Investigating the Expression and the Activity Patterns of Proteasomal Subunits in Livers with HBV infection and HBV-Derived HCC

Background & Aims: Hepatocellular Carcinoma (HCC) is the most prevalent types of liver cancer worldwide, with chronic infection of Hepatitis B Virus (HBV) being a major risk factor. The ubiquitin-proteasome system plays a critical role in protein degradation, cellular homeostasis, and cell cycle regulation. Dysregulation of proteasomal activity has been implicated in various cancers, including HCC. However, the specific expression patterns of proteasomal subunits in HBV infection and HBV-induced HCC remain poorly understood. Additionally, it is not known whether the mRNA expression of proteasome subunits correlates with the activity. Methods & Results: To fill this knowledge gap, we analyzed the proteasomal subunit mRNA expression levels in a liver-humanized mouse model after HBV infection. We found that the chymotrypsin-like activity (β5) subunit of the proteasome (PSMB5) was overexpressed after HBV infection. β5-deficient cells showed lower cell surface MHC I levels and increased accumulation of ubiquitinated proteins indicating an expression-function correlation. Similar to the mRNA expression data, protein levels of β5 subunit was higher in HBV-infected patient livers, and the infected liver tissue showed higher chymotrypsin-like proteolytic activity. The Protein Atlas data analysis also indicated that higher mRNA expression of β5 is associated with poor prognosis in HCC. Conclusions In summary, HBV infection increases both protein levels and the proteolytic activity of proteasomes in infected livers. The dynamics of protein degradation by proteasomes in HBV infected livers with HCC is of great importance to be able to develop better treatment strategies.