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PMID:19264593

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Citation

Qin, J, Zhai, J, Hong, R, Shan, S, Kong, Y, Wen, Y, Wang, Y, Liu, J and Xie, Y (2009) Prospero-related homeobox protein (Prox1) inhibits hepatitis B virus replication through repressing multiple cis regulatory elements. J. Gen. Virol. 90:1246-55

Abstract

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.

Links

PubMed Online version:10.1099/vir.0.006007-0

Keywords

Antigens, Viral/genetics; Antigens, Viral/metabolism; Cell Line; DNA, Viral/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Gene Expression Regulation, Viral/physiology; Genome, Viral; Hepatitis B virus/immunology; Hepatitis B virus/physiology; Hepatocyte Nuclear Factor 1/metabolism; Hepatocytes/metabolism; Hepatocytes/virology; Homeodomain Proteins/metabolism; Humans; RNA, Viral/metabolism; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism; Regulatory Elements, Transcriptional/physiology; Transcription Factors/genetics; Transcription Factors/metabolism; Tumor Suppressor Proteins/metabolism; Virus Replication/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NR5A2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92786

F

Seeded From UniProt

complete

HUMAN:HNF1A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92786

F

Seeded From UniProt

complete

HUMAN:PROX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P20823

F

Seeded From UniProt

complete

HUMAN:PROX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O00482

F

Seeded From UniProt

complete

HUMAN:PROX1

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PROX1

involved_in

GO:0045071: negative regulation of viral genome replication

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR5A2

involved_in

GO:0045070: positive regulation of viral genome replication

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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