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Conventional and unconventional mechanisms for capping viral mRNA

Nature Reviews Microbiology volume 10, pages 51–65 (2012)Cite this article

Subjects

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.

Abstract

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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Figure 1: RNA cap structure and canonical capping mechanisms.
Figure 2: RNA 5′ ends in the mammalian-virus world.
Figure 3: Unconventional capping pathways.
Figure 4: Structural constituents of viral capping machineries, folds and mechanisms.
Figure 5: Unconventional capping machineries. Endonucleases and cap-binding PB2.
Figure 6: Sensing of viral RNA by the innate immune system.

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Acknowledgements

The authors are in debt to all previous and current laboratory members, too numerous to name, for their contributions and involvement in the study of viral RNA replication and capping. Special thanks go to B. Selisko for her tireless dedication to and help with the scientific elaboration of this manuscript. This work was supported in part through funding by the Fondation pour la Recherche Médicale (Programme Aide aux équipes), the French Direction Générale de l'Armement (contrat 07co404), Infectiopôle-Sud and the European Union Seventh Framework Programme (FP7/2007–2013) through the project SILVER (Small inhibitor leads against emerging RNA viruses; grant agreement 260644).

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  1. 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

    Etienne Decroly, François Ferron, Julien Lescar & Bruno Canard

  2. School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore

    Julien Lescar

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  1. Etienne Decroly
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  2. François Ferron
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  3. Julien Lescar
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DATABASES

Protein Data Bank

1AV6

1CKM

1CKN

1CKO

1EJ6

1L9V

1YN9

2BHR

2JHC

2P41

2QZE

2VDW

2VQZ

2XI5

3HW4

3JSB

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Glossary

Pre-mRNA splicing

A post-transcriptional modification of pre-mRNA, in which introns are excised and exons are joined in order to form a translationally functional, mature mRNA.

γ-phosphate

The third phosphate attached at the 5′ end of the ribose moiety of a nucleotide.

'Ping-pong' mechanism

A two-step mechanism in which a substrate molecule first forms a (covalent) link with the enzyme and is then transferred to an acceptor molecule to yield a product.

Poly(A) tail

A string of AMP that is added to the 3′ end of mRNA.

NUDIX hydrolase superfamily

A family of proteins that hydrolyse a wide range of organic pyrophosphates, including NDPs, NTPs, dinucleoside and diphosphoinositol polyphosphates, nucleotide sugars and RNA caps, with varying degrees of substrate specificity.

Single-stranded positive-sense RNA viruses

(ss(+)RNA viruses). Viruses that have or produce mRNAs that are co-linear to their genomic RNA.

43S pre-initiation complex

A multiprotein complex composed of eukaryotic translation initiation factor 3 (eIF3), eIF4A, eIF4E and eIF4G associated with the small ribosomal subunit. This pre-initiation complex scans the mRNA towards the 'start' codon (typically AUG), where translation is initiated.

Single-stranded negative-sense RNA viruses

(ss(−)RNA viruses). Viruses that have or produce mRNAs that are complementary to their genomic RNA.

Ambisense RNA viruses

Viruses (such as members of the families Arenaviridae and Bunyaviridae) that have or produce both mRNAs that are co-linear to and mRNAs that are complementary to their genomic RNA, although most mRNAs are complementary in polarity.

β-phosphate

The second phosphate attached at the 5′ end of the ribose moiety of a nucleotide.

Walker A and B motifs

Motifs that are present in nucleotide-binding proteins but also in a range of proteins with widely varying functions, including ATP synthases, myosins, transducins, helicases, kinases and RecA proteins. The Walker A motif contains a phosphate-binding loop (P-loop) motif with the consensus sequence GXXXGK(T/S), and the Walker B motif contains the consensus sequence (R/K)XXXXGXXXXLhhhhD (in which h refers to any hydrophobic residue).

Nucleophilic attack

Generally, a starting point for a chemical reaction; a doublet of electrons selectively attacks the positive or partially positive charge of the atomic nucleus in order to create a new chemical bond.

α-phosphate

The first phosphate attached at the 5′ end of the ribose moiety of a nucleotide.

pKa value

The acid dissociation constant, a quantitative measurement of the strength of a chemical group as an acid in solution. It corresponds to the pH value at which half of the ionizable group is either protonated or deprotonated.

ε-amino group

A positively charged group found at the extremity of a lysine side chain. The ε-amino group is a primary amine and, owing to its high pKa value, it is reactive and often participates in reactions at the active site of enzymes.

Stem loop

A hairpin structure in single-stranded RNA or DNA, resulting from intramolecular base-pairing when two regions of the same strand contain partial or perfect anti-complementary nucleotide sequences.

Cell-based replicon assays

Assays that allow one to follow the replication of a 'minimal viral genome' encoding the viral replication complex but no structural or envelope proteins, which are usually replaced by reporter genes (such as luciferase or chloramphenicol acetyl transferase genes).

Viral antigenomes

Viral RNAs that are complementary strands to the genome. The antigenome strand is used as a matrix for the synthesis of new viral genomes, and of viral mRNAs in the case of positive-sense RNA viruses.

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Decroly, E., Ferron, F., Lescar, J. et al. Conventional and unconventional mechanisms for capping viral mRNA. Nat Rev Microbiol 10, 51–65 (2012). https://doi.org/10.1038/nrmicro2675

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