Key Points
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In plants and insects, virus-induced gene silencing (VIGS) is a mechanism whereby double-stranded features of viral genomes are recognized and processed by Dicer-like enzymes to generate antiviral small RNA molecules. The diversification and specialization of silencing components that are observed in both types of organisms might have arisen primarily as an adaptation to optimal recognition and processing of various double-stranded forms of pathogenic RNA molecules.
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No single RNA-silencing component has been broadly implicated in antiviral defence in plants so far. This probably reflects the functional redundancy and/or combinatorial interactions between individual members of large protein families that account for the remarkable diversity and complexity of plant RNA-silencing pathways.
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DNA viruses might be restricted by RNA silencing that acts at the transcriptional level. This occurs through small RNA pathways that direct chromatin modifications that are involved in epigenetic control of transposable elements and endogenous loci.
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The miRNA pathway might also restrict accumulation of viruses that produce nuclear transcripts that are folded in a way that mimics the structure of endogenous miRNA precursors. These are normally processed in the nucleus by Dicer-like enzymes to ensure regulatory functions in the cell. This phenomenon has been documented in human cells that are infected by the Epstein–Barr virus, transcripts of which are processed into at least five distinct miRNA molecules.
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In plants, nematodes and fungi, but not in Drosophila melanogaster or humans, primary VIGS reactions might be amplified through the activities of host-encoded RNA-dependent RNA polymerases (RdRPs). Amplification is also involved in the systemic spread of silencing, providing a form of genetic immune system that ensures clearance of viral and sub-viral pathogens.
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Plant and insect viruses have developed a range of counter-defensive measures against RNA silencing, one of which is the production of highly diverse suppressor proteins that inhibit distinct steps of the silencing pathway. Strategies for silencing suppression are varied and include the direct inhibition of silencing-effector molecules, recruitment of endogenous pathways that negatively control RNA silencing and modification of the host transcriptome.
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Viral suppression of RNA silencing often — although not always — has adverse effects on host biology, and forms the basis of some of the developmental and cytopathic symptoms that are associated with virus infections in plants, and probably other organisms. This is, at least partly, an incidental consequence of the primary suppression of VIGS at an intermediate step that is shared with the miRNA pathway.
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Viruses can also evade RNA silencing through a range of means that include sub-cellular compartmentalization and loss of silencing-target sequences due to high mutation rates. They might also deliberately hijack their host silencing pathways to establish optimal infection conditions.
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It remains unclear whether RNA silencing naturally limits viral infections in vertebrates as it does in plants and insects. Potent dsRNA-triggered defence pathways, such as the vertebrate interferon response, might mask or supplant the putative RNA-silencing response that is elicited by viruses in those organisms.
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It is possible that cellular microRNA molecules, rather than virus-derived siRNA molecules, might contribute to antiviral defence in vertebrates. This might be indirect, for example, by controlling the accumulation of basic compatibility factors, or direct, owing to the sequence complementarity of miRNA molecules to parasitic nucleic acids.
Abstract
In eukaryotes, small RNA molecules engage in sequence-specific interactions to inhibit gene expression by RNA silencing. This process fulfils fundamental regulatory roles, as well as antiviral functions, through the activities of microRNAs and small interfering RNAs. As a counter-defence mechanism, viruses have evolved various anti-silencing strategies that are being progressively unravelled. These studies have not only highlighted our basic understanding of host–parasite interactions, but also provide key insights into the diversity, regulation and evolution of RNA-silencing pathways.
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Acknowledgements
I thank all my laboratory colleagues for fruitful discussions. I am particularly grateful to S. Wei Ding, B. Cullen, T. Hohn and M. Poogin for providing access to data before their publication. Many thanks also to J. Carrington, E. Chapman, M.-B. Wang, P. Waterhouse, T. Hall, J. Vargason, L. Chaerle and C. Masuta for providing many of the items used for illustrations. Work in my laboratory is supported by the Centre National de la Recherche Scientifique, the Federation of European Biochemical Societies and the European Molecular Biological Organisation.
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DATABASES
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Glossary
- EPISOMES
-
Genetic elements that can replicate independently in eukaryotic nuclei.
- VIROID
-
An autonomously replicating subviral pathogen of plants with a circular, rod-like RNA genome that contains no ORF. Viroids account for some of the most devastating diseases of plants.
- SALICYLIC ACID
-
A compound that is involved in plant defence against insects and pathogens; it has intrinsic anti-microbial properties.
- PATHOGENICITY DETERMINANT
-
A factor that is not strictly required for virus replication, but is nevertheless needed for its efficient accumulation at the cellular or systemic level.
- ECOTYPE
-
A population within a species that has developed distinct morphological or physiological characteristics as an adaptation to a specific environment, and which persists when individuals are moved to a different environment.
- PROTOPLAST
-
A plant cell from which the cell wall has been removed by mechanical or enzymatic means. Protoplasts can be prepared from primary tissues of most plant organs, as well as from cultured plant cells.
- MERISTEM
-
A plant tissue that is usually made up of small cells that can divide indefinitely. Meristems give rise either to similar cells or to cells that differentiate into mature tissues, including reproductive tissues that produce seeds and pollen.
- INTERFERONS
-
(IFNs). A group of glycoproteins, produced by various cell types, that prevent viral replication in newly infected cells and, in some cases, modulate specific cellular functions. They are produced in response to a range of stimuli, including exposure to dsRNA.
- HUMORAL IMMUNE RESPONSE
-
A bodily defence reaction that is mediated by antibodies (produced by B cells) that specifically neutralize invading antigens.
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Voinnet, O. Induction and suppression of RNA silencing: insights from viral infections. Nat Rev Genet 6, 206–220 (2005). https://doi.org/10.1038/nrg1555
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DOI: https://doi.org/10.1038/nrg1555
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