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JMJD2D stabilises and cooperates with HBx protein to promote HBV transcription and replication

Xu Kong1,2, Zuofeng Liu1,3, Ruyi Zhang1,2

  • 1Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China.

JHEP Reports : Innovation in Hepatology
|September 13, 2023
PubMed

Insights

Targeting the host factor JMJD2D offers a new strategy against chronic hepatitis B (CHB) infection. Inhibiting JMJD2D reduces hepatitis B virus (HBV) replication by stabilizing HBx protein and enhancing HBV transcription.

Area of Science:

  • Hepatology
  • Virology
  • Molecular Biology

Background:

  • Hepatitis B virus (HBV) infection is a significant global health challenge.
  • Transcriptional regulation of covalently closed circular DNA (cccDNA) is a key factor in persistent chronic hepatitis B (CHB) infection.
  • Targeting host factors for cccDNA silencing presents a novel therapeutic strategy.

Purpose of the Study:

  • To investigate the role of Jumonji C domain-containing (JMJD2) protein subfamily members (JMJD2A-2D) in HBV replication.
  • To determine the mechanism by which JMJD2D influences HBV cccDNA transcription and replication.
  • To evaluate JMJD2D as a potential therapeutic target for CHB.

Main Methods:

  • Lentivirus-based RNA interference was used to suppress JMJD2A-2D expression in HBV-infected cells.
  • JMJD2D-knockout mice were generated for in vivo experiments.
  • Co-immunoprecipitation, ubiquitylation, and chromatin immunoprecipitation assays were employed to study JMJD2D-HBx interactions and cccDNA regulation.

Main Results:

  • JMJD2D expression was significantly upregulated in HBV-infected mouse livers and human hepatoma cells.
  • Downregulation of JMJD2D inhibited cccDNA transcription and HBV replication.
  • JMJD2D stabilizes HBx by inhibiting TRIM14-mediated degradation and acts as a co-activator for HBx, enhancing HBV replication. A JMJD2D inhibitor (5C-8-HQ) suppressed HBV replication.

Conclusions:

  • JMJD2D plays a crucial role in regulating HBV transcription and replication by stabilizing HBx.
  • JMJD2D is identified as a potential diagnostic biomarker and a promising drug target for CHB and HBV-associated hepatocarcinoma.
  • Targeting JMJD2D represents a novel translational approach for treating chronic hepatitis B infection.
Abstract

Keywords:
Chronic hepatitis BHBV replicationHBxIntervention targetJMJD2DcccDNA transcription

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