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Nature. 2014 Oct 16;514(7522):372-375. doi: 10.1038/nature13590. Epub 2014 Aug 10.

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

Author information

1
Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
2
Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, D-53127 Bonn, Germany.
3
Department of Pediatrics, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.
4
Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.
5
Instituto de Biología Funcional y Genómica. Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, Zacarías González 2, 37007, Salamanca, Spain.
6
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, D7235 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2581, USA.
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Contributed equally

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.

PMID:
25119032
PMCID:
PMC4201573
DOI:
10.1038/nature13590
[Indexed for MEDLINE]
Free PMC Article

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