Viral subversion of the host protein synthesis machinery

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Key Points

Although viruses encode many of the functions that are required for viral replication, they are completely reliant on the protein synthesis machinery that is present in their host cells.
Recruiting cellular ribosomes to translate viral mRNAs represents a crucial step in the replication of all viruses.
To ensure translation of their mRNAs, viruses use a diverse collection of strategies (probably pirated from their cellular hosts) to commandeer key translation factors that are required for the initiation, elongation and termination steps of translation.
Viruses also neutralize host defences that seek to incapacitate the translation machinery in infected cells.

Abstract

Viruses rely on the translation machinery of the host cell to produce the proteins that are essential for their replication. Here, Walsh and Mohr discuss the diverse strategies by which viruses subvert the host protein synthesis machinery and regulate the translation of viral mRNAs.

Abstract

Viruses are fully reliant on the translation machinery of their host cells to produce the polypeptides that are essential for viral replication. Consequently, viruses recruit host ribosomes to translate viral mRNAs, typically using virally encoded functions to seize control of cellular translation factors and the host signalling pathways that regulate their activity. This not only ensures that viral proteins will be produced, but also stifles innate host defences that are aimed at inhibiting the capacity of infected cells for protein synthesis. Remarkably, nearly every step of the translation process can be targeted by virally encoded functions. This Review discusses the diverse strategies that viruses use to subvert host protein synthesis functions and regulate mRNA translation in infected cells.

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Most cited references 115

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Didier Raoult, Stéphane Audic, Catherine Robert … (2004)

We recently reported the discovery and preliminary characterization of Mimivirus, the largest known virus, with a 400-nanometer particle size comparable to mycoplasma. Mimivirus is a double-stranded DNA virus growing in amoebae. We now present its 1,181,404-base pair genome sequence, consisting of 1262 putative open reading frames, 10% of which exhibit a similarity to proteins of known functions. In addition to exceptional genome size, Mimivirus exhibits many features that distinguish it from other nucleocytoplasmic large DNA viruses. The most unexpected is the presence of numerous genes encoding central protein-translation components, including four amino-acyl transfer RNA synthetases, peptide release factor 1, translation elongation factor EF-TU, and translation initiation factor 1. The genome also exhibits six tRNAs. Other notable features include the presence of both type I and type II topoisomerases, components of all DNA repair pathways, many polysaccharide synthesis enzymes, and one intein-containing gene. The size and complexity of the Mimivirus genome challenge the established frontier between viruses and parasitic cellular organisms. This new sequence data might help shed a new light on the origin of DNA viruses and their role in the early evolution of eukaryotes.

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Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication.

Alexander Karlas, Nikolaus Machuy, Yujin Shin … (2010)

Influenza A virus, being responsible for seasonal epidemics and reoccurring pandemics, represents a worldwide threat to public health. High mutation rates facilitate the generation of viral escape mutants, rendering vaccines and drugs directed against virus-encoded targets potentially ineffective. In contrast, targeting host cell determinants temporarily dispensable for the host but crucial for virus replication could prevent viral escape. Here we report the discovery of 287 human host cell genes influencing influenza A virus replication in a genome-wide RNA interference (RNAi) screen. Using an independent assay we confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the current pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. Notably, a subset of these common hits was also essential for replication of a highly pathogenic avian H5N1 strain. In-depth analyses of several factors provided insights into their infection stage relevance. Notably, SON DNA binding protein (SON) was found to be important for normal trafficking of influenza virions to late endosomes early in infection. We also show that a small molecule inhibitor of CDC-like kinase 1 (CLK1) reduces influenza virus replication by more than two orders of magnitude, an effect connected with impaired splicing of the viral M2 messenger RNA. Furthermore, influenza-virus-infected p27(-/-) (cyclin-dependent kinase inhibitor 1B; Cdkn1b) mice accumulated significantly lower viral titres in the lung, providing in vivo evidence for the importance of this gene. Thus, our results highlight the potency of genome-wide RNAi screening for the dissection of virus-host interactions and the identification of drug targets for a broad range of influenza viruses.

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The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit.

Alexandre Dias, Denis Bouvier, Thibaut Crépin … (2009)

The influenza virus polymerase, a heterotrimer composed of three subunits, PA, PB1 and PB2, is responsible for replication and transcription of the eight separate segments of the viral RNA genome in the nuclei of infected cells. The polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique 'cap-snatching' mechanism. The PB2 subunit binds the 5' cap of host pre-mRNAs, which are subsequently cleaved after 10-13 nucleotides by the viral endonuclease, hitherto thought to reside in the PB2 (ref. 5) or PB1 (ref. 2) subunits. Here we describe biochemical and structural studies showing that the amino-terminal 209 residues of the PA subunit contain the endonuclease active site. We show that this domain has intrinsic RNA and DNA endonuclease activity that is strongly activated by manganese ions, matching observations reported for the endonuclease activity of the intact trimeric polymerase. Furthermore, this activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the influenza endonuclease. The crystal structure of the domain reveals a structural core closely resembling resolvases and type II restriction endonucleases. The active site comprises a histidine and a cluster of three acidic residues, conserved in all influenza viruses, which bind two manganese ions in a configuration similar to other two-metal-dependent endonucleases. Two active site residues have previously been shown to specifically eliminate the polymerase endonuclease activity when mutated. These results will facilitate the optimisation of endonuclease inhibitors as potential new anti-influenza drugs.

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Author and article information

Contributors

Derek Walsh: derek.walsh@nyumc.org

Bio :

Derek Walsh received his Ph.D. in cell biology from Dublin City University in Ireland and did postdoctoral work at New York University School of Medicine, USA, in biochemistry and molecular virology. He became a principal investigator at Dublin City University in 2006, where his laboratory investigates translational control in poxvirus- and herpesvirus-infected cells.

Ian Mohr: ian.mohr@med.nyu.edu

Bio :

Ian Mohr was a graduate student at Cold Spring Harbor Laboratory, Laurel Hollow, New York, and received his Ph.D. in microbiology and molecular genetics from the State University of New York at Stony Brook. He did postdoctoral work in biochemistry and molecular biology at the University of California, Berkeley, USA, and joined the faculty at New York University School of Medicine in 1996. Presently, he is Professor of Microbiology and a member of the New York University Cancer Institute. His laboratory focuses on virus–host interactions that control translation.

Journal

Journal ID (nlm-ta): Nat Rev Microbiol

Journal ID (iso-abbrev): Nat. Rev. Microbiol

Title: Nature Reviews. Microbiology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1740-1526

ISSN (Electronic): 1740-1534

Publication date (Electronic): 17 October 2011

Publication date (Print): 2011

Volume: 9

Issue: 12

Pages: 860-875

Affiliations

[1 ]GRID grid.15596.3e, ISNI 0000000102380260, National Institute for Cellular Biotechnology, Dublin City University, ; 9 Dublin Ireland

[2 ]GRID grid.137628.9, ISNI 0000 0004 1936 8753, Department of Microbiology and New York University Cancer Institute, , New York University School of Medicine, ; New York, 10016 New York USA

[3 ]GRID grid.137628.9, ISNI 0000 0004 1936 8753, Present Address: Present address: Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA., ; ,

Article

Publisher ID: BFnrmicro2655

DOI: 10.1038/nrmicro2655

PMC ID: 7097311

PubMed ID: 22002165

SO-VID: 60c059fe-da5b-47ea-83e3-04c9f8e3338a

License:

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.