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Teng, Y.* ; Xu, Z.* ; Zhao, K.* ; Zhong, Y.* ; Wang, J.* ; Zhao, L.* ; Zheng, Z.* ; Hou, W.* ; Zhu, C.* ; Chen, X.* ; Protzer, U. ; Li, Y.* ; Xia, Y.*

Novel function of SART1 in HNF4α transcriptional regulation contributes to its antiviral role during HBV infection.

J. Hepatol. 75, 1072-1082 (2021)
Open Access Green: Postprint online available 07/2022
BACKGROUND & AIMS: Our understanding about the interaction of the Hepatitis B virus (HBV) with its host cells is still quite limited. Spliceosome associated factor 1 (SART1) has recently been found to restrict Hepatitis C Virus. We aim to dissect its role in HBV infection that remains a big threat to global health. METHODS: SART1 was knocked down by RNA interference and over-expressed by lentiviral or adeno-associated virus (AAV) vectors in HBV infected cell cultures and in vivo in HBV replicating mice evaluating HBV replication markers. Luciferase reporter assays were used to determine viral or host factor promoter activities, and chromatin immunoprecipitation (ChIP) to investigate protein-DNA interactions. RESULTS: In HBV infected cell cultures, downregulation of SART1 did not affect HBV cccDNA but resulted in markedly enhancing HBV RNA, antigen expression and progeny virus production. On the other hand, HBV transcription and replication were significantly inhibited by overexpression of SART1. Similar results were observed in AAV-HBV infected mice persistently replicating HBV. Inhibition of Janus kinases showed no effect SART1-mediated inhibition of HBV replication. HBV promoter assays revealed that SART1 reduced HBV core promoter activity. By screening known HBV transcription factors, we found that SART1 specifically suppressed the expression of hepatocyte nuclear factor 4α (HNF4α). Luciferase reporter and ChIP assays demonstrated a direct downregulation of HNF4α expression by association of SART1 with HNF4α proximal P1 promoter element. CONCLUSIONS: We identify SART1 as a novel host factor suppressing HBV cccDNA transcription. Besides its effect on interferon stimulated genes, SART1 exerts an anti-HBV activity by suppressing HNF4α expression that is essential for transcription of HBV cccDNA. LAY SUMMARY: Hepatitis B virus (HBV) infects hepatocytes and establishes a covalently closed circular DNA (cccDNA), which remains a major obstacle for antiviral treatments. Spliceosome associated factor 1 (SART1) has been described to inhibit hepatitis C virus infection through direct regulation of interferon stimulated genes. In this study, by using various HBV models, we demonstrate that SART1 restrains HBV cccDNA transcription through suppression of HBV key transcription factor HNF4α.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Core Promoter ; Covalently Closed Circular Dna (cccdna) ; Hepatitis B Virus (hbv) ; Hepatocyte Nuclear Factor 4 Alpha (hnf4α) ; Spliceosome Associated Factor 1 (sart1); Hepatitis-b-virus; Terminal Repeat Retrotransposon; Gene; Replication; Mechanisms; Protein; Snrnp
ISSN (print) / ISBN 0168-8278
e-ISSN 1600-0641
Quellenangaben Volume: 75, Issue: 5, Pages: 1072-1082 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status Peer reviewed
Grants German Research Association (DFG)
Open Fund Project of State Key Laboratory of Virology
Foundation for Innovative Research Groups of Hubei Health Commission
Foundation for Innovative Research Groups of the National Natural Science Foundation of Hubei
Gilead Sciences Research Scholars Program in Liver Disease Asia
Hubei Province's Outstanding Medical Academic Leader Program
Fundamental Research Funds for the Central Universities
National Natural Science Foundation of China