期刊
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
卷 14, 期 6, 页码 1177-1198出版社
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2022.08.002
关键词
Cohesin; cccDNA; HBx; SMC3
资金
- National Key Research and Development Program [2021YFC2300603]
- National Science Foundation of China [81830017, 81902051, 32170157]
- Taishan Scholarship [tspd20181201]
- Major Basic Research Project of Shandong Natural Science Foundation [ZR2020ZD12]
- Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong
- Key Research and Development Program of Shandong [2019GSF108238]
This study identified the cohesin/CTCF complex as a critical host restriction factor for cccDNA-driven HBV replication. The cohesin complex binds to cccDNA with the help of CTCF and reshapes the confirmation of cccDNA to prevent RNA polymerase II enrichment, resulting in reduced HBV replication. Interestingly, the HBV X protein transcriptionally reduces the expression of the structural maintenance of chromosomes complex to partially relieve the inhibitory role of the cohesin complex on HBV replication.
BACKGROUND & AIMS: Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV), existing as a stable mini-chromosome in the hepatocyte, is responsible for persistent HBV infection. Maintenance and sustained replication of cccDNA require its interaction with both viral and host proteins. However, the cccDNA-interacting host factors that limit HBV replication remain elusive. METHODS: Minicircle HBV (MC-HBV), a recombinant cccDNA, was constructed based on chimeric intron and minicircle DNA technology. By mass spectrometry based on pull-down with biotinylated MC-HBV, the cccDNA-hepatocyte interaction profile was mapped. HBV replication was assessed in different cell models that support cccDNA formation. RESULTS: MC-HBV supports persistent HBV replication and mimics the cccDNA minichromosome. The MC-HBV-based screen identified cohesin complex as a cccDNA binding host factor, leading to reduced HBV replication. Mechanistically, with the help of CCCTC-binding factor (CTCF), which has specific binding sites on cccDNA, cohesin loads on cccDNA and reshapes cccDNA confirmation to prevent RNA polymerase II enrichment. Interestingly, HBV X protein transcriptionally reduces structural maintenance of chromosomes complex expression to partially relieve the inhibitory role of the cohesin complex on HBV replication. CONCLUSIONS: Our data not only provide a feasible approach to explore cccDNA-binding factors, but also identify cohesin/CTCF complex as a critical host restriction factor for cccDNA-driven HBV replication. These findings provide a novel insight into cccDNA-host interaction and targeted therapeutic intervention for HBV infection.
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