Cited by 557interferon and immune responsesImmune Response and InflammationRNA regulation and disease

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Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates

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Goubau, Delphine, Schlee, Martin, Deddouche, Safia, Pruijssers, Andrea J., Zillinger, Thomas, Goldeck, Marion, Schuberth, Christine, Van der Veen, Annemarthe G., Fujimura, Tsutomu, Rehwinkel, Jan, Iskarpatyoti, Jason A., Barchet, Winfried, Ludwig, Janos, Dermody, Terence S., Hartmann, Gunther, Reis e Sousa, Caetano·2014·Nature

DOI 10.1038/nature13590PMC PMC4201573

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Abstract

Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-α and β; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.

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Background
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Ledwith, M. P., Nipper, T., Davis, K. A., Üresin, D., Zhang, Z., Kleer, M., Khaperskyy, D. A., McCormick, C., Komarova, A. V., & Mehle, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.12.642847 · Cited by 2
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Sampaio, N. G., Gearing, L. J., Dias, A. G., Chauveau, L., Odon, V., Cursi, C., Mayer, A., Ratnadiwakara, M., Änkö, M., Hertzog, P. J., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-6466919/v1 · Cited by 2
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Authors: Goubau, D., Schlee, M., Deddouche, S., Pruijssers, A. J., Zillinger, T., Goldeck, M., Schuberth, C., Van der Veen, A. G., Fujimura, T., Rehwinkel, J., Iskarpatyoti, J. A., Barchet, W., Ludwig, J., Dermody, T. S., Hartmann, G., & Reis e Sousa, C.
Affiliations: Cancer Research UK (GB)
University Hospital Bonn (DE)
Vanderbilt University (US)
Consejo Superior de Investigaciones Científicas (ES)
Corresponding author: Goubau, Delphine
ORCID: Schlee, Martin
Pruijssers, Andrea J.
Zillinger, Thomas
Goldeck, Marion
Fujimura, Tsutomu
Rehwinkel, Jan
Barchet, Winfried
Dermody, Terence S.
Hartmann, Gunther
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2014-08-10
Volume: 514
Issue: 7522
Pages: 372-375
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature13590
PMC: PMC4201573
OpenAlex: W2156869719
Cited by: 557
References: 36
Citations by year: 2026: 16 · 2025: 40 · 2024: 43 · 2023: 34 · 2022: 54 · 2021: 56 · 2020: 51 · 2019: 51 · 2018: 62 · 2017: 44 · 2016: 43 · 2015: 55 · 2014: 8
FWCI: 22.85
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Funders: Cancer Research UK (15689, A3598)
National Institute of Allergy and Infectious Diseases (R01AI038296, R37AI038296, R01AI050800)
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: RIG-I, antiviral innate immunity, RIG-I-like receptors, MDA5, MAVS, type I interferon, reovirus, L-A virus, viral RNA recognition, self/non-self discrimination, cytosolic RNA sensing, RNA-dependent protein kinase, interferon-stimulated genes, interferon lambda
MeSH terms: DEAD Box Protein 58, Animals, Base Sequence, Female, Immunity, Innate, Male, Diphosphates, Reoviridae, RNA, Viral, Genome, Viral, Base Pairing, Mice, DEAD-box RNA Helicases

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Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates

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