Cytosolic 5′-Triphosphate Ended Viral Leader Transcript of Measles Virus as Activator of the RIG I-Mediated Interferon Response

Plumet, Sébastien; Herschke, Florence; Bourhis, Jean-Marie; Valentin, Hélène; Longhi, Sonia; Gerlier, Denis

doi:10.1371/journal.pone.0000279

Cited by 165 publications

(178 citation statements)

References 55 publications

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“…Also, a current study shows differential recognition of poly I:C by RIG-I and MDA-5 in a much lower size range (30). Few reports exist that show direct recognition of particular viral RNAs by RIG-I in the setting of infection with a living virus (5,31). In cases where data of this kind is available, these RNAs (the leader RNAs of negative-stranded RNA viruses and the EBERs of EBV) are comparably small, and contain hairpin-like structures in addition to and in proximity of a 5Ј-triphosphate end.…”

Section: Discussionmentioning

confidence: 52%

5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I

Schmidt

Schwerd²,

Hamm³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

352

337

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The ATPase retinoid acid-inducible gene (RIG)-I senses viral RNA in the cytoplasm of infected cells and subsequently activates cellular antiviral defense mechanisms. RIG-I recognizes molecular structures that discriminate viral from host RNA. Here, we show that RIG-I ligands require base-paired structures in conjunction with a free 5-triphosphate to trigger antiviral signaling. Hitherto unavailable chemically synthesized 5-triphosphate RNA ligands do not trigger RIG-I-dependent IFN production in cells, and they are unable to trigger the ATPase activity of RIG-I without a base-paired stretch. Consistently, immunostimulatory RNA from cells infected with a virus recognized by RIG-I is sensitive to double-strand, but not single-strand, specific RNases. In vitro, base-paired stretches and the 5-triphosphate bind to distinct sites of RIG-I and synergize to trigger the induction of signaling competent RIG-I multimers. Strengthening our model of a bipartite molecular pattern for RIG-I activation, we show that the activity of supposedly ''single-stranded'' 5-triphosphate RNAs generated by in vitro transcription depends on extended and base-paired by-products inadvertently, but commonly, produced by this method. Together, our findings accurately define a minimal molecular pattern sufficient to activate RIG-I that can be found in viral genomes or transcripts.immunostimulatory RNA ͉ melanoma differentiation-associated protein 5 ͉ retinoid acid-inducible gene-I-like helicases ͉ virus infection ͉ interferon production

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Section: Discussionmentioning

confidence: 52%

5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I

Schmidt

Schwerd²,

Hamm³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

352

337

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“…N protein levels in C ko and WT virus-infected cells, when quantified relative to ␤-actin, differed by less than 1.5-fold over the time period of 12 to 48 h after infection (data not shown) (35). Additionally, others previously found that none of the MV mRNAs, when tested individually by ectopic plasmid-based expression, were able to activate IFN-␤ gene transcription, including the N transcript (25). The N protein expression level by itself, therefore, does not likely account for the increased levels of IRF-3 activation and IFN-␤ transcription seen with the C ko virus compared to the WT or V ko virus.…”

Section: Irf-3 Phosphorylation Is Enhanced In C Ko -Infected Comparedmentioning

confidence: 87%

“…The MV C mutant induces IFN-␤ through the IPS-1 adapter. MV replicates in the cytoplasm and activates the RIG-I sensor due to the presence of cytosolic 5Ј-triphosphate-containing viral transcripts (24,25), but paradoxically, the V protein of MV blocks the mda-5 sensor of the RLR IFN-␤ induction pathway (6,18). Furthermore, TLR3 signaling through the adapter TRIF is impaired by V proteins of rubulaviruses but not by the MV V protein (14).…”

Section: Irf-3 Phosphorylation Is Enhanced In C Ko -Infected Comparedmentioning

confidence: 99%

Mechanisms of Protein Kinase PKR-Mediated Amplification of Beta Interferon Induction by C Protein-Deficient Measles Virus

