Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion
Oncogene. 2005-05-09; 24(31): 4921-4933
DOI: 10.1038/sj.onc.1208673
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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.