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Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion

Oncogene volume 24, pages 4921–4933 (2005)Cite this article

Abstract

Hepatitis C virus (HCV) core, known to be involved in liver carcinogenesis, is processed in the endoplasmic reticulum (ER). We thus investigated the impact of three HCV core isolates on ER stress, ER calcium signalling and apoptosis. We show that HCV core constructs trigger hyperexpression of Grp78/BiP, Grp 94, calreticulin and sarco/endoplasmic reticulum calcium ATPase, inducing ER stress. By using the ER-targeted aequorin calcium probe, we found that ER calcium depletion follows ER stress in core-expressing cells. HCV core induces apoptosis through overexpression of the CHOP/GADD153 proapoptotic factor, Bax translocation to mitochondria, mitochondrial membrane depolarization, cytochrome c release, caspase-3 and PARP cleavage. Furthermore, reversion of HCV core-induced ER calcium depletion (by transfection of SERCA2) completely abolished mitochondrial membrane depolarization, suggesting that both ER stress (through CHOP overexpression) and calcium signalling play a major role in the HCV core-mediated control of apoptosis. ER stress and apoptosis were also found in a proportion of HCV-full-length replicon-expressing cells and in the liver of HCV core transgenic mice. In conclusion, our data demonstrate that HCV core deregulates the control of apoptosis by inducing ER stress and ER calcium depletion providing new elements to understand the mechanisms involved in HCV-related liver chronic diseases.

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Acknowledgements

We thank Professor C Bréchot for helpful discussion and for supporting the project, Dr Guido Kroemer for helpfull discussion, Dr Kazuhiko Koike for providing transgenic mice, Dr G Perlemuter for providing samples, Mrs Anny Souques for technical assistance. This work was supported by grants from INSERM (Institut National de Santé et Recherche Médicale), ARC (Association pour la Recherche contre le Cancer), LNC (Ligue Nationale contre le Cancer), and ANRS (Association Nationale de Recherche sur le SID A). N Benali-Furet was supported by a grant from ARC.

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Authors and Affiliations

  1. Department of Liver Cancer and Molecular Virology, Inserm U370-Pasteur Institute, Paris, F-75015, France

    Naoual L Benali-Furet, Ludivine Houel, David Lagorce & Patrizia Paterlini-Bréchot

  2. Paris V University, CHU Necker, Paris, F-75005, France

    Naoual L Benali-Furet, Ludivine Houel, David Lagorce & Patrizia Paterlini-Bréchot

  3. Department of Experimental Medicine, University of Ferrara, Italy

    Mounia Chami & Rosario Rizzuto

  4. Institut Européen de Chimie et Biologie, Inserm E347, Pessac, F-33600, France

    Francesca De Giorgi & François Ichas

  5. Inserm U531, IFR31, Institut Louis Bugnard, CHU Rangueil Bat L3, TSA 50032, Toulouse, F-31059, France

    Fabienne Vernejoul & Louis Buscail

  6. Department of Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 345, Heidelberg, 69120, Germany

    Ralf Bartenschlager

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  1. Naoual L Benali-Furet
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Correspondence to Patrizia Paterlini-Bréchot.

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Benali-Furet, N., Chami, M., Houel, L. et al. Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. Oncogene 24, 4921–4933 (2005). https://doi.org/10.1038/sj.onc.1208673

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