The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

Yoneyama, Mitsutoshi; Kikuchi, Mani; Natsukawa, Takashi; Shinobu, Noriaki; Imaizumi, Tadaatsu; Miyagishi, Makoto; Taira, Kazunari; Akira, Shizuo; Fujita, Takashi

doi:10.1038/ni1087

Cited by 3,501 publications

(3,275 citation statements)

References 55 publications

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“…Retinoic acid inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are RNA helicase-containing cytoplasmic proteins. The RNA helicase domains of RIG-I and MDA5 bind directly to double-stranded RNA (dsRNA) and induce production of type I interferons (Kang et al, 2002;Andrejeva et al, 2004;Yoneyama et al, 2004). Upon binding to dsRNA, representing either the viral genome or viral replication intermediate, RIG-I and MDA5 induce the activation of IRF3 and NF-kB.…”

Section: Retinoic Acid Inducible Gene I and Melanoma Differentiation-mentioning

confidence: 99%

“…Upon binding to dsRNA, representing either the viral genome or viral replication intermediate, RIG-I and MDA5 induce the activation of IRF3 and NF-kB. Interestingly, initiation of these signaling cascade is abrogated by point mutations in the Walker-type ATP-binding site, suggesting that their ATPase activity is required for signaling (Yoneyama et al, 2004). The link between these two proteins and NF-kB remains somewhat unclear ( Figure 5c); however overexpression of the N-terminal CARD domain alone is sufficient to induce signaling.…”

Section: Retinoic Acid Inducible Gene I and Melanoma Differentiation-mentioning

confidence: 99%

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NF-κB and the immune response

2006

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Section: Retinoic Acid Inducible Gene I and Melanoma Differentiation-mentioning

confidence: 99%

Section: Retinoic Acid Inducible Gene I and Melanoma Differentiation-mentioning

confidence: 99%

NF-κB and the immune response

2006

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“…Retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are cytoplasmic RNA helicases [1][2][3], which signal the presence of viral RNA through the adaptor, IFN-b promoter stimulator-1 (IPS-1) (also known as mitochondrial antiviral signaling protein/caspase recruitment domain (CARD) adaptor inducing IFN-b (Cardif)/virus-induced signaling adaptor) to produce IFN-b [4][5][6][7]. IPS-1 localizes on the outer membrane of the mitochondria via its C-terminus [6].…”

Section: Introductionmentioning

confidence: 99%

DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

et al. 2010

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Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR) are members of the DEAD box helicases, and recognize viral RNA in the cytoplasm, leading to IFN-b induction through the adaptor IFN-b promoter stimulator-1 (IPS-1) (also known as Cardif, mitochondrial antiviral signaling protein or virus-induced signaling adaptor). Since uninfected cells usually harbor a trace of RIG-I, other RNA-binding proteins may participate in assembling viral RNA into the IPS-1 pathway during the initial response to infection. We searched for proteins coupling with human IPS-1 by yeast two-hybrid and identified another DEAD (Asp-Glu-AlaAsp) box helicase, DDX3 (DEAD/H BOX 3). DDX3 can bind viral RNA to join it in the IPS-1 complex. Unlike RIG-I, DDX3 was constitutively expressed in cells, and some fraction of DDX3 is colocalized with IPS-1 around mitochondria. The 622-662 a.a DDX3 C-terminal region (DDX3-C) directly bound to the IPS-1 CARD-like domain, and the whole DDX3 protein also associated with RLR. By reporter assay, DDX3 helped IPS-1 up-regulate IFN-b promoter activation and knockdown of DDX3 by siRNA resulted in reduced IFN-b induction. This activity was conserved on the DDX3-C fragment. DDX3 only marginally enhanced IFN-b promoter activation induced by transfected TANK-binding kinase 1 (TBK1) or I-kappa-B kinase-e (IKKe). Forced expression of DDX3 augmented virus-mediated IFN-b induction and host cell protection against virus infection. Hence, DDX3 is an antiviral IPS-1 enhancer. IntroductionRetinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are cytoplasmic RNA helicases [1][2][3], which signal the presence of viral RNA through the adaptor, IFN-b promoter stimulator-1 (IPS-1) (also known as mitochondrial antiviral signaling protein/caspase recruitment domain (CARD) adaptor inducing IFN-b (Cardif)/virus-induced signaling adaptor) to produce . IPS-1 localizes on the outer membrane of the mitochondria via its C-terminus [6]. Its Nterminus consists of a CARD domain, which interacts with the CARD domains of RIG-I and MDA5. Viral RNA resulting from penetration or replication are believed to assemble in the CARDinteracting helicase complex to activate the cytoplasmic IFNinducing pathway. Although non-infected cells usually express minimal amounts of RIG-I/MDA5, the final output of type I IFN is efficiently induced at an early stage of infection to protect host cells from viral spreading.Once IPS-1 is activated, the kinase complex consisting of TANK-homologous proteins and virus-activated kinases induce nuclear translocation of IFN regulatory factor-3 (IRF-3) to activate the IFN promoter [8]. NAK-associated protein 1, TANKbinding kinase 1 (TBK1) and I-kappa-B kinase-e (IKKe) are components of the kinase complex that phosphorylates IRF-3 to induce type I IFN [9,10]. RIG-I recognizes products of various RNA viruses, while MDA5 recognizes products of picornaviruses 940Frontline [1,11]. RIG-I and MDA5 share the helicase domain, which is classified into the DEAD (Asp-Glu-Ala-Asp) box helicase...

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“…RLR‐dependent signalling events were stimulated in these cells by overexpressing a constitutively active version of RIG‐I (GFP‐RIG‐I‐CARD, 3). Twenty‐four hours after the co‐transfection, GFP‐RIG‐I‐CARD was transfected and, 6 hrs after, the production of mRNA of two ISGs (IRF1 and viperin) was quantified by RT‐qPCR.…”

Section: Resultsmentioning

confidence: 99%

Hepatitis C virus NS3‐4A inhibits the peroxisomal MAVS‐dependent antiviral signalling response

Ferreira

Magalhães

Camões

et al. 2016

J Cellular Molecular Medi

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Hepatitis C virus (HCV) is the cause of one of the most prevalent viral infections worldwide. Upon infection, the HCV genome activates the RIG‐I‐MAVS signalling pathway leading to the production of direct antiviral effectors which prevent important steps in viral propagation. MAVS localizes at peroxisomes and mitochondria and coordinate the activation of an effective antiviral response: peroxisomal MAVS is responsible for a rapid but short‐termed antiviral response, while the mitochondrial MAVS is associated with the activation of a stable response with delayed kinetics.The HCV NS3‐4A protease was shown to specifically cleave the mitochondrial MAVS, inhibiting the downstream response.In this study, we have analysed whether HCV NS3‐4A is also able to cleave the peroxisomal MAVS and whether this would have any effect on the cellular antiviral response. We show that NS3‐4A is indeed able to specifically cleave this protein and release it into the cytosol, a mechanism that seems to occur at a similar kinetic rate as the cleavage of the mitochondrial MAVS. Under these conditions, RIG‐I‐like receptor (RLR) signalling from peroxisomes is blocked and antiviral gene expression is inhibited. Our results also show that NS3‐4A is able to localize at peroxisomes in the absence of MAVS. However, mutation studies have shown that this localization pattern is preferred in the presence of a fully cleavable MAVS. These findings present evidence of a viral evasion strategy that disrupts RLR signalling on peroxisomes and provide an excellent example of how a single viral evasion strategy can block innate immune signalling from different organelles.

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The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

Cited by 3,501 publications

References 55 publications

NF-κB and the immune response

NF-κB and the immune response

DEAD/H BOX 3 (DDX3) helicase binds the RIG‐I adaptor IPS‐1 to up‐regulate IFN‐β‐inducing potential

Hepatitis C virus NS3‐4A inhibits the peroxisomal MAVS‐dependent antiviral signalling response

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