Antiviral RNA Interference in Mammalian Cells

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Science  11 Oct 2013:
Vol. 342, Issue 6155, pp. 235-238
DOI: 10.1126/science.1241930

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Viral Defenses

In plants and invertebrates, RNA interference (RNAi) functions as an innate antiviral defense mechanism. Viruses that infect plants and invertebrates have evolved viral suppressors of RNAi (VSRs) that disable the RNAi pathway. Whether mammals use RNAi as a defense against viruses has been less clear (see the Perspective by Sagan and Sarnow). Li et al. (p. 231) and Maillard et al. (p. 235) studied mammalian cell lines and baby mice productively infected with RNA viruses and observed the production of virus-derived small RNAs (vsRNAs). When the putative VSR proteins of the infecting viruses were disabled, host RNAi-derived vsRNAs were much increased and the viruses were rapidly cleared and unable to mount a full-blown infection. Thus, RNAi also has an innate antiviral function in mammals.


In antiviral RNA interference (RNAi), the DICER enzyme processes virus-derived double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that guide ARGONAUTE proteins to silence complementary viral RNA. As a counterdefense, viruses deploy viral suppressors of RNAi (VSRs). Well-established in plants and invertebrates, the existence of antiviral RNAi remains unknown in mammals. Here, we show that undifferentiated mouse cells infected with encephalomyocarditis virus (EMCV) or Nodamura virus (NoV) accumulate ~22-nucleotide RNAs with all the signature features of siRNAs. These derive from viral dsRNA replication intermediates, incorporate into AGO2, are eliminated in Dicer knockout cells, and decrease in abundance upon cell differentiation. Furthermore, genetically ablating a NoV-encoded VSR that antagonizes DICER during authentic infections reduces NoV accumulation, which is rescued in RNAi-deficient mouse cells. We conclude that antiviral RNAi operates in mammalian cells.

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