Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4

Wen Jye Lin, Jie Li, Yi Fen Lee, Shauh Der Yeh, Saleh Altuwaijri, Jing Hsiung Ou, Chawnshang Chang

Research output: Contribution to journalArticle

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Abstract

The TR4 orphan receptor is a member of the nuclear receptor superfamily that modulates gene expression via binding to the AGGTCA direct repeat hormone response element. Here we report a functional study of TR4 interaction with the core promoter of the hepatitis B virus (HBV). The electrophoretic mobility shift assay shows that TR4 can bind to the direct repeat 1 sequence element (AGGTTAAAGGTCT, nucleotide coordinates 1757-1769, TR4RE-HBV) on the HBV core promoter. TR4 also can enhance the activity of a synthetic luciferase reporter linked with four copies of TR4RE-HBV in either liver HepG2 or non-liver H1299 cells in a dose-dependent manner. Surprisingly, TR4 represses the activity of a luciferase reporter containing the entire HBV genome sequences. Moreover, mutation of this TR4RE-HBV site in the HBV core promoter diminishes the TR4 suppression effect. This TR4-induced suppression of HBV core promoter activity is further confirmed by primer extension analysis of the HBV core RNAs, showing that TR4 represses both pre-core and core mRNAs. Further dissection of this repressive mechanism indicates that TR4 may suppress the HBV core promoter activity via repressing HNF4α-mediated transactivation by protein-protein interactions without inhibition of HNF4α DNA binding. Furthermore, our results indicate that the N- and C-terminal regions of TR4 protein are required for TR4-HNF4α interaction. It is possible that TR4-HNF4α interaction may block the HNF4α function that results in the suppression of HBV gene expression. Together, these results demonstrate that TR4 can serve as a negative modulator in the transcriptional regulation of HBV core gene expression.

Original languageEnglish
Pages (from-to)9353-9360
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number11
DOIs
Publication statusPublished - Mar 14 2003
Externally publishedYes

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Nuclear Receptor Subfamily 2, Group C, Member 2
Viruses
Hepatitis B virus
Gene expression
Nucleic Acid Repetitive Sequences
Luciferases
Gene Expression
Dissection
Electrophoretic mobility
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4. / Lin, Wen Jye; Li, Jie; Lee, Yi Fen; Yeh, Shauh Der; Altuwaijri, Saleh; Ou, Jing Hsiung; Chang, Chawnshang.

In: Journal of Biological Chemistry, Vol. 278, No. 11, 14.03.2003, p. 9353-9360.

Research output: Contribution to journalArticle

Lin, Wen Jye ; Li, Jie ; Lee, Yi Fen ; Yeh, Shauh Der ; Altuwaijri, Saleh ; Ou, Jing Hsiung ; Chang, Chawnshang. / Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 11. pp. 9353-9360.
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