Recognition of 5′-triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative strand virus

By M. Schlee, Andreas Roth, V. Hornung, C. A. Hagmann, Vera Wimmenauer, W. Barchet, C. Coch, M. Janke, Aleksandra Mihailović, G. Wardle and 11 more. 2009

816 citations recorded by the source corpus.

Antiviral immunity is triggered by immunorecognition of viral nucleic acids. The cytosolic helicase RIG-I is a key sensor of viral infections and is activated by RNA containing a triphosphate at the 5′end. The exact structure of RNA activating RIG-I remains controversial. Here we established a chemical approach for 5′triphosphate oligoribonucleotide synthesis and found that synthetic single-stranded 5′triphosphate oligoribonucleotides were unable to bind and activate RIG-I. Conversely, the addition of the synthetic complementary strand resulted in optimal binding and activation of RIG-I. Short double strand conformation with base pairing of the nucleoside carrying the 5′triphosphate was required. RIG-I activation was impaired by a 3′overhang at the 5′triphosphate end. These results define the structure of RNA for full RIG-I activation and explain how RIG-I detects negative strand RNA viruses which lack long double-stranded RNA but do contain panhandle blunt short double-stranded 5′triphosphate RNA in their single-stranded genome.

Subfields: Animal Science and Zoology, Immunology, Infectious Diseases

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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): “…or 50-diphosphate (p2dsRNA), which are prevalent on viral genomic RNAs and replication intermediates (Baum et al., 2010; Chiang et al., 2015; Goubau et al., 2014; Goulet et al., 2013; Linehan et al., 2018; Liu et al., 2015; Schlee et al., 2009; Schmidt et al., 2009; Te Velthuis et al., 2018).”
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).”
Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists (2015, background): “In vitro-synthesized RNA with a 5=-terminal triphosphate moiety was first identified as a RIG-I agonist (29, 30); however, more recently, it was discovered that a 5=-diphosphate terminus could also be recognized by RIG-I to mediate an antiviral response (10).”
RIG-I detects viral genomic RNA during negative-strand RNA virus infection. (2010, background): “…of NS1 to associate with stimulatory RNAs is due to its propensity to recognize RNA secondary structure determinants important for RIG-I activation (Schlee et al., 2009b; Schmidt et al., 2009) and is consistent with the finding that NS1 binds agonistic RNA in the absence of functional RIG-I…”
Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5 (2011, neutral): “In addition, RIG-I can specifically recognize 5 ′ -triphosphate groups on single-stranded RNA and (partially) dsRNA 9–11 .”
ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA (2015, background): “…ends containing either 50 triphosphate (ppp) or 50 diphosphate (pp) moieties (Goubau et al., 2014; Hornung et al., 2006; Pichlmair et al., 2006; Schlee et al., 2009; Schmidt et al., 2009) and not 2’ OH methylated at the first 5’ terminal nucleotide (Schuberth-Wagner et al., 2015). ppp-dsRNA…”
Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing (2010, background): “It is yet unclear whether ssRNA, even in the presence of a 5′-triphosphate group, is capable of inducingRIG-I activity, and at least in the case of shorter RNA molecules it appears that some double-stranded characteristics are required for its activation (12, 13).”
Structural basis for m7G recognition and 2′-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I (2016, neutral): “Longer RNAs have a more robust cell signaling response (8).”
Pathogen Recognition by the Innate Immune System (2011, background): “It was thought that single-stranded RNAs bearing a 5′ triphosphate were the only essential component for this recognition [50, 51]; however, recent studies suggest that, during the enzymatic synthesis of RNA, a secondary structure for double stranded RNA is generated, which acts as a RIG-I ligand [5”
RIG-I dependent sensing of poly(dA-dT) via the induction of an RNA polymerase III transcribed RNA intermediate (2009, neutral): “Of note, the in vitro –transcribed RNA species were completely sensitive to treatment with RNase III, in agreement with the finding that in vitro –transcribed RNA critically requires dsRNA conformation for its RIG-I-stimulatory activit”
An evolving arsenal: viral RNA detection by RIG-I-like receptors (2014, neutral): “In RIG-I, the CTD has evolved to engage in a high affinity interaction with a triphosphate group [13,17,18 ] present at the dsRNA termini of deposited genomic RNA [19,20] or replicative intermediates [21] of target viruses (Figure 1 Detection).”
RNA binding activates RIG-I by releasing an autorepressed signaling domain (2019, background): “The pathogen-associated molecular pattern (PAMP) recognized by RIG-I has been identified as a 5′-triphosphorylated blunt duplex RNA (6).”