HBV Infection Drives PSMB5-Dependent Proteasomal Activation in Humanized Mice and HBV-Associated HCC

Area of Science:

• Molecular Biology
• Hepatology
• Oncology

Background:

• Hepatocellular carcinoma (HCC) is a major liver cancer strongly linked to Hepatitis B Virus (HBV) infection.
• The ubiquitin-proteasome system regulates protein degradation and is implicated in cancer, but its role in HBV-related HCC is unclear.
• Specific proteasomal subunit expression and activity during HBV infection and HCC require further definition.

Purpose of the Study:

• To investigate proteasomal subunit expression and activity in HBV infection and HBV-induced HCC.
• To determine the association between proteasomal mRNA expression and proteasomal activity.
• To uncover HBV-specific molecular alterations in the ubiquitin-proteasome system.

Main Methods:

• Analysis of mRNA expression profiles of proteasomal subunits in HBV-infected humanized mouse models.
• Functional studies assessing the impact of β5 subunit deficiency on MHC I levels and ubiquitinated protein accumulation.
• Examination of β5 mRNA/protein levels and chymotrypsin-like activity in HBV-infected patient livers.
• Correlation analysis of β5 mRNA expression with clinical prognosis using Protein Atlas data.

Main Results:

• Hepatitis B Virus (HBV) infection consistently overexpresses the chymotrypsin-like activity (β5) proteasome subunit (PSMB5).
• PSMB5 deficiency reduces cell surface MHC I and increases ubiquitinated protein accumulation, confirming its role in proteasomal activity.
• HBV-infected human and mouse livers show elevated PSMB5 levels and enhanced chymotrypsin-like activity.
• Higher PSMB5 mRNA expression correlates with poor clinical prognosis in Hepatocellular carcinoma (HCC) patients.

Conclusions:

• HBV infection significantly alters proteasome function by increasing PSMB5 expression and activity in liver cells.
• Proteasomal dysregulation plays a critical role in HBV-associated liver pathology and Hepatocellular carcinoma (HCC) development.
• Targeting proteasome dynamics presents a potential therapeutic strategy and biomarker avenue for HBV-related liver diseases and Hepatocellular carcinoma (HCC).