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

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          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 ds RNAs 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 ds RNA 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that RNAi constitutes an ancient antiviral strategy conserved from plants to mammals that precedes but has not been superseded by vertebrate evolution of the IFN system.

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          Most cited references 46

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          Small silencing RNAs: an expanding universe.

          Since the discovery in 1993 of the first small silencing RNA, a dizzying number of small RNA classes have been identified, including microRNAs (miRNAs), small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs). These classes differ in their biogenesis, their modes of target regulation and in the biological pathways they regulate. There is a growing realization that, despite their differences, these distinct small RNA pathways are interconnected, and that small RNA pathways compete and collaborate as they regulate genes and protect the genome from external and internal threats.
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            Argonaute2 is the catalytic engine of mammalian RNAi.

            Gene silencing through RNA interference (RNAi) is carried out by RISC, the RNA-induced silencing complex. RISC contains two signature components, small interfering RNAs (siRNAs) and Argonaute family proteins. Here, we show that the multiple Argonaute proteins present in mammals are both biologically and biochemically distinct, with a single mammalian family member, Argonaute2, being responsible for messenger RNA cleavage activity. This protein is essential for mouse development, and cells lacking Argonaute2 are unable to mount an experimental response to siRNAs. Mutations within a cryptic ribonuclease H domain within Argonaute2, as identified by comparison with the structure of an archeal Argonaute protein, inactivate RISC. Thus, our evidence supports a model in which Argonaute contributes "Slicer" activity to RISC, providing the catalytic engine for RNAi.
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              RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.

              Double-stranded RNA (dsRNA) produced during viral replication is believed to be the critical trigger for activation of antiviral immunity mediated by the RNA helicase enzymes retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We showed that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5'-phosphates. This is blocked by the influenza protein nonstructured protein 1 (NS1), which is found in a complex with RIG-I in infected cells. These results identify RIG-I as a ssRNA sensor and potential target of viral immune evasion and suggest that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
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                Author and article information

                Contributors
                pierre.maillard@crick.ac.uk
                caetano@crick.ac.uk
                Journal
                EMBO J
                EMBO J
                10.1002/(ISSN)1460-2075
                EMBJ
                embojnl
                The EMBO Journal
                John Wiley and Sons Inc. (Hoboken )
                0261-4189
                1460-2075
                04 November 2016
                01 December 2016
                04 November 2016
                : 35
                : 23 ( doiID: 10.1002/embj.v35.23 )
                : 2505-2518
                Affiliations
                [ 1 ] Immunobiology LaboratoryThe Francis Crick Institute LondonUK
                [ 2 ] Institute of TechnologyUniversity of Tartu TartuEstonia
                [ 3 ]Present address: Open Innovation Access PlatformSanofi Strasbourg StrasbourgFrance
                Author notes
                [* ] Corresponding author. Tel: +44 20 3796 1310; E‐mail: caetano@ 123456crick.ac.uk

                Corresponding author. Tel: +44 20 3796 1280; E‐mail: pierre.maillard@ 123456crick.ac.uk

                Article
                EMBJ201695086
                10.15252/embj.201695086
                5167344
                27815315
                © 2016 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 6, Tables: 0, Pages: 14, Words: 10128
                Product
                Funding
                Funded by: The Francis Crick Institute
                Funded by: Cancer Research UK
                Award ID: FC001136
                Funded by: UK Medical Research Council
                Award ID: FC001136
                Funded by: Wellcome Trust
                Award ID: FC001136
                Funded by: Swiss National Science Foundation
                Funded by: Netherlands Organization for Scientific Research
                Categories
                Article
                Articles
                Custom metadata
                2.0
                embj201695086
                01 December 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.0 mode:remove_FC converted:19.12.2016

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