Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion.
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.
Benali-Furet
Naoual L
NL
Department of Liver Cancer and Molecular Virology, Inserm U370-Pasteur Institute, Paris F-75015, France.
Chami
Mounia
M
Houel
Ludivine
L
De Giorgi
Francesca
F
Vernejoul
Fabienne
F
Lagorce
David
D
Buscail
Louis
L
Bartenschlager
Ralf
R
Ichas
François
F
Rizzuto
Rosario
R
Paterlini-Bréchot
Patrizia
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000502:physiology* / Q000821:virology; D000091342:Endoplasmic Reticulum Chaperone BiP; D016174:Hepacivirus / Q000472:pathogenicity*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007425:Intracellular Membranes / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000502:physiology / Q000821:virology*; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D014162:Transfection
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D002118:Calcium