Inhibition of RIG-I-Dependent Signaling to the Interferon Pathway during Hepatitis C Virus Expression and Restoration of Signaling by IKKε

Breiman, Adrien; Grandvaux, Nathalie; Lin, Rongtuan; Ottone, Catherine; Akira, Shizuo; Yoneyama, Mitsutoshi; Fujita, Takashi; Hiscott, John; Meurs, Éliane

doi:10.1128/jvi.79.7.3969-3978.2005

Cited by 157 publications

(146 citation statements)

References 68 publications

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“…Future studies are needed to examine the mechanism involved in NS5B-mediated inhibition of the IFN signaling pathway. Finally, in support of the studies by Foy et al 42 and Breiman et al, 50 we showed that NS3/4A protease had the ability to inhibit IRF-7-induced IFN-␣ promoter activation (Fig. 6).…”

Section: Discussionsupporting

confidence: 70%

“…This finding is not surprising and is even expected because NS3/4A can inhibit the signaling pathways leading to the activation of the IRF-3 and IRF-7. 42,50 In conclusion, our study demonstrating that HCV has the ability to undermine intracellular innate immunity of the host cells provides a plausible mechanism responsible for HCV persistence in the hepatic cells. Our data, in conjunction with the reports by Foy et al 3 and Wang et al, 39 suggest that HCV not only interferes with the IRF-3-mediated early protein pathway of type I IFNs, but also inhibits IRF-7-mediated IFN-␣ activation in the hepatic cells.…”

Section: Discussionmentioning

confidence: 99%

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Hepatitis C Virus Inhibits Intracellular Interferon Alpha Expression in Human Hepatic Cell Lines *

Zhang

Lin

et al. 2005

Hepatology

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Inhibits Intracellular Interferon Alpha Expression in Human Hepatic Cell Lines *

Zhang

Lin

et al. 2005

Hepatology

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“…The persistence of HCV infection is caused in part by the suppression of the host immune system by HCV viral proteins, such as the NS3/4A serine protease. 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].…”

Section: Mavs Signaling In the Rig-i Pathwaymentioning

confidence: 98%

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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“…99 Studies with IMCV further showed that this adaptor could physically associate with TLR adaptor TRIF, TRAF2 and TRAF6, that are essential signaling components of the NF-kB pathway induced by viral dsRNA recognition by TLR3. 98 Interestingly, Meylan et al, 97 showed that IMCV adaptor was the target and inactivated by NS3/4A a serine protease of HCV already known to block the RIG-I signaling pathway 100,101 and inactivate TRIF by proteolytic cleavage. 102 Finally, the most intriguing feature of this adaptor is that the C-terminal transmembrane domain, essential for IMCV signaling, targets the protein to the mitochondria.…”

Section: Helicasesmentioning

confidence: 99%

TIR, CARD and PYRIN: three domains for an antimicrobial triad

2006

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Innate immunity to microorganisms in mammals has gained a substantial interest during the last decade. The discovery of the Toll-like receptor (TLR) family has allowed the identification of a class of membrane-spanning receptors dedicated to microbial sensing. TLRs transduce downstream signaling via their intracellular Toll-interleukin-1 receptor (TIR) domain. More recently, the role of intracellular microbial sensors has been uncovered. These molecules include the Nod-like receptors Nod1, Nod2, Ipaf and Nalps, together with the helicase domain-containing antiviral proteins RIG-I and Mda-5. The intracellular microbial sensors lack the TIR domain, but instead transduce downstream signals via two domains also implicated in homophilic protein-protein interactions, the caspase activation and recruitment domain (CARD) and PYRIN domains. In light with these recent findings, we propose that TIR, CARD and PYRIN domains represent the three arms of innate immune detection of microorganisms in mammals.

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Inhibition of RIG-I-Dependent Signaling to the Interferon Pathway during Hepatitis C Virus Expression and Restoration of Signaling by IKKε

Cited by 157 publications

References 68 publications

Hepatitis C Virus Inhibits Intracellular Interferon Alpha Expression in Human Hepatic Cell Lines *

Hepatitis C Virus Inhibits Intracellular Interferon Alpha Expression in Human Hepatic Cell Lines *

Antiviral innate immunity pathways

TIR, CARD and PYRIN: three domains for an antimicrobial triad

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