Antiviral Immunity Directed by Small RNAs

Ding, Shou‐Wei; Voinnet, Olivier

doi:10.1016/j.cell.2007.07.039

Cited by 1,321 publications

(1,314 citation statements)

References 98 publications

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“…The failure to observe RNAi after virus infection of IFN‐deficient cells suggests several non‐mutually exclusive possibilities. Many viruses, including vertebrate ones, encode putative VSRs that might obscure RNAi effects on virus accumulation (Ding & Voinnet, 2007; Haasnoot et al , 2007; Wu et al , 2010). We did not detect an effect of RNAi on resistance to IAV ΔNS1 or EMCV ΔL, yet the role of other putative VSRs warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…These can serve as substrates for Dicer to generate virus‐derived siRNAs (viRNAs) (Ding & Voinnet, 2007; Kemp & Imler, 2009; Swarts et al , 2014; tenOever, 2016) that are loaded onto RISC and target complementary viral RNA to block virus replication. Indeed, viRNA‐mediated RNAi constitutes the primary antiviral defence strategy of plants and invertebrates (Ding & Voinnet, 2007; Kemp & Imler, 2009; Swarts et al , 2014; tenOever, 2016). Consequently, plant and insect viruses have evolved virulence factors called viral suppressors of RNA silencing (VSRs) that block various steps of the antiviral RNAi mechanism (Haasnoot et al , 2007; Wu et al , 2010).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…In contrast to the protein‐based type I IFN system found in vertebrates, antiviral immunity in plants and invertebrates relies on an RNA‐based, sequence‐specific defence pathway known as RNA interference (RNAi; Ding & Voinnet, 2007; Kemp & Imler, 2009; Wilson & Doudna, 2013; tenOever, 2016). The importance of RNAi in antiviral defence in these organisms is underscored by the evolution in most plant and insect viruses of viral‐encoded RNAi antagonists, known as viral suppressors of RNA silencing (VSRs) that block various steps in the RNAi pathway (Ding & Voinnet, 2007; Wu et al , 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The importance of RNAi in antiviral defence in these organisms is underscored by the evolution in most plant and insect viruses of viral‐encoded RNAi antagonists, known as viral suppressors of RNA silencing (VSRs) that block various steps in the RNAi pathway (Ding & Voinnet, 2007; Wu et al , 2010). In the absence of VSRs, viral dsRNA generated during viral infection and replication is rapidly cleaved by the type III ribonuclease Dicer into virus‐derived small interfering RNAs (viRNAs), which are loaded onto an Argonaute (Ago) family protein to form the RNA‐induced silencing complex (RISC) that targets complementary viral RNA for cleavage (Ding & Voinnet, 2007; Kemp & Imler, 2009; Wilson & Doudna, 2013; tenOever, 2016). Interestingly, the RLR family and Dicer share the conserved DExD/H helicase domain and have comparable substrate specificity (dsRNA) although their respective functions (signalling versus catalytic processing) are distinct (MacKay et al , 2014; Paro et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

et al. 2018

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In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG‐I‐like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon‐stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG‐I, MDA5 and, the least‐studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus‐derived double‐stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We show that LGP2 associates with Dicer and inhibits cleavage of dsRNA into siRNAs both in vitro and in cells. Further, we show that in differentiated cells lacking components of the IFN response, ectopic expression of LGP2 interferes with RNAi‐dependent suppression of gene expression. Conversely, genetic loss of LGP2 uncovers dsRNA‐mediated RNAi albeit less strongly than complete loss of the IFN system. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs. LGP2‐mediated antagonism of dsRNA‐mediated RNAi may help ensure that viral dsRNA substrates are preserved in order to serve as targets of antiviral ISG proteins.

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“…17,18 Although it has remained unclear whether long dsRNA can also be processed by mammalian Dicer into small interfering RNA with antiviral activity, 19 this is one of the main features of innate immunity against viral RNA in plants, fungi and invertebrates. 20 To circumvent these defense mechanisms, a multitude of viruses encode suppressors of RNA interference (RNAi) with some of them being functional across kingdom borders. Interestingly, Nodamuravirus B2 protein (NovB2), important to establish lethal infections in insects and mammals, was shown to bind to long dsRNA and interfere with Dicermediated cleavage as well as post Dicer processes.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms controlling titer and expression of bidirectional lentiviral and gammaretroviral vectors

et al. 2009

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Bidirectional lentiviral vectors mediate expression of two or more cDNAs from a single internal promoter. In this study, we examined mechanisms that control titer and expression properties of this vector system. To address whether the bidirectional design depends on lentiviral (LV) backbone components, especially the Rev/Rev responsive element (RRE) system, we constructed similar expression cassettes for LV and gammaretroviral (GV) vectors. Bidirectional expression levels could be adjusted by the use of different internal promoters. Furthermore, removal of the constitutive RNA transport element of Mason-Pfizer monkey virus, used in first generation bidirectional LV vectors, improved gene expression. Titers of bidirectional vectors were B10-fold reduced in comparison to unidirectional vectors, independent of the Rev/RRE interaction. We reasoned that titer reductions were due to the formation of interfering double-stranded RNA in packaging cells. Indeed, cotransfection of Nodamuravirus B2 protein, an RNA interference suppressor, increased bidirectional vector titers at least fivefold. We validated the potential of high titer bidirectional vectors by coexpressing a fluorescent marker with O 6 -methylguanine-DNA methyltransferase from integrating, or with Cre recombinase from integrating and non-integrating GV and LV backbones. This allowed for the tracking of chemoprotected and recombined cells by fluorescence marker expression.

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Antiviral Immunity Directed by Small RNAs

Cited by 1,321 publications

References 98 publications

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

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

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

Mechanisms controlling titer and expression of bidirectional lentiviral and gammaretroviral vectors

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