Review Article | Published:

RNA viruses and the host microRNA machinery

Nature Reviews Microbiology volume 11, pages 169180 (2013) | Download Citation

Abstract

Gene silencing by small RNAs (sRNAs) occurs in all three domains of life. In recent years, our appreciation of the diverse functions of sRNAs has increased, and we have identified roles for these RNAs in cellular differentiation, fitness and pathogen defence. Interestingly, although plants, nematodes and arthropods use sRNAs to combat viral infections, chordates have replaced this defence strategy with one based exclusively on proteins. This limits chordate use of sRNAs to the silencing of genome-encoded transcripts and has resulted in viruses that do not perturb sRNA-related cellular processes. This evolutionary phenomenon provides an opportunity to exploit the pre-existing chordate sRNA pathways in order to generate a range of virus-based biological tools. Here, I discuss the relationship between sRNAs and RNA viruses, detail how microRNA expression can be harnessed to control RNA viruses and describe how RNA viruses can be designed to deliver sRNAs.

Key points

  • Small RNAs (sRNAs) are used by plants, nematodes and arthropods in cellular defence against viruses.

  • In chordates, sRNAs were replaced with a protein-based system to inhibit viral replication.

  • microRNAs (miRNAs) are eukaryotic sRNAs that function to fine-tune host gene expression.

  • In chordates, miRNAs do not inhibit RNA viruses, and RNA viruses do not inhibit miRNAs.

  • RNA viruses can be engineered to interact with the host miRNA pathways, and miRNAs can be used to control viral tropism.

  • RNA viruses can also be used to deliver sRNAs.

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Acknowledgements

The author thanks the members of his laboratory, both past and present, for excellent discussions on the issues addressed in this Review and for help with the illustrations, and apologizes to those whose relevant work could not be cited here. The author is indebted to the Pew Charitable Trust and to Burroughs Wellcome for their continued support to freely explore these areas of research.

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  1. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.  benjamin.tenoever@mssm.edu

    • Benjamin R. tenOever

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The author declares no competing financial interests.

Glossary

RNAi

An activity by which a small RNA negatively impacts the functionality of an mRNA.

Clustered regularly interspaced short palindromic repeat RNAs

(crRNAs). 57-nucleotide RNAs that are used to target phages in a sequence-specific manner.

PIWI-interacting RNAs

(piRNAs). RNAs that are 30 nucleotides long and are responsible for detecting foreign DNA and repressing transposable elements.

Virus-derived interfering RNAs

(viRNAs). RNAs that are 21 nucleotides in length, processed from a viral genomic source by the host and used to silence viral replication.

MicroRNAs

(miRNAs). Host-derived small RNAs that are generated by endonucleases to fine-tune mRNA and protein levels.

RNA-dependent RNA polymerase

A polymerase that generates nascent RNA from an RNA template. This polymerase is commonly used by RNA viruses for genome replication and is also used in plants and nematodes for the amplification of virus-derived interfering RNAs.

RNA-induced silencing complex

(RISC). A complex of RNA-binding proteins and an Argonaute protein that, together, are responsible for small-RNA-mediated silencing of target RNAs.

Pathogen-associated molecular patterns

Structures that are common among a group of pathogens and are constrained from rapid evolutionary change. These structures are used in cellular recognition of the pathogen.

Small interfering RNA

(siRNA). RNA that is capable of RNA-induced silencing complex (RISC)-mediated mRNA silencing and binds its target with perfect complementarity.

Short hairpin RNA

(shRNA). An 60 nucleotide stem–loop RNA that can serve as a substrate for Dicer.

Artificial miRNAs

Small RNAs that maintain the secondary structure and sequence of a specific microRNA but encode changes in the stem of the hairpin, resulting in a distinct small RNA.

Pattern recognition receptors

Cellular proteins that are responsible for the recognition of pathogen-associated molecular patterns.

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https://doi.org/10.1038/nrmicro2971

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