Hepatitis B Virus Inhibits Autophagic Degradation By Impairing Lysosomal Maturation

Autophagy is a conserved eukaryotic catabolic reaction that sequesters protein aggregates and damaged organelles into autophagosomes for lysosomal degradation. Deficient autophagy has been associated with a variety of human diseases including ageing, metabolic syndrome, neurodegeneration, and especially cancer. Hepatitis B virus X (HBx) protein is essential in the development of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Recently, the activation of autophagy by HBx has been identified in hepatic cells. However, this hardly explains the current widely-accepted concept that a defect rather than an enhancement of autophagy is associated with the development of carcinoma. The underlying mechanism and the relevance of HBx-activated autophagy to the carcinogenesis caused by HBV remain elusive.In this study, we investigated the molecular mechanism of HBV/HBx-induced autophagy by transfection of HBV genomic DNA and HBx in hepatic and hepatoma cells. We found that HBV-or HBx-induced autophagosome formation was accompanied by unchanged mTOR activity. Expression of HBV DNA or HBx-GFP dramatically raised the protein level of p62, the typical autophagic cargo proteins, but not p62mRNA level. Further functional analysis indicated that HBx dramatically inhibited lysosomal degradative capacity which led to a drop in autophagic degradation and the accumulation of autophagosome and p62. HBx impaired the maturation of cathepsin D by inhibition of lysosome acidification which led to the accumulation of immature lysosomes. Moreover, clinical specimen test found increased p62and immature lysosomal hydrolase cathepsin D in human liver tissues with chronic HBV infection and HBV-associated liver cancer. These data suggest that a repressive effect of HBx on lysosomal function is responsible for the inhibition of autophagic degradation, and this may be critical to the development of HBV-associated hepatocellular carcinoma.