Abstract
The RNA interference (RNAi) pathway is a potent antiviral defense mechanism in plants and invertebrates, in response to which viruses evolved suppressors of RNAi. In mammals, the first line of defense is mediated by the type I interferon system (IFN); however, the degree to which RNAi contributes to antiviral defense is still not completely understood. Recent work suggests that antiviral RNAi is active in undifferentiated stem cells and that antiviral RNAi can be uncovered in differentiated cells in which the IFN system is inactive or in infections with viruses lacking putative viral suppressors of RNAi. In this review, we describe the mechanism of RNAi and its antiviral functions in insects and mammals. We draw parallels and highlight differences between (antiviral) RNAi in these classes of animals and discuss open questions for future research.
Highlights
RNA interference (RNAi) or RNA silencing was first described in the model organism Caenorhabditis elegans [1] and following this ground-breaking discovery, studies in the field of small, noncodingRNAs have advanced tremendously
Vertebrates rely on the protein-based interferon system (IFN) response to combat viral infections, whereas the RNAi machinery, known for its potent antiviral activity in invertebrates, is conserved but primarily functions in gene regulation
The function of these proteins in both the miRNA and small interfering RNAs (siRNAs) pathways makes it difficult to genetically dissect the role of the RNAi pathway in inhibiting viral replication. The notion that both the IFN response and RNAi rely on double-stranded RNA (dsRNA) to initiate the antiviral response adds another level of complexity
Summary
RNA interference (RNAi) or RNA silencing was first described in the model organism Caenorhabditis elegans [1] and following this ground-breaking discovery, studies in the field of small, noncoding. Three classes of small RNAs exist: small interfering RNAs (siRNAs), microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) [2,5]. These RNAs guide Argonaute proteins onto target RNAs via Watson-Crick base pairing, usually resulting in gene silencing [6]. We will discuss recent work on the antiviral function of RNAi in mammals, focusing on negative and positive-sense RNA viruses (excluding retroviruses). Special attention will be given to stem cells, which seem to have specific characteristics, both in the interferon response and antiviral RNAi. To avoid ambiguity, we will only consider “classical” antiviral RNAi, in which viral dsRNA is processed into viral siRNAs to limit virus infection; we will not consider miRNA-dependent effects on virus replication
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