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

• Published in: Nature (London) 2014-10, Vol.514 (7522), p.372-375
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/109; 13/95; 631/250/262/2106/2518; 9/10; Analysis; Animals; Antiviral agents; Base Pairing; Base Sequence; DEAD Box Protein 58; DEAD-box RNA Helicases - metabolism; Diphosphates - metabolism; Female; Genome, Viral - genetics; Genomes; Health aspects; Humanities and Social Sciences; Immune system; Immunity, Innate; Immunology; Infections; letter; Male; Mammals; Melanoma; Mice; multidisciplinary; Phosphatase; Phosphates; Pyrophosphates; Reoviridae - genetics; Reoviridae - immunology; Reoviridae - physiology; RNA; RNA, Viral - chemistry; RNA, Viral - genetics; RNA, Viral - metabolism; Science; Synthesis; Transfer RNA; Viruses; Yeasts
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13590

The innate immune receptor RIG-I is shown to sense 5′-diphosphate RNAs as found in some viral genomes in addition to its well characterized activation by RNAs bearing 5′-triphosphate moieties. Broad viral recognition by RIG-I RIG-I (retinoic acid-inducible gene I) is an important innate immune sensor of RNA viruses that can be activated by RNAs bearing 5′ triphosphate moieties. This paper shows that RIG-I also senses 5′ diphosphate RNAs as found in some viral genomes. Such RNAs are found in some viruses but not in uninfected cells, so this finding extends the number of viruses that can be detected by a single innate immune sensor that does not compromise self/non-self discrimination. 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 1 , 2 . 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.