Calpain Activation by Hepatitis C Virus Proteins Inhibits the Extrinsic Apoptotic Signaling Pathway

Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.
Hepatology (Impact Factor: 11.06). 11/2009; 50(5):1370-9. DOI: 10.1002/hep.23169
Source: PubMed


An unresolved question regarding the physiopathology of hepatitis C virus (HCV) infection is the remarkable efficiency with which host defenses are neutralized to establish chronic infection. Modulation of an apoptotic response is one strategy used by viruses to escape immune surveillance. We previously showed that HCV proteins down-regulate expression of BH3-only Bcl2 interacting domain (Bid) in hepatocytes of HCV transgenic mice. As a consequence, cells acquire resistance to Fas-mediated apoptosis, which in turn leads to increased persistence of experimental viral infections in vivo. This mechanism might participate in the establishment of chronic infections and the resulting pathologies, including hepatocellular carcinoma. We now report that Bid is also down-regulated in patients in the context of noncirrhotic HCV-linked tumorigenesis and in the HCV RNA replicon system. We show that the nonstructural HCV viral protein NS5A is sufficient to activate a calpain cysteine protease, leading to degradation of Bid. Moreover, pharmacological inhibitors of calpains restore both the physiological levels of Bid and the sensitivity of cells toward a death receptor-mediated apoptotic signal. Finally, human HCV-related tumors and hepatocytes from HCV transgenic mice that display low Bid expression contain activated calpains. CONCLUSION: Calpains activated by HCV proteins degrade Bid and thus dampen apoptotic signaling. These results suggest that inhibiting calpains could lead to an improved efficiency of immune-mediated elimination of HCV-infected cells.

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Available from: Yannick Simonin, Feb 06, 2014
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    • "For HCV-induced apoptosis, both host and viral factors have been implicated, however, the molecular mechanisms and the specific factor(s) which perpetuate this process remains largely unknown. The Bcl-2 family members are the major molecular players in programmed cell death (Edlich et al., 2011; Hardwick and Soane, 2013), with some BH3-only proteins reported to play a role in HCV infection (Simonin et al., 2009). The BH3-only pro-apoptotic members, which are the allosteric regulators of the Bcl-2 family members, are known to bind strongly to the pro-survival members through their BH3 domains thereby antagonizing their pro-survival function (Chen et al., 2005). "
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    ABSTRACT: Hepatitis C virus (HCV) induces cytopathic effects in the form of hepatocytes apoptosis thought to be resulted from the interaction between viral proteins and host factors. Using pathway specific PCR array, we identified 9 apoptosis-related genes that are dysregulated during HCV infection, of which the BH3-only pro-apoptotic Bcl-2 family protein, BIK, was consistently up-regulated at the mRNA and protein levels. Depletion of BIK protected host cells from HCV-induced caspase-3/7 activation but not the inhibitory effect of HCV on cell viability. Furthermore, viral RNA replication and release were significantly suppressed in BIK-depleted cells and over-expression of the RNA-dependent RNA polymerase, NS5B, was able to induce BIK expression. Immunofluorescence and co-immunoprecipitation assays showed co-localization and interaction of BIK and NS5B, suggesting that BIK may be interacting with the HCV replication complex through NS5B. These results imply that BIK is essential for HCV replication and that NS5B is able to induce BIK expression.
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    • "In other systems (e.g., Hepatitis C) activation of calpains have been shown to inhibit the host's extrinsic apoptotic signaling pathway, which is necessary for successful infection. (Simonin et al., 2009). Consequently, the possession of such a protease in the AaV genome might allow for avoidance of the host's virus exclusion strategy. "
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    • "Indeed, expression levels of BCLXL (an anti-apoptotic factor) are elevated in HCC [48]. Furthermore, a recent report indicated that BID (a pro-apoptotic member) is down-regulated in a subset of HCCs in the context of viral hepatitis [49]. The pro-apoptotic BAD reportedly exert an important regulatory role in cell death in normal liver cells. "
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