McAllister

Toth

Zhang

et al. 2010

J Virol

106

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The measles virus P gene products V and C antagonize the host interferon (IFN) response, blocking both IFN signaling and production. Using Moraten vaccine strain-derived measles virus and isogenic mutants deficient for either V or C protein production (V ko and C ko , respectively), we observed that the C Measles virus (MV), a member of the genus Morbillivirus of the Paramyxoviridae, causes an acute febrile illness. Despite an effective vaccine, measles continues to cause extreme morbidity and mortality worldwide (10), and recently, there has been a resurgence of measles in industrialized countries, where a lack of adherence to vaccine recommendations is an increasing problem (5, 12). The need for improved MV vaccines (11), together with the potential for use of engineered MV vaccine strains with defined mechanisms of attenuation as oncolytic viruses for cancer therapy (4), further justify ongoing efforts to gain an enhanced understanding of the host response to MV infection at the molecular level.The 15.9-kb negative-stranded RNA genome of MV consists of six genes (N, P/V/C, M, F, H, and L). The P gene is polycistronic, encoding the V and C nonstructural proteins in addition to P, a structural phosphoprotein and essential cofactor for the viral polymerase (2, 3, 10). The V protein shares its N-terminal 231 amino acids with P, but the C-terminal 68 amino acids are unique because of the pseudotemplated G insertion that causes a frameshift in V mRNA, whereas the C protein is synthesized by an alternative translation initiation AUG codon positioned 22 nucleotides downstream of the P/V translation start codon (3, 11). V and C are accessory proteins that serve a variety of functions including the modulation of the host innate immune response to MV infection (8, 9, 27). Isogenic MV mutants that are defective for the expression of either V or C have been generated. Strong adaptive immune responses, but dysregulated innate responses, are seen with these mutants (4,8,35).An important component of the host innate antiviral response is the interferon (IFN) response. IFNs are proinflammatory cytokines that possess antiviral activity (27,31). IFN action involves IFN binding to cognate receptors and subsequent prototypical JAK-STAT signal transduction that leads to the expression of IFN-stimulated genes, whose products inhibit virus growth. IFN production involves the recognition of pathogen-associated molecular patterns including viral RNAs by retinoic acid-inducible protein (RIG-I)-like cytosolic receptors (RLRs) and membrane-associated Toll-like receptors (TLRs). The RLR and TLR3 sensors signal through cognate adapter proteins, including IPS-1 and TRIF, respectively, to transcriptionally activate IFN expression (36,40). In the case of the IFN-␤ gene, IFN regulatory factor 3 (IRF-3) and nuclear factor B (NF-B) are activated by RLR or TLR signaling, enter the nucleus, and function together with activating transcription factor 2 (ATF-2)/c-jun to constitute the IFN-␤ enhanceosome that drives IFN-␤ transcription (22).The antago...

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“…In these viruses, the nucleoprotein immediately associates with neosynthesized genomic RNA, thus preventing the formation of dsRNA (9). Analysis of the innate immune response against negative-strand RNA viruses in mammals revealed that triphosphate groups at the 5′ ends of the uncapped viral RNAs, rather than long dsRNAs, play a critical role in the induction of IFN synthesis (10)(11)(12)(13). One may therefore wonder whether the Dcr-2-mediated antiviral response, which is triggered by dsRNA, can provide immunity against a negativestrand RNA virus in insect hosts.…”

Section: Rift Valley Fever Virus (Rvf) a Bunyavirus That Is Transmitmentioning

confidence: 99%

RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila

Mueller

Gausson

Vodovar

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

135

134

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Activation of innate antiviral responses in multicellular organisms relies on the recognition of structural differences between viral and cellular RNAs. Double-stranded (ds)RNA, produced during viral replication, is a well-known activator of antiviral defenses and triggers interferon production in vertebrates and RNAi in invertebrates and plants. Previous work in mammalian cells indicates that negative-strand RNA viruses do not appear to generate dsRNA, and that activation of innate immunity is triggered by the recognition of the uncapped 5′ ends of viral RNA. This finding raises the question whether antiviral RNAi, which is triggered by the presence of dsRNA in insects, represents an effective host-defense mechanism against negative-strand RNA viruses. Here, we show that the negative-strand RNA virus vesicular stomatitis virus (VSV) does not produce easily detectable amounts of dsRNA in Drosophila cells. Nevertheless, RNAi represents a potent response to VSV infection, as illustrated by the high susceptibility of RNAi-defective mutant flies to this virus. VSV-derived small RNAs produced in infected cells or flies uniformly cover the viral genome, and equally map the genome and antigenome RNAs, indicating that they derive from dsRNA. Our findings reveal that RNAi is not restricted to the defense against positive-strand or dsRNA viruses but can also be highly efficient against a negative-strand RNA virus. This result is of particular interest in view of the frequent transmission of medically relevant negative-strand RNA viruses to humans by insect vectors.deep sequencing | arbovirus | Dicer-2 | AGO2 | small RNA profiling

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Cytosolic 5′-Triphosphate Ended Viral Leader Transcript of Measles Virus as Activator of the RIG I-Mediated Interferon Response

Cited by 165 publications

References 55 publications

5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I

5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I

Mechanisms of Protein Kinase PKR-Mediated Amplification of Beta Interferon Induction by C Protein-Deficient Measles Virus

RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila

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