Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity

Li, Xiao Dong; Sun, Lijun; Seth, Rashu B.; Pineda, Gabriel; Chen, Zhijian J.

doi:10.1073/pnas.0508531102

Cited by 752 publications

(681 citation statements)

References 28 publications

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“…23 The Cardif/ IKK⑀ association could represent an important threat for HCV, which can be alleviated through the NS3/4A-mediated cleavage of Cardif. 18,22,23 We showed that IKK⑀ overexpression provoked inhibition of HCV expression. Based on these results, one might expect to find increased hepatic expression of IKK⑀ in chronic hepatitis C as an adaptive response to halt HCV replication through the action of one or several of the antiviral molecules induced by IKK⑀.…”

Section: Discussionmentioning

confidence: 99%

“…21 However, HCV interferes with IFN induction through the action of its NS3/4A protease, which can cleave Cardif. 18,22,23 In addition, the NS3/4A protease can cleave the TRIF adapter, which links the IFN-inducing kinases to the dsRNA-activated TLR3, 24 thus emphasizing the importance of these two IFN signaling pathways and the necessity for the virus to inhibit them to favor its propagation.…”

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confidence: 99%

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The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

et al. 2006

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H epatitis C virus (HCV) infection leads to the development of chronic hepatitis in 60% to 90% of infected individuals, cirrhosis in 0.5% to 30% of cases, and hepatocellular carcinoma at a rate of 1% to 3% per year. 1 The current approved treatment for HCV infection is pegylated interferon alpha (IFN-␣) in combination with ribavirin. This leads to clearance of the virus in 50% to 80% of cases, depending on the infecting HCV genotype. In particular, HCV of genotype 1 is the most resistant to IFN treatment. 2 HCV can interfere with the response of cells to IFN, through its viral proteins targeting either the IFN-activated JAK/STAT signaling pathway 3-5 or through other processes, leading to inhibition of action of the IFN-induced antiviral proteins. 6 In addition to this, HCV interferes with IFN induction, and more generally, with the induction of the innate immune response. The innate immune response is triggered in response to a variety of pathogens, such as bacteria and viruses, and is essential for a rapid limitation in the spread or action of these pathogens. IFN induction can take place after interaction of extracellular nucleic acids to members of the Toll-like receptor family 7-10 and after viral intrusion in the cytoplasm through the interaction of viral double-stranded RNAs (dsRNAs) with specific RNA helicases, such as RIG-I 11 or MDA-5. 12 For instance, the From the

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

et al. 2006

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“…Previous studies have shown that NS3/4A inhibits the induction of IFN-β by the RIG-I signaling pathway [32][33][34], however, the target of NS3/4A was not known previously. Two groups have now shown that MAVS is the long-sought target of NS3/4A [28,35]. NS3/4A cleaves MAVS at Cys-508, which is located only a few residues before the mitochondrial targeting domain of MAVS.…”

Section: Mavs Signaling In the Rig-i Pathwaymentioning

confidence: 99%

Antiviral innate immunity pathways

2006

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Recent studies have uncovered two signaling pathways that activate the host innate immunity against viral infection. One of the pathways utilizes members of the Toll-like receptor (TLR) family to detect viruses that enter the endosome through endocytosis. The TLR pathway induces interferon production through several signaling proteins that ultimately lead to the activation of the transcription factors NF-κB, IRF3 and IRF7. The other antiviral pathway uses the RNA helicase RIG-I as the receptor for intracellular viral double-stranded RNA. RIG-I activates NF-κB and IRFs through the recently identified adaptor protein MAVS, a CARD domain containing protein that resides in the mitochondrial membrane. MAVS is essential for antiviral innate immunity, but it also serves as a target of Hepatitis C virus (HCV), which employs a viral protease to cleave MAVS off the mitochondria, thereby allowing HCV to escape the host immune system.

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“…20 The cysteine protease NS3/4A of hepatitis C virus cleaves VISA and the TLR3 adapter protein TRIF, thereby blocking RIG-I-and TLR3-mediated induction of the type I IFNs. 21,22 The A52 and A46 proteins of vaccinia virus target multiple TIR proteins, including TRIF, to block TLR3-and TLR4-mediated induction of type I IFNs. 23,24 The results of virushost interactions may determine the outcome of a viral infection: elimination of the viruses or the establishment of successful infection.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

Wang

Mao

et al. 2010

Cell Mol Immunol

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Viral RNAs produced during viral infection are recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). A central adapter protein downstream of RIG-I and MDA5 is the mitochondrial membrane protein virus-induced signaling adaptor (VISA), which mediates the induction of type I interferons (IFNs) through the activation of transcription factors such as nuclear factor-kappaB (NF-kB) and IFN-regulatory factor-3 (IRF3). Here we found that hepatitis B virus (HBV)-encoded X protein (HBx) acts as an inhibitor of virus-triggered IRF3 activation and IFN-b induction. Reporter and plaque assays indicate that HBx inhibits signaling by components upstream but not downstream of VISA. Immunoprecipitation experiments indicate that HBx interacts with VISA and disrupts the association of VISA with its upstream and downstream components. These findings suggest that HBx acts as a suppressor of virus-triggered induction of type I IFNs, which explains the observation that HBV causes transient and chronic infection in hepatocytes but fails to activate the pattern recognition receptor-mediated IFN induction pathways.

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Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity

Cited by 752 publications

References 28 publications

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

The protein kinase IKKε can inhibit HCV expression independently of IFN and its own expression is downregulated in HCV-infected livers

Antiviral innate immunity pathways

Hepatitis B virus X protein suppresses virus-triggered IRF3 activation and IFN-β induction by disrupting the VISA-associated complex

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