2000)
    Article CAS Google Scholar
  22. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)
    Article ADS CAS Google Scholar
  23. Chang, T. H., Liao, C. L. & Lin, Y. L. Flavivirus induces interferon-beta gene expression through a pathway involving RIG-I-dependent IRF-3 and PI3K-dependent NF-κB activation. Microbes Infect. 8, 157–171 (2006)
    Article CAS Google Scholar
  24. Melchjorsen, J. et al. Activation of innate defense against a paramyxovirus is mediated by RIG-I and TLR7 and TLR8 in a cell-type-specific manner. J. Virol. 79, 12944–12951 (2005)
    Article CAS Google Scholar
  25. Hoshino, K., Kaisho, T., Iwabe, T., Takeuchi, O. & Akira, S. Differential involvement of IFN-β in Toll-like receptor-stimulated dendritic cell activation. Int. Immunol. 14, 1225–1231 (2002)
    Article CAS Google Scholar
  26. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529–1531 (2004)
    Article ADS CAS Google Scholar
  27. Mori, Y. et al. Nuclear localization of Japanese encephalitis virus core protein enhances viral replication. J. Virol. 79, 3448–3458 (2005)
    Article CAS Google Scholar
  28. Kato, A. et al. Characterization of the amino acid residues of sendai virus C protein that are critically involved in its interferon antagonism and RNA synthesis down-regulation. J. Virol. 78, 7443–7454 (2004)
    Article CAS Google Scholar

Download references

Acknowledgements

We thank all colleagues in our laboratory, K. Takeda, T. Shioda, E. Nakayama and K. Kiyotani for helpful discussions, A. Kato, T. Abe, Y. Mori, B. S. Kim and A. Palmenberg for viruses and plasmids, M. Hashimoto for secretarial assistance, and Y. Fujiwara, M. Shiokawa, N. Kitagaki and A. Shibano for technical assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan, and from the 21st Century Center of Excellence Program of Japan.

Author information

Author notes

  1. Hiroki Kato and Osamu Takeuchi: *These authors contributed equally to this work

Authors and Affiliations

  1. Department of Host Defense,
    Hiroki Kato, Osamu Takeuchi, Masahiro Yamamoto, Kosuke Matsui, Satoshi Uematsu, Andreas Jung & Shizuo Akira
  2. Department of Molecular Virology, Research Institute for Microbial Diseases, University, Osaka
    Yoshiharu Matsuura
  3. ERATO, Japan Science and Technology Agency, 3-1 Yamada-oka, Suita, 565-0871, Osaka, Japan
    Hiroki Kato, Osamu Takeuchi, Shintaro Sato, Taro Kawai, Ken J. Ishii & Shizuo Akira
  4. Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Shogoin, 606-8507, Sakyo-ku, Kyoto, Japan
    Mitsutoshi Yoneyama & Takashi Fujita
  5. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
    Osamu Yamaguchi & Kinya Otsu
  6. Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
    Tohru Tsujimura
  7. Department of Medical Technology, Shinshu University School of Allied Medical Sciences, 3-1-1 Asahi, 390-8621, Matsumoto, Japan
    Chang-Sung Koh
  8. Immunobiology Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, WC2A 3PX, London, UK
    Caetano Reis e Sousa

Authors

  1. Hiroki Kato
  2. Osamu Takeuchi
  3. Shintaro Sato
  4. Mitsutoshi Yoneyama
  5. Masahiro Yamamoto
  6. Kosuke Matsui
  7. Satoshi Uematsu
  8. Andreas Jung
  9. Taro Kawai
  10. Ken J. Ishii
  11. Osamu Yamaguchi
  12. Kinya Otsu
  13. Tohru Tsujimura
  14. Chang-Sung Koh
  15. Caetano Reis e Sousa
  16. Yoshiharu Matsuura
  17. Takashi Fujita
  18. Shizuo Akira

Corresponding author

Correspondence toShizuo Akira.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Kato, H., Takeuchi, O., Sato, S. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature 441, 101–105 (2006). https://doi.org/10.1038/nature04734

Download citation