Inactivation of the type I interferon pathway reveals long double‐stranded RNA‐mediated RNA interference in mammalian cells. (4th November 2016)

• Record Type: Journal Article
• Authors: Maillard, Pierre V; Van der Veen, Annemarthe G; Deddouche‐Grass, Safia; Rogers, Neil C; Merits, Andres; Reis e Sousa, Caetano
• Is Part Of: EMBO journal. Volume 35:Number 23(2016)
• Page Start: 2505
• Page End: 2518
• Publication Date: 2016-11-04
• Subjects: RNA interference -- double‐stranded RNA -- innate immunity -- viral infection; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201695086
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: RNA interference (RNAi) elicited by long double‐stranded (ds) or base‐paired viral RNA constitutes the major mechanism of antiviral defence in plants and invertebrates. In contrast, it is controversial whether it acts in chordates. Rather, in vertebrates, viral RNAs induce a distinct defence system known as the interferon (IFN) response. Here, we tested the possibility that the IFN response masks or inhibits antiviral RNAi in mammalian cells. Consistent with that notion, we find that sequence‐specific gene silencing can be triggered by long dsRNAs in differentiated mouse cells rendered deficient in components of the IFN pathway. This unveiled response is dependent on the canonical RNAi machinery and is lost upon treatment of IFN‐responsive cells with type I IFN. Notably, transfection with long dsRNA specifically vaccinates IFN‐deficient cells against infection with viruses bearing a homologous sequence. Thus, our data reveal that RNAi constitutes an ancient antiviral strategy conserved from plants to mammals that precedes but has not been superseded by vertebrate evolution of the IFN system. Synopsis: Somatic mammalian cells, like those of insects, nematodes and plants, are equipped to process long double‐stranded RNA substrates into short interfering RNAs that can restrict viral infection. However, the mammalian‐specific interferon pathway masks or inhibits this more ancient mechanism of antiviral defence. Long double‐stranded RNA‐mediated RNA interference (dsRNAi) is functionally active in mammalian differentiated cells. DsRNAi is revealed in cells defective in the interferon pathway. DsRNAi specifically vaccinates cells against subsequent infection with viruses bearing homologous sequences. The impact of dsRNAi in cell‐intrinsic mammalian immunity to virus infection awaits further studies. Abstract : While RNAi is a known antiviral mechanism in plants and invertebrates, its contribution in mammals is only revealed upon ablation of the interferon pathway.