Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway

Authors

  • Yannick Simonin,

    1. Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
    2. Université de Montpellier 2 and Université de Montpellier 1, Montpellier, France
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  • Olivier Disson,

    1. Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
    2. Université de Montpellier 2 and Université de Montpellier 1, Montpellier, France
    Current affiliation:
    1. Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France
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  • Hervé Lerat,

    1. Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
    2. Université de Montpellier 2 and Université de Montpellier 1, Montpellier, France
    Current affiliation:
    1. INSERM, U955, Hôpital Henri Mondor, 94010 Créteil, France
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  • Etienne Antoine,

    1. Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
    2. Université de Montpellier 2 and Université de Montpellier 1, Montpellier, France
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  • Fabien Binamé,

    1. Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
    2. Université de Montpellier 2 and Université de Montpellier 1, Montpellier, France
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  • Arielle R. Rosenberg,

    1. Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe Avenir “Virologie de l'hépatite C”, Institut Cochin, Paris, France
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  • Solange Desagher,

    1. Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
    2. Université de Montpellier 2 and Université de Montpellier 1, Montpellier, France
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  • Patrice Lassus,

    1. Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
    2. Université de Montpellier 2 and Université de Montpellier 1, Montpellier, France
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  • Paulette Bioulac-Sage,

    1. Hôpital Pellegrin, Service d'Anatomie Pathologique, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France
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  • Urszula Hibner

    Corresponding author
    1. Centre National de la Recherche Scientifique (CNRS), UMR 5535, Institut de Génétique Moléculaire de Montpellier, Montpellier, France
    2. Université de Montpellier 2 and Université de Montpellier 1, Montpellier, France
    • Institut de Génétique Moléculaire de Montpellier CNRS UMR 5535, 1919 route de Mende, 34293 Montpellier cedex 5, France
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    • phone: +33 467 613 656


  • Potential conflict of interest: Nothing to report.

Abstract

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. (Hepatology 2009.)

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