Related Experiment Video

Updated: Aug 5, 2026

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
05:55

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System

Published on: December 21, 2019

HBx Downregulates TFEB via the CUL4A/CUL4B-DDB1 Axis to Disrupt Lysosomal Function in Hepatocellular Carcinoma Cells

Chunyan Zhang1,2, Yuanping Han2, Huan Yang2,3

  • 1School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang 712046, China.

Cells
|July 27, 2026
PubMed

Insights

Hepatitis B virus X protein (HBx) disrupts lysosomal function by downregulating TFEB, a key regulator of lysosome biogenesis. This mechanism involves the CUL4A/CUL4B-DDB1 E3 ubiquitin ligase complex, impacting liver disease progression.

Area of Science:

  • Hepatology
  • Molecular Virology
  • Cell Biology

Background:

  • Hepatitis B virus (HBV) infection causes chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC).
  • The HBV-encoded X protein (HBx) is crucial for viral replication and pathogenesis, affecting host cellular processes like autophagy and lysosomal function.
  • The precise mechanisms by which HBx impairs lysosomal biogenesis and autophagic degradation are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying HBx-mediated disruption of lysosomal biogenesis and autophagic degradation.
  • To investigate the role of transcription factor EB (TFEB) in HBx-induced lysosomal dysfunction.
  • To identify the host factors and pathways involved in HBx's effects on lysosomes.

Main Methods:

  • Investigated the effect of HBx on TFEB expression and localization in HBV-infected cells.
  • Utilized cell-based assays to assess lysosomal acidification and autophagosome-lysosome fusion.
  • Employed mutagenesis studies to examine the role of the DDB1-interacting motif in HBx.
  • Analyzed the involvement of the CUL4A/CUL4B-DDB1 E3 ubiquitin ligase complex in HBx-mediated TFEB downregulation.

Main Results:

  • HBx downregulates TFEB, a master regulator of lysosomal biogenesis.
  • HBx-induced TFEB downregulation impairs lysosomal acidification and autophagosome-lysosome fusion.
  • HBx-mediated TFEB downregulation requires the CUL4A/CUL4B-DDB1 E3 ubiquitin ligase complex.
  • HBx mutants lacking DDB1-binding ability fail to downregulate TFEB and disrupt lysosomal function.

Conclusions:

  • HBx disrupts lysosomal function by downregulating TFEB through a CUL4A/CUL4B-DDB1-dependent mechanism.
  • This pathway contributes to HBV-associated liver pathogenesis.
  • Targeting the HBx-TFEB-lysosome axis presents a potential therapeutic strategy for HBV infection.

Keywords:
CUL4A/CUL4BHBxTFEBhepatocellular carcinomalysosome

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