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Interplay between SIRT1 and hepatitis B virus X protein in the activation of viral transcription
- Source :
- Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1860:491-501
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Hepatitis B virus (HBV) genome is organized into a minichromosome known as covalently closed circular DNA (cccDNA), which serves as the template for all viral transcripts. SIRT1 is an NAD+-dependent protein deacetylase which activates HBV transcription by promoting the activity of cellular transcription factors and coactivators. How SIRT1 and viral transactivator X protein (HBx) might affect each other remains to be clarified. In this study we show synergy and mutual dependence between SIRT1 and HBx in the activation of HBV transcription. All human sirtuins SIRT1 through SIRT7 activated HBV gene expression. The steady-state levels of SIRT1 protein were elevated in HBV-infected liver tissues and HBV-replicating hepatoma cells. SIRT1 interacted with HBx and potentiated HBx transcriptional activity on precore promoter and covalently closed circular DNA (cccDNA) likely through a deacetylase-independent mechanism, leading to more robust production of cccDNA, pregenomic RNA and surface antigen. SIRT1 and HBx proteins were more abundant when both were expressed. SIRT1 promoted the recruitment of HBx as well as cellular transcriptional factors and coactivators such as PGC-1α and FXRα to cccDNA. Depletion of SIRT1 suppressed HBx recruitment. On the other hand, SIRT1 recruitment to cccDNA was compromised when HBx was deficient. Whereas pharmaceutical agonists of SIRT1 such as resveratrol activated HBV transcription, small-molecule inhibitors of SIRT1 including sirtinol and Ex527 exhibited anti-HBV activity. Taken together, our findings revealed not only the interplay between SIRT1 and HBx in the activation of HBV transcription but also new strategies and compounds for developing antivirals against HBV.
- Subjects :
- 0301 basic medicine
Hepatitis B virus
Carcinoma, Hepatocellular
Transcription, Genetic
endocrine system diseases
viruses
Biophysics
Biology
Virus Replication
medicine.disease_cause
Biochemistry
03 medical and health sciences
Transactivation
Sirtuin 1
Structural Biology
Transcription (biology)
Gene expression
Genetics
medicine
Humans
Viral Regulatory and Accessory Proteins
Molecular Biology
Transcription factor
Liver Neoplasms
Hep G2 Cells
cccDNA
Hepatitis B
Molecular biology
digestive system diseases
enzymes and coenzymes (carbohydrates)
HBx
030104 developmental biology
Liver
Trans-Activators
Protein deacetylase
DNA, Circular
hormones, hormone substitutes, and hormone antagonists
Protein Binding
Subjects
Details
- ISSN :
- 18749399
- Volume :
- 1860
- Database :
- OpenAIRE
- Journal :
- Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
- Accession number :
- edsair.doi.dedup.....b8a631372b6ad7d6c3fad365081daeae