Forkhead O Transcription Factor 4 Restricts HBV Covalently Closed Circular DNA Transcription and HBV Replication through Genetic Downregulation of Hepatocyte Nuclear Factor 4 Alpha and Epigenetic Suppression of Covalently Closed Circular DNA via Interacting with Promyelocytic Leukemia Protein

Autor:	Yuqi Li, Minjing He, Ruijie Gong, Ziteng Wang, Lin Lu, Shu Peng, Zhiyun Duan, Ying Feng, Yi Liu, Bo Gao
Rok vydání:	2022
Předmět:	Hepatitis B virus Transcription Genetic Immunology Down-Regulation Forkhead Transcription Factors Promyelocytic Leukemia Protein Virus Replication Microbiology Epigenesis Genetic Hepatitis B Chronic Hepatocyte Nuclear Factor 4 Virology Insect Science DNA Viral Humans DNA Circular
Zdroj:	Journal of Virology. 96
ISSN:	1098-5514 0022-538X
DOI:	10.1128/jvi.00546-22
Popis:	Nuclear located hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) remains the key obstacle to cure chronic hepatitis B (CHB). In our previous investigation, it was found that FoxO4 could inhibit HBV core promoter activity through downregulating the expression of HNF4α. However, the exact mechanisms whereby FoxO4 inhibits HBV replication, especially its effect on cccDNA, remain unclear. Here, our data further revealed that FoxO4 could effectively inhibit cccDNA mediated transcription and HBV replication without affecting cccDNA level. Mechanistic study showed that FoxO4 could cause epigenetic suppression of cccDNA. Although FoxO4-mediated downregulation of HNF4α contributed to inhibiting HBV core promoter activity, it had little effect on cccDNA epigenetic regulation. Further, it was found that FoxO4 could colocalize within promyelocytic leukemia protein (PML) nuclear bodies and interact with PML. Of note, PML was revealed to be critical for FoxO4-mediated inhibition of cccDNA epigenetic modification and of the following cccDNA transcription and HBV replication. Furthermore, FoxO4 was found to be downregulated in HBV-infected hepatocytes and human liver tissues, and it was negatively correlated with cccDNA transcriptional activity in CHB patients. Together, these findings highlight the role of FoxO4 in suppressing cccDNA transcription and HBV replication via genetic downregulation of HNF4α and epigenetic suppression of cccDNA through interacting with PML. Targeting FoxO4 may present as a new therapeutic strategy against chronic HBV infection.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::19844374bd4e7ffb160f909f5c770534 https://doi.org/10.1128/jvi.00546-22 Zobrazit plný text záznamu