Antiviral immunity via RIG-I-mediated recognition of RNA bearing 59-diphosphates

Abstract

Mammalian cells possess mechanisms todetect and defend themselves from invading viruses. In the cytosol, theRIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded byDDX58) andMDA5 (melanomadifferentiation-associated gene 5; encodedby IFIH1) sense atypical RNAs associated with virus infection1,2. Detection triggers a signalling cascade via the adaptorMAVS that culminates in the production of type I interferons (IFN-α and β; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5are 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 1-3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5′-diphosphates (5′pp). Genomes from mammalian reoviruses with 5′pptermini, 5′pp-RNA isolated fromyeast L-Avirus, and base-paired 5′pp-RNAs made by in vitro transcription or chemical synthesis, all bindtoRIG-I and serve asRIG-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 powerfulmeans of self/non-self discrimination by the innate immune system.