Hepatitis C virus core protein inhibits apoptosis through functional modulation of the PML/p53 tumor suppressor pathway

Abstract

Tumor suppressor protein promyelocytic leukaemia (PML) is implicated in apoptosis regulation and antiviral response. PML localizes predominantly to PML-nuclear bodies (PML-NBs), nuclear multiprotein complexes regulating tumor suppressor protein p53 activity. Consistent with a function of PML in the cellular antiviral response, PML-NBs represent preferential targets in viral infections. In the case of hepatitis C virus (HCV) infection, important characteristics are non-responsiveness to IFN-therapy and development of hepatocellular carcinoma (HCC). However, the mechanisms which lead to development of HCC are largely unknown. Here we show that HCV core protein localizes to the cell nucleus in PML-NBs and interacts with endogenously expressed PML isoform IV (PML-IV), a key regulator of p53 activity. Importantly, we found that HCV core protein inhibits PML-IV-induced apoptosis and interferes with the coactivator function of PML-IV for proapoptotic p53 target genes including CD95 (Fas/APO–1). In particular, HCV core expression abrogated PML-IV-mediated p53 serine 15 phosphorylation, a site implicated in p53 activation whose phosphorylation was previously linked to increased PML-NB formation. Taken together, our findings suggest a potential mechanism for HCV-associated development of HCC through HCV core-mediated inactivation of the PML tumor suppressor pathway. Keywords: HCV core, Hepatitis C, apoptosis, hepatocallular carcinoma, liver, nuclear bodies