RNA Interference Functions as an Antiviral Immunity Mechanism in Mammals

Li, Yang; Lü, Jinfeng; Han, Yanhong; Fan, Xiaohu; Ding, Shou‐Wei

doi:10.1126/science.1241911

Cited by 311 publications

(461 citation statements)

References 40 publications

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“…No consensus has been reached concerning its antiviral effect in mammals and the effect may be dependent on the virus and the cells used. 15,[60][61][62] RNAi inactivation results in increased viral replication when cells from different species than the natural host are infected, in latently infected cells or in embryonic stem cells, 12,13,25,63 but has the opposite effect in cells that allow high levels of viral replication. 35,64,65 Viral si-(vsi)RNAs are highly abundant in many, if not all, herpesviridae species, where they regulate the viral life cycle.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that RNAi can directly inhibit viral replication while others have demonstrated that viruses can and do utilize cellular and viral miRNAs and RNAi-associated proteins to enhance viral replication. [9][10][11][12][13][14][15] For example, Human Immunodeficiency Virus-1 (HIV-1) is not restricted by RNAi, 16 while adenovirus is severely restricted, which may limit its use as an oncolytic virus. [17][18][19] The apparent absence of RNAi restriction of some viruses could be explained by the counteraction of encoded viral RNA silencing suppressors (RSSs).…”

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confidence: 99%

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HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

et al. 2015

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Several proteins and RNAs expressed by mammalian viruses have been reported to interfere with RNA interference (RNAi) activity. We investigated the ability of the HIV-1-encoded RNA elements Trans-Activation Response (TAR) and RevResponse Element (RRE) to alter RNAi. MicroRNA let7-based assays showed that RRE is a potent suppressor of RNAi activity, while TAR displayed moderate RNAi suppression. We demonstrate that RRE binds to TAR-RNA Binding Protein (TRBP), an essential component of the RNA Induced Silencing Complex (RISC). The binding of TAR and RRE to TRBP displaces small interfering (si)RNAs from binding to TRBP. Several stem-deleted RRE mutants lost their ability to suppress RNAi activity, which correlated with a reduced ability to compete with siRNA-TRBP binding. A lentiviral vector expressing TAR and RRE restricted RNAi, but RNAi was restored when Rev or GagPol were coexpressed. Adenoviruses are restricted by RNAi and encode their own suppressors of RNAi, the Virus-Associated (VA) RNA elements. RRE enhanced the replication of wild-type and VA-deficient adenovirus. Our work describes RRE as a novel suppressor of RNAi that acts by competing with siRNAs rather than by disrupting the RISC. This function is masked in lentiviral vectors co-expressed with viral proteins and thus will not affect their use in gene therapy. The potent RNAi suppressive effects of RRE identified in this study could be used to enhance the expression of RNAi restricted viruses used in oncolysis such as adenoviruses.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

et al. 2015

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“…However, Dicer's catalytic function appears mainly confined to precursor microRNA (pre‐miRNA) processing, and its antiviral capacity in mammals remains much debated (Parameswaran et al , 2010; Cullen et al , 2013; Li et al , 2013, 2016; Maillard et al , 2013; Backes et al , 2014; Ding & Voinnet, 2014; Kennedy et al , 2015; Jeffrey et al , 2017; tenOever, 2017). Some studies have reported that RNAi can impact antiviral immunity in mammals during influenza A virus, hepatitis C virus, Nodamura virus and, more recently, human enterovirus 71 infection (Wang et al , 2006; Matskevich & Moelling, 2007; Li et al , 2013, 2016; Maillard et al , 2013; Qiu et al , 2017). In contrast, others have found low abundance of viRNAs in mammalian somatic cells infected with various viruses, and only a modest effect of Dicer deficiency on viral replication, suggesting that RNAi is not an active mechanism of antiviral defence in most mammalian cell types (Parameswaran et al , 2010; Girardi et al , 2013; Backes et al , 2014; Bogerd et al , 2014; Schuster et al , 2017).…”

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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“…Whether RNAi also acts as an antiviral mechanism in mammals is hotly debated (Parameswaran et al , 2010; Cullen et al , 2013; Li et al , 2013; Maillard et al , 2013; Backes et al , 2014; Ding & Voinnet, 2014; Kennedy et al , 2015). Infection of mammalian somatic cells with various viruses results in little accumulation of viRNA (Parameswaran et al , 2010; Girardi et al , 2013; Backes et al , 2014; Bogerd et al , 2014) and, where tested, virus replication is only modestly affected in Dicer‐defective cells (Wang et al , 2006b; Matskevich & Moelling, 2007; Bogerd et al , 2014).…”

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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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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RNA Interference Functions as an Antiviral Immunity Mechanism in Mammals

Cited by 311 publications

References 40 publications

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

HIV-1 RRE RNA acts as an RNA silencing suppressor by competing with TRBP-bound siRNAs

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

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

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