The Ubiquitin-Proteasome System in Hepatitis B Virus Infection and Hepatocarcinogenesis: Viral Manipulation and Therapeutic Targets

TL;DR

This review explores how the hepatitis B virus manipulates the ubiquitin-proteasome system to support its life cycle and promote liver cancer, highlighting potential therapeutic strategies.

Contribution

The paper provides a comprehensive overview of HBV-UPS interactions and evaluates novel therapeutic approaches targeting these interactions.

Findings

HBV proteins, particularly HBV X protein, manipulate host E3 ligases to alter ubiquitination and promote viral replication.

Disruption of ubiquitin-proteasome system homeostasis contributes to impaired antiviral signaling and tumor progression.

Therapeutic strategies targeting UPS components show promise in inhibiting HBV and hepatocarcinogenesis.

Abstract

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma. To sustain viral life cycle, HBV modulates host pathways controlling protein turnover and innate immunity. Critical events in the HBV life cycle include the conversion of relaxed-circular DNA to covalently closed circular DNA, transcriptional activation of viral genes, and the synthesis and maturation of structural and regulatory proteins. These processes are tightly linked to the ubiquitin-proteasome system (UPS), the central machinery for post-translational control. Disruption of UPS homeostasis impairs antiviral signaling and drives malignant progression. Among HBV proteins, HBV X protein reshapes protein ubiquitination by recruiting or redirecting host E3 ligases. These alterations elevate the stability of virus-facilitating mediators, downregulate interferon-stimulated responses, and expedite the turnover of key tumor suppressors. In parallel, the host counters by attaching degradative ubiquitin chains to viral antigens or downregulating proviral modifications through deubiquitinases (DUBs). In this review, we consolidate current knowledge of the HBV-UPS interplay, dissecting molecular circuits that govern ubiquitin-driven degradation and detailing the specific E3 ligases hijacked by the virus. Finally, we evaluate therapeutic potentials that target HBV-UPS interaction, ranging from broad-spectrum proteasome inhibitors and selective DUB antagonists to proteolysis targeting chimeras.

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