title: Interplay between SIRT1 and hepatitis B virus X protein in the activation of viral transcription.
abstract: Hepatitis B virus (HBV) genome is organized into a minichromosome known as covalently closed circular DNA (cccDNA), which serves as the template for all viral transcripts. SIRT1 is an NAD+-dependent protein deacetylase which activates HBV transcription by promoting the activity of cellular transcription factors and coactivators. How SIRT1 and viral transactivator X protein (HBx) might affect each other remains to be clarified. In this study we show synergy and mutual dependence between SIRT1 and HBx in the activation of HBV transcription. All human sirtuins SIRT1 through SIRT7 activated HBV gene expression. The steady-state levels of SIRT1 protein were elevated in HBV-infected liver tissues and HBV-replicating hepatoma cells. SIRT1 interacted with HBx and potentiated HBx transcriptional activity on precore promoter and covalently closed circular DNA (cccDNA) likely through a deacetylase-independent mechanism, leading to more robust production of cccDNA, pregenomic RNA and surface antigen. SIRT1 and HBx proteins were more abundant when both were expressed. SIRT1 promoted the recruitment of HBx as well as cellular transcriptional factors and coactivators such as PGC-1α and FXRα to cccDNA. Depletion of SIRT1 suppressed HBx recruitment. On the other hand, SIRT1 recruitment to cccDNA was compromised when HBx was deficient. Whereas pharmaceutical agonists of SIRT1 such as resveratrol activated HBV transcription, small-molecule inhibitors of SIRT1 including sirtinol and Ex527 exhibited anti-HBV activity. Taken together, our findings revealed not only the interplay between SIRT1 and HBx in the activation of HBV transcription but also new strategies and compounds for developing antivirals against HBV.
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; Shaanxi Key Laboratory of Biodegradable Materials, College of Chemical Engineering, Northwest University, 229 Taibai Road North, Xi'an 710069, China; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Deng
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Ka-Yiu Edwin
authors.initials: KE
authors.lastname: Kong
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Gao
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Hei-Man Vincent
authors.initials: HV
authors.lastname: Tang
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Vidyanath
authors.initials: V
authors.lastname: Chaudhary
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Yun
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Microbiology, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Chi-Ping
authors.initials: CP
authors.lastname: Chan
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong; Department of Medicine, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong.
authors.forename: Danny Ka-Ho
authors.initials: DK
authors.lastname: Wong
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong; Department of Medicine, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong.
authors.forename: Man-Fung
authors.initials: MF
authors.lastname: Yuen
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong; State Key Laboratory for Liver Research, The University of Hong Kong, 5 Sassoon Road, Pokfulam, Hong Kong. Electronic address: dyjin@hku.hk.
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics; D004270:DNA, Circular / Q000235:genetics; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics; D011485:Protein Binding; D056564:Sirtuin 1 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication / Q000235:genetics
chemical_list: D004270:DNA, Circular; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D056564:Sirtuin 1
keywords: HBx; Hepatitis B virus; SIRT1; Sirtuin; cccDNA