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Prospero-related homeobox protein (Prox1) inhibits hepatitis B virus replication through repressing multiple cis regulatory elements

Jun Qin^1,

Jianwei Zhai^1,2,

¹ 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
² Graduate School of Chinese Academy of Sciences, Beijing 100049, PR China
³ Key Laboratory of Medical Molecular Virology, Institute of Medical Microbiology, Shanghai Medical College, Fudan University, Shanghai 200032, PR China
⁴ Institute of Biomedical Sciences, Fudan University, Shanghai 200032, PR China

Correspondence
Jing Liu
liujing{at}sibs.ac.cn
Youhua Xie
yhxie{at}sibs.ac.cn

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.

These authors contributed equally to this work.

Supplementary figures are available with the online version of this paper.