title: Requirement of CRTC1 coactivator for hepatitis B virus transcription.
abstract: Transcription of hepatitis B virus (HBV) from the covalently closed circular DNA (cccDNA) template is essential for its replication. Suppressing the level and transcriptional activity of cccDNA might have anti-HBV effect. Although cellular transcription factors, such as CREB, which mediate HBV transcription, have been well described, transcriptional coactivators that facilitate this process are incompletely understood. In this study we showed that CREB-regulated transcriptional coactivator 1 (CRTC1) is required for HBV transcription and replication. The steady-state levels of CRTC1 protein were elevated in HBV-positive hepatoma cells and liver tissues. Ectopic expression of CRTC1 or its homolog CRTC2 or CRTC3 in hepatoma cells stimulated the activity of the preS2/S promoter of HBV, whereas overexpression of a dominant inactive form of CRTC1 inhibited HBV transcription. CRTC1 interacts with CREB and they are mutually required for the recruitment to the preS2/S promoter on cccDNA and for the activation of HBV transcription. Accumulation of pregenomic RNA (pgRNA) and cccDNA was observed when CRTC1 or its homologs were overexpressed, whereas the levels of pgRNA, cccDNA and secreted HBsAg were diminished when CRTC1 was compromised. In addition, HBV transactivator protein HBx stabilized CRTC1 and promoted its activity on HBV transcription. Our work reveals an essential role of CRTC1 coactivator in facilitating and supporting HBV transcription and replication.
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Hei-Man Vincent
authors.initials: HM
authors.lastname: Tang
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Chi-Ping
authors.initials: CP
authors.lastname: Chan
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Yun
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Vidyanath
authors.initials: V
authors.lastname: Chaudhary
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Deng
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Kit-San
authors.initials: KS
authors.lastname: Yuen
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong Department of Pathology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Kin-Hang
authors.initials: KH
authors.lastname: Kok
authors.affiliation: Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong dyjin@hku.hk.
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
mesh_terms: D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication
chemical_list: C500984:CRTC1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D015534:Trans-Activators; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein