These authors contributed equally to this work.
Article first published online: 24 SEP 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 6, pages 2116–2124, December 2012
How to Cite
van Breugel, P. C., Robert, E. I., Mueller, H., Decorsière, A., Zoulim, F., Hantz, O. and Strubin, M. (2012), Hepatitis B virus X protein stimulates gene expression selectively from extrachromosomal DNA templates. Hepatology, 56: 2116–2124. doi: 10.1002/hep.25928
Potential conflict of interest: Nothing to report.
- Issue published online: 4 DEC 2012
- Article first published online: 24 SEP 2012
- Accepted manuscript online: 28 JUN 2012 07:15AM EST
- Manuscript Accepted: 15 JUN 2012
- Manuscript Received: 4 JAN 2012
- French National Agency for Research against AIDS and viral hepatitis (ANRS)
- Swiss National Science Foundation. Grant Number: 31003A-127384
- Canton of Geneva
Chronic hepatitis B virus (HBV) infection is a major risk factor for liver cancer development. HBV encodes the hepatitis B virus X (HBx) protein that promotes transcription of the viral episomal DNA genome by the host cell RNA polymerase II. Here we provide evidence that HBx accomplishes this task by a conserved and unusual mechanism. Thus, HBx strongly stimulates expression of transiently transfected reporter constructs, regardless of the enhancer and promoter sequences. This activity invariably requires HBx binding to the cellular UV-damaged DDB1 E3 ubiquitin ligase, suggesting a common mechanism. Unexpectedly, none of the reporters tested is stimulated by HBx when integrated into the chromosome, despite remaining responsive to their cognate activators. Likewise, HBx promotes gene expression from the natural HBV episomal template but not from a chromosomally integrated HBV construct. The same was observed with the HBx protein of woodchuck HBV. HBx does not affect nuclear plasmid copy number and functions independently of CpG dinucleotide methylation. Conclusion: We propose that HBx supports HBV gene expression by a conserved mechanism that acts specifically on episomal DNA templates independently of the nature of the cis-regulatory sequences. Because of its uncommon property and key role in viral transcription, HBx represents an attractive target for new antiviral therapies. (HEPATOLOGY 2012;56:2116–2124)