cccDNA Surrogate MC-HBV-Based Screen Identifies Cohesin Complex as a Novel HBV Restriction Factor.
Cell Mol Gastroenterol Hepatol
; 14(6): 1177-1198, 2022.
Article
en En
| MEDLINE
| ID: mdl-35987451
ABSTRACT
BACKGROUND & AIMS:
Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV), existing as a stable minichromosome 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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
ADN Circular
/
Virus de la Hepatitis B
Tipo de estudio:
Prognostic_studies
Idioma:
En
Año:
2022
Tipo del documento:
Article