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      Conventional and unconventional mechanisms for capping viral mRNA


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          Key Points

          • mRNAs are protected at their 5′ ends by a cap structure consisting of an N7-methylated GTP molecule linked to the first transcribed nucleotide by a 5′–5′ triphosphate bond.

          • The cap structure is essential for RNA splicing, export and stability, and allows the ribosomal complex to recognize mRNAs and ensure their efficient translation.

          • Uncapped RNA molecules are degraded in cytoplasmic granular compartments called processing bodies and may be detected as 'non-self' by the host cell, triggering antiviral innate immune responses through the production of interferons.

          • Conventional RNA capping (that is, of mRNAs from the host cell and from DNA viruses) requires hydrolysis of the 5′ γ-phosphate of RNA by an RNA triphosphatase, transfer of a GMP molecule onto the 5′-end of RNA by a guanylyltransferase, and methylation of this guanosine by an (guanine-N7)-methyltransferase. Subsequent methylations on the first and second transcribed nucleotides by (nucleoside-2′- O)-methyltransferases form cap-1 and cap-2 structures.

          • Viruses have evolved highly diverse capping mechanisms to acquire cap structures using their own or cellular capping machineries, or by stealing cap structures from cellular mRNAs.

          • Virally encoded RNA-capping machineries are diverse in terms of their genetic components, protein domain organization, enzyme structures, and reaction mechanisms and pathways, making viral RNA capping an attractive target for antiviral-drug design.


          Capping the 5′ end of eukaryotic mRNAs with a 7-methylguanosine moiety enables efficient splicing, nuclear export and translation of mRNAs, and also limits their degradation by cellular exonucleases. Here, Canard and colleagues describe how viruses synthesize their own mRNA cap structures or steal them from host mRNAs, allowing efficient synthesis of viral proteins and avoidance of host innate immune responses.


          In the eukaryotic cell, capping of mRNA 5′ ends is an essential structural modification that allows efficient mRNA translation, directs pre-mRNA splicing and mRNA export from the nucleus, limits mRNA degradation by cellular 5′–3′ exonucleases and allows recognition of foreign RNAs (including viral transcripts) as 'non-self'. However, viruses have evolved mechanisms to protect their RNA 5′ ends with either a covalently attached peptide or a cap moiety (7-methyl-Gppp, in which p is a phosphate group) that is indistinguishable from cellular mRNA cap structures. Viral RNA caps can be stolen from cellular mRNAs or synthesized using either a host- or virus-encoded capping apparatus, and these capping assemblies exhibit a wide diversity in organization, structure and mechanism. Here, we review the strategies used by viruses of eukaryotic cells to produce functional mRNA 5′-caps and escape innate immunity.

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          Most cited references141

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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
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            RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.

            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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              Intracellular pattern recognition receptors in the host response.

              The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and eliminate them. Indeed, Toll-like receptors are a class of membrane receptors that sense extracellular microbes and trigger anti-pathogen signalling cascades. Recently, intracellular microbial sensors have also been identified, including NOD-like receptors and the helicase-domain-containing antiviral proteins RIG-I and MDA5. Some of these cytoplasmic molecules sense microbial, as well as non-microbial, danger signals, but the mechanisms of recognition used by these sensors remain poorly understood. Nonetheless, it is apparent that these proteins are likely to have critical roles in health and disease.

                Author and article information

                Nat Rev Microbiol
                Nat. Rev. Microbiol
                Nature Reviews. Microbiology
                Nature Publishing Group UK (London )
                5 December 2011
                : 10
                : 1
                : 51-65
                [1 ]GRID grid.463764.4, ISNI 0000 0004 1798 275X, Centre National de la Recherche Scientifique and Aix-Marseille Université, UMR 6098, Architecture et Fonction des Macromolécules Biologiques, ; 163 avenue de Luminy, Marseille cedex 09, 13288 France
                [2 ]GRID grid.59025.3b, ISNI 0000 0001 2224 0361, School of Biological Sciences, Nanyang Technological University, ; 60 Nanyang Drive, Singapore, 637551 Republic of Singapore
                © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2011

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                © Springer Nature Limited 2012

                virology,cellular microbiology,pathogens,innate immunity,virus-host interactions


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