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Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates
Open accessAbstract
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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“Through recognition of TLR3 in endosomes or retinoic acid-inducible gene I, melanoma differentiation-associated protein 5, and inflammasomes in the cytoplasm,96, 97, 98, 99 depending on the amount, dsRNAs might overactivate innate immunity and lead to adverse events.”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [97]
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Metadata
- 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
- Venue
- Nature
- Published
- 2014-08-10
- Volume
- 514
- Issue
- 7522
- Pages
- 372-375
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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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