Prospero-related homeobox protein (Prox1) inhibits hepatitis B virus replication through repressing multiple cis regulatory elements.
Hepatitis B virus (HBV) gene transcription is controlled by viral promoters and enhancers, the activities of which are regulated by a number of cellular factors as well as virally encoded proteins. Negative regulation of HBV cis-element activities by cellular factors has been reported less widely than their activation. In this study, we report that nuclear factor Prospero-related homeobox protein (Prox1) represses HBV antigen expression and genome replication in cultured hepatocytes. By using reporter-gene analysis, three of the four HBV promoters, namely the enhancer II/core promoter (ENII/Cp), preS1 promoter (Sp1) and enhancer I/X promoter, were identified as targets for Prox1-mediated repression. Mechanistic analysis then revealed that, for ENII/Cp, Prox1 serves as a corepressor of liver receptor homologue 1 (LRH-1) and downregulates LRH-1-mediated activation of ENII/Cp, whereas for Sp1, Prox1 partially represses Sp1 activity by interacting directly with hepatocyte nuclear factor 1. Identification of Prox1 as an HBV repressor will help in the understanding of detailed interactions between viral cis elements and host cellular factors and may also form the basis for new anti-HBV intervention therapeutics.
Qin
Jun
J
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Zhai
Jianwei
J
Graduate School of Chinese Academy of Sciences, Beijing 100049, PR China.|State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Hong
Ran
R
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Shan
Shifang
S
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Kong
Yuying
Y
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Wen
Yumei
Y
Institute of Biomedical Sciences, Fudan University, Shanghai 200032, PR China.|Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
Wang
Yuan
Y
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Liu
Jing
J
Institute of Biomedical Sciences, Fudan University, Shanghai 200032, PR China.|Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.
Xie
Youhua
Y
Institute of Biomedical Sciences, Fudan University, Shanghai 200032, PR China.|Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Shanghai Medical College, Fudan University, Shanghai 200032, PR China.|State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D016679:Genome, Viral; D006515:Hepatitis B virus / Q000276:immunology / Q000502:physiology*; D051537:Hepatocyte Nuclear Factor 1 / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D012367:RNA, Viral / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*; D000098551:Prospero-Related Homeobox 1 Protein
D000956:Antigens, Viral; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C082631:NR5A2 protein, human; D012367:RNA, Viral; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D051537:Hepatocyte Nuclear Factor 1