Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus

Meylan, Etienne; Curran, Joseph; Hofmann, Kay; Moradpour, Darius; Binder, Marco; Bartenschlager, Ralf; Tschopp, Jürg

doi:10.1038/nature04193

Cited by 2,174 publications

(1,935 citation statements)

References 31 publications

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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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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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“…HCV NS3‐4A was shown to cleave the mitochondrial MAVS, leading to the dislocation of the N‐terminal fragment of MAVS from the mitochondria to the cytosol and inhibiting the MAVS‐dependent immune response 8, 11. Also the MAM‐localized MAVS was shown to be cleaved by this viral protein 23.…”

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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“…53 An exciting recent development was the identification by several different groups of a new CARD-containing adaptor protein, Cardif/MAVS/ IPS-1/VISA, that activates NF-kB in response to virus infection, here referred to as MCARD for the lack of a better term. 54,55 MCARD binds RIG-I to promote activation of NF-kB and IRF3. But HCV, an important cause of chronic liver disease, specifically targets MCARD.…”

Section: Molecular Target Of Hepatitis C Virus Ns3-4a Proteasementioning

confidence: 99%

“…The HCV serine protease NS3-4A, which is required to cleave viral polyproteins during virus replication, also cleaves after Cys508 of MCARD, causing a potent inhibition of signaling. 54 Therefore, the anti-viral compound BILN2061, which inhibits the NS3-4A protease, will presumably also impair the ability of HCV to overcome host-defense mechanisms.…”

Section: Molecular Target Of Hepatitis C Virus Ns3-4a Proteasementioning

confidence: 99%

Alternate functions of viral regulators of cell death

et al. 2006

Cell Death Differ

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Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus

Cited by 2,174 publications

References 31 publications

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

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

Alternate functions of viral regulators of cell death

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