Inactivation of the type I interferon pathway reveals long double‐stranded RNA ‐mediated RNA interference in mammalian cells

Abstract

RNA interference ( RNA i) 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 RNA s induce a distinct defence system known as the interferon ( IFN ) response. Here, we tested the possibility that the IFN response masks or inhibits antiviral RNA i in mammalian cells. Consistent with that notion, we find that sequence‐specific gene silencing can be triggered by long ds RNA s in differentiated mouse cells rendered deficient in components of the IFN pathway. This unveiled response is dependent on the canonical RNA i machinery and is lost upon treatment of IFN ‐responsive cells with type I IFN . Notably, transfection with long ds RNA specifically vaccinates IFN ‐deficient cells against infection with viruses bearing a homologous sequence. Thus, our data reveal that RNA i constitutes an ancient antiviral strategy conserved from plants to mammals that precedes but has not been superseded by vertebrate evolution of the IFN system. image Somatic mammalian cells, like those of insects, nematodes and plants, are equipped to process long double‐stranded RNA substrates into short interfering RNA s 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 (ds RNA i) is functionally active in mammalian differentiated cells. Ds RNA i is revealed in cells defective in the interferon pathway. Ds RNA i specifically vaccinates cells against subsequent infection with viruses bearing homologous sequences. The impact of ds RNA i in cell‐intrinsic mammalian immunity to virus infection awaits further studies.