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      A Conserved Histidine in the RNA Sensor RIG-I Controls Immune Tolerance to N 1-2′O-Methylated Self RNA

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          Summary

          The cytosolic helicase retinoic acid-inducible gene-I (RIG-I) initiates immune responses to most RNA viruses by detecting viral 5′-triphosphorylated RNA (pppRNA). Although endogenous mRNA is also 5′-triphosphorylated, backbone modifications and the 5′-ppp-linked methylguanosine ( m7G) cap prevent immunorecognition. Here we show that the methylation status of endogenous capped mRNA at the 5′-terminal nucleotide (N 1) was crucial to prevent RIG-I activation. Moreover, we identified a single conserved amino acid (H830) in the RIG-I RNA binding pocket as the mediator of steric exclusion of N 1-2′O-methylated RNA. H830A alteration (RIG-I(H830A)) restored binding of N 1-2′O-methylated pppRNA. Consequently, endogenous mRNA activated the RIG-I(H830A) mutant but not wild-type RIG-I. Similarly, knockdown of the endogenous N 1-2′O-methyltransferase led to considerable RIG-I stimulation in the absence of exogenous stimuli. Studies involving yellow-fever-virus-encoded 2′O-methyltransferase and RIG-I(H830A) revealed that viruses exploit this mechanism to escape RIG-I. Our data reveal a new role for cap N 1-2′O-methylation in RIG-I tolerance of self-RNA.

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          Highlights

          • •

            N 1-2′O-methylation is crucial to block RIG-I activation by viral and self RNA

          • •

            Self-RNA exclusion is singularly governed by the conserved H830 in RIG-I

          • •

            H830A alteration leads to indiscriminate recognition of endogenous RNA by RIG-I

          • •

            Cellular N 1-2′O-methyltransferase knockdown renders endogenous RNA stimulatory

          Abstract

          The cytosolic receptor RIG-I initiates immune responses against most RNA viruses by detecting viral RNA. Schlee and colleagues report that a conserved amino acid in the RNA binding pocket prevents recognition of endogenous RNA bearing a N 1-2′O-methyl group as a marker of “self” and that flaviviruses exploit this tolerance mechanism for immunoescape.

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          Most cited references 26

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          RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.

           Albert Tan,  Tanja I Näslund,  Andreas Pichlmair … (2007)
          Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
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            Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA.

             Eva Kowalinski,  Thomas Lunardi,  Andrew A. McCarthy … (2011)
            RIG-I is a key innate immune pattern-recognition receptor that triggers interferon expression upon detection of intracellular 5'triphosphate double-stranded RNA (5'ppp-dsRNA) of viral origin. RIG-I comprises N-terminal caspase activation and recruitment domains (CARDs), a DECH helicase, and a C-terminal domain (CTD). We present crystal structures of the ligand-free, autorepressed, and RNA-bound, activated states of RIG-I. Inactive RIG-I has an open conformation with the CARDs sequestered by a helical domain inserted between the two helicase moieties. ATP and dsRNA binding induce a major rearrangement to a closed conformation in which the helicase and CTD bind the blunt end 5'ppp-dsRNA with perfect complementarity but incompatibly with continued CARD binding. We propose that after initial binding of 5'ppp-dsRNA to the flexibly linked CTD, co-operative tight binding of ATP and RNA to the helicase domain liberates the CARDs for downstream signaling. These findings significantly advance our molecular understanding of the activation of innate immune signaling helicases. Copyright © 2011 Elsevier Inc. All rights reserved.
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              IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA.

               Jacques Colinge,  Maria Górna,  Tilmann Bürckstümmer … (2011)
              Antiviral innate immunity relies on the recognition of microbial structures. One such structure is viral RNA that carries a triphosphate group on its 5' terminus (PPP-RNA). By an affinity proteomics approach with PPP-RNA as the 'bait', we found that the antiviral protein IFIT1 (interferon-induced protein with tetratricopeptide repeats 1) mediated binding of a larger protein complex containing other IFIT family members. IFIT1 bound PPP-RNA with nanomolar affinity and required the arginine at position 187 in a highly charged carboxy-terminal groove of the protein. In the absence of IFIT1, the growth and pathogenicity of viruses containing PPP-RNA was much greater. In contrast, IFIT proteins were dispensable for the clearance of pathogens that did not generate PPP-RNA. On the basis of this specificity and the great abundance of IFIT proteins after infection, we propose that the IFIT complex antagonizes viruses by sequestering specific viral nucleic acids.
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                Author and article information

                Contributors
                Martin Schlee
                Journal
                Journal ID (nlm-ta): Immunity
                Journal ID (iso-abbrev): Immunity
                Title: Immunity
                Publisher: Elsevier Inc.
                ISSN (Print): 1074-7613
                ISSN (Electronic): 1097-4180
                Publication date PMC-release: 14 July 2015
                Publication date (Print): 21 July 2015
                Publication date (Electronic): 14 July 2015
                Volume: 43
                Issue: 1
                Pages: 41-51
                Affiliations
                [1 ]Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53105 Bonn, Germany
                [2 ]German Center for Infection Research Cologne-Bonn
                [3 ]Institute of Molecular Medicine, University Hospital, University of Bonn, 53105 Bonn, Germany
                [4 ]Department of Virology, Bernhard-Nocht-Institute for Tropical Medicine, 20259 Hamburg, Germany
                [5 ]Institute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany
                Author notes
                [∗ ]Corresponding author martin.schlee@ 123456uni-bonn.de
                [6]

                Present address: Department of Otolaryngology, Head and Neck Surgery, University of Tübingen, 72076 Tübingen, Germany

                [7]

                Co-first author

                [8]

                Co-senior author

                Article
                Publisher ID: S1074-7613(15)00259-9
                DOI: 10.1016/j.immuni.2015.06.015
                PMC ID: 7128463
                PubMed ID: 26187414
                Copyright statement: Copyright © 2015 Elsevier Inc. All rights reserved.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Subject: Article

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                ScienceOpen disciplines: Immunology

                Keywords: cap, mrna, mtr1, rig-i, virus, immune recognition of rna, 5′-triphosphate rna, 2′o-methyl, innate immune tolerance mechanism

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