Hepatitis C virus core protein activates proteasomal activator 28 gamma to downregulate p16 levels via ubiquitin-independent proteasomal degradation

Proteasomal activator 28 gamma (PA28 gamma), an essential constituent of the 20S proteasome, is frequently overexpressed in hepatocellular carcinoma. Hepatitis C virus (HCV) core protein is recently known to activate PA28 gamma expression in human hepatocytes via upregulation of p53 levels; however, its role in HCV tumorigenesis remains unknown. Here, we found that HCV core-activated PA28 gamma downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HCV core protein activated the Rb-E2F pathway to stimulate cell cycle progression from G1 to S phase, resulting in an increase in cell proliferation. The potential of HCV core protein to induce these effects was almost completely abolished by either PA28 gamma knockdown or p16 overexpression, confirming the role of the PA28 gamma-mediated p16 degradation in HCV tumorigenesis.

Automated summary

PA28 gamma activated by HCV core protein degrades p16 levels, leading to increased cell proliferation in hepatocellular carcinoma.