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

By D. Goubau, M. Schlee, Safia Deddouche, A. Pruijssers, T. Zillinger, Marion Goldeck, Christine Schuberth, Annemarthe G. van der Veen, T. Fujimura, J. Rehwinkel and 6 more. 2014

547 citations recorded by the source corpus.

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.

Subfields: Animal Science and Zoology, Immunology, Molecular Biology

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Citations in the corpus

The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, background): “Years of work by many labs has shown that the most potent triggers of the RIG-I response in biochemical experiments, in cells, and in living animals are double-stranded RNAs (dsRNAs), containing a blunt, base-paired terminus that is decorated with a 50-triphosphate (p3dsRNA) or 50-diphosphate (p2dsR”
A minimal RNA ligand for potent RIG-I activation in living mice (2017, background): “Recent studies indicate that RNAs bearing a diphosphate at the 5′ terminus are bona fide ligands for RIG-I (33).”
ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA (2015, background): “ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5’ triphosphate dsRNA.”
Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5 (2015, unknown): “They recognize RNA species harboring 5′-triphosphate or diphosphate ends and/or double-stranded features (dsRNA) [3–7] that are physiologically absent from the cytosol (see [2] for review).”
Coronavirus infections and immune responses (2020, background): “MDAS‐recognized RNA is characterized by long double‐stranded RNA more than 1 kbp. Crystal structure analysis shows that the helicase and CTD structure of MDA5 are also surrounded by double‐stranded RNA, the same as RIG‐I.”
mRNA capping: biological functions and applications (2016, unknown): “While MDA5 interacts with long dsRNA (66–70), RIG-I interacts strongly with short dsRNA, and less so with 5 -ppp and 5 -pp ssRNA (71–75).”
Establishing the role of ATP for the function of the RIG-I innate immune sensor (2015, background): “, 2015), yet these RNAs do not induce immune signaling by RIGI, even at saturating concentrations (Schlee et al., 2009; Baum et al., 2010; Goubau et al., 2014).”
Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants (2018, background): “Specifically, RIG-I detects dsRNA ends harbouring 5’ tri- or diphosphates (Goubau et al., 2014; Schlee et al., 2009; Schmidt et al., 2009).”