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Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses
Abstract
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.
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“However, several RNA structural features have been described as immunostimulatory due to interactions with various RNA sensors such as Toll-like receptors, RIG-I, and PKR.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [11]
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Metadata
- Authors
- Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K. J., Yamaguchi, O., Otsu, K., Tsujimura, T., Koh, C.-S., Reis e Sousa, C., Matsuura, Y., Fujita, T., & Akira, S.
- Affiliations
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Japan Science and Technology Agency (JP)
- Kyoto University (JP)
- The University of Osaka (JP)
- Hyogo Medical University (JP)
- Shinshu University (JP)
- Corresponding author
- Akira, Shizuo
- ORCID
- Venue
- Nature
- Published
- 2006-04-09
- Volume
- 441
- Issue
- 7089
- Pages
- 101-105
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2028575270
- Cited by
- 3,888
- References
- 28
- Citations by year
- 2026: 143 · 2025: 156 · 2024: 146 · 2023: 163 · 2022: 176 · 2021: 204 · 2020: 182 · 2019: 169 · 2018: 169 · 2017: 175 · 2016: 169 · 2015: 182 · 2014: 233 · 2013: 218 · 2012: 236
- FWCI
- 88.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- MDA5, RIG-I, double-stranded RNA recognition, antiviral innate immunity, interferon production, poly(I:C), paramyxovirus, influenza virus, Japanese encephalitis virus, picornavirus, viral susceptibility
- MeSH terms
- DEAD Box Protein 58, Interferon-Induced Helicase, IFIH1, Animals, Encephalitis Virus, Japanese, Encephalomyocarditis virus, Immunity, Innate, RNA Viruses, RNA, Double-Stranded, RNA, Viral, RNA Helicases, Mice, DEAD-box RNA Helicases
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