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cccDNA Surrogate MC-HBV-Based Screen Identifies Cohesin Complex as a Novel HBV Restriction Factor
Zhuanchang Wu1, Liyuan Wang1, Xin Wang2
1Key Laboratory for Experimental Teratology of Ministry of Education and Dept. Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China.
Cellular and Molecular Gastroenterology and Hepatology
|August 20, 2022
Summary
Researchers identified the cohesin/CTCF complex as a key host factor limiting hepatitis B virus (HBV) replication by binding to covalently closed circular DNA (cccDNA). This discovery offers new therapeutic targets for persistent HBV infections.
Area of Science:
- Virology
- Molecular Biology
- Hepatology
Background:
- Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) establishes persistent infections.
- Host-viral protein interactions are crucial for HBV replication, but limiting host factors remain unknown.
Purpose of the Study:
- To identify host factors that interact with HBV cccDNA and restrict viral replication.
- To elucidate the mechanism of host restriction on HBV cccDNA.
Main Methods:
- Construction of a recombinant minicircle HBV (MC-HBV) mimicking cccDNA.
- Mass spectrometry-based pull-down assay to map cccDNA-interacting proteins.
- Assessment of HBV replication in various cell models.
Main Results:
- The cohesin complex was identified as a cccDNA-binding host factor that reduces HBV replication.
- CCCTC-binding factor (CTCF) facilitates cohesin loading onto cccDNA, reshaping it to inhibit RNA polymerase II enrichment.
- HBV X protein antagonizes cohesin's inhibitory effect by downregulating the cohesin complex.
Conclusions:
- The cohesin/CTCF complex acts as a critical host restriction factor against HBV cccDNA replication.
- This study presents a novel method for discovering cccDNA-binding factors.
- Findings offer new insights into cccDNA-host interactions and potential therapeutic strategies for HBV.
