Skip to main content
NCBI home page
Virologica Sinica logoLink to Virologica Sinica
. 2013 Jul 2;28(4):216–222. doi: 10.1007/s12250-013-3344-3

GCN5 acetyltransferase inhibits PGC1α-induced hepatitis B virus biosynthesis

Xiaohui Tian 1, Fei Zhao 1, Zhikui Cheng 1, Ming Zhou 1, Xiaoguang Zhi 1, Jiafu Li 3, Kanghong Hu 1,2,✉
PMCID: PMC8208399  PMID: 23913178

Abstract

Hepatitis B virus (HBV) biosynthesis is primarily restricted to hepatocytes due to the governing of liver-enriched nuclear receptors (NRs) on viral RNA synthesis. The liver-enriched NR hepatocyte nuclear factor 4α (HNF4α), the key regulator of genes implicated in hepatic glucose metabolism, is also a primary determinant of HBV pregenomic RNA synthesis and HBV replication. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) coactivates and further enhances the effect of HNF4α on HBV biosynthesis. Here, we showed that the acetyltransferase General Control Non-repressed Protein 5 (GCN5) acetylated PGC1α, leading to alteration of PGC1α from a transcriptionally active state into an inactive state. As a result, the coactivation activity of PGC1α on HBV transcription and replication was suppressed. Apparently, an acetylation site mutant of PGC1α (PGC1αR13) still had coactivation activity as GCN5 could not suppress the coactivation activity of the mutant. Moreover, a catalytically inactive acetyltransferase mutant GCN5m, due to the loss of acetylation activity, failed to inhibit the coactivation function of PGC1α in HBV biosynthesis. Our results demonstrate that GCN5, through its acetyltransferase activity, inhibits PGC1α-induced enhancement of HBV transcription and replication both in vitro and in vivo.

Keywords: Hepatitis B Virus (HBV), PGC1α, GCN5, Acetylation

References

  1. Ardawi M S, Ashy A A, Jamal Y S, Khoja S M. Metabolic control of hepatic gluconeogenesis in response to sepsis. J Lab Clin Med. 1989;114:579–586. [PubMed] [Google Scholar]
  2. Doitsh G, Shaul Y. Enhancer I predominance in hepatitis B virus gene expression. Mol Cell Biol. 2004;24:1799–1808. doi: 10.1128/MCB.24.4.1799-1808.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Guo H, Zhou T, Jiang D, Cuconati A, Xiao G H, Block T M, Guo J T. Regulation of hepatitis B virus replication by the phosphatidylinositol 3-kinase-akt signal transduction pathway. J Virol. 2007;81:10072–10080. doi: 10.1128/JVI.00541-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Lerin C, Rodgers J T, Kalume D E, Kim S H, Pandey A, Puigserver P. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab. 2006;3:429–438. doi: 10.1016/j.cmet.2006.04.013. [DOI] [PubMed] [Google Scholar]
  5. Li L, Oropeza C E, Kaestner K H, McLachlan A. Limited effects of fasting on hepatitis B virus (HBV) biosynthesis in HBV transgenic mice. J Virol. 2009;83:1682–1688. doi: 10.1128/JVI.02208-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Li X, Monks B, Ge Q, Birnbaum M J. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature. 2007;447:1012–1016. doi: 10.1038/nature05861. [DOI] [PubMed] [Google Scholar]
  7. Liu X, Tesfai J, Evrard Y A, Dent S Y, Martinez E. c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation. J Biol Chem. 2003;278:20405–20412. doi: 10.1074/jbc.M211795200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Nassal M. Hepatitis B viruses: reverse transcription a different way. Virus Res. 2008;134:235–249. doi: 10.1016/j.virusres.2007.12.024. [DOI] [PubMed] [Google Scholar]
  9. Ondracek C R, McLachlan A. Role of peroxisome proliferator-activated receptor gamma coactivator 1alpha in AKT/PKB-mediated inhibition of hepatitis B virus biosynthesis. J Virol. 2011;85:11891–11900. doi: 10.1128/JVI.00832-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ondracek C R, Reese V C, Rushing C N, Oropeza C E, McLachlan A. Distinct regulation of hepatitis B virus biosynthesis by peroxisome proliferator-activated receptor gamma coactivator 1alpha and small heterodimer partner in human hepatoma cell lines. J Virol. 2009;83:12545–12551. doi: 10.1128/JVI.01624-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ondracek C R, Rushing C N, Reese V C, Oropeza C E, McLachlan A. Peroxisome proliferator-activated receptor gamma Coactivator 1alpha and small heterodimer partner differentially regulate nuclear receptor-dependent hepatitis B virus biosynthesis. J Virol. 2009;83:12535–12544. doi: 10.1128/JVI.01623-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Oropeza C E, Li L, McLachlan A. Differential inhibition of nuclear hormone receptor-dependent hepatitis B virus replication by the small heterodimer partner. J Virol. 2008;82:3814–3821. doi: 10.1128/JVI.02507-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Potthoff M J, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck B N, Mangelsdorf D J, Kliewer S A, Burgess S C. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A. 2009;106:10853–10858. doi: 10.1073/pnas.0904187106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Qiao L, Wu Q, Lu X, Zhou Y, Fernandez-Alvarez A, Ye L, Zhang X, Han J, Casado M, Liu Q. SREBP-1a activation by HBx and the effect on hepatitis B virus enhancer II/core promoter. Biochem Biophys Res Commun. 2013;432:643–649. doi: 10.1016/j.bbrc.2013.02.030. [DOI] [PubMed] [Google Scholar]
  15. Reese V, Ondracek C, Rushing C, Li L, Oropeza C E, McLachlan A. Multiple nuclear receptors may regulate hepatitis B virus biosynthesis during development. Int J Biochem Cell Biol. 2011;43:230–237. doi: 10.1016/j.biocel.2009.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Reese V C, Oropeza C E, McLachlan A. Independent activation of hepatitis B virus biosynthesis by retinoids, peroxisome proliferators, and bile acids. J Virol. 2013;87:991–997. doi: 10.1128/JVI.01562-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rodgers J T, Lerin C, Haas W, Gygi S P, Spiegelman B M, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434:113–118. doi: 10.1038/nature03354. [DOI] [PubMed] [Google Scholar]
  18. Schmoll D, Wasner C, Hinds C J, Allan B B, Walther R, Burchell A. Identification of a cAMP response element within the glucose-6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells. Biochem J. 1999;338(Pt2):457–463. doi: 10.1042/0264-6021:3380457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Shlomai A, Shaul Y. The “metabolovirus” model of hepatitis B virus suggests nutritional therapy as an effective anti-viral weapon. Med Hypotheses. 2008;71:53–57. doi: 10.1016/j.mehy.2007.08.032. [DOI] [PubMed] [Google Scholar]
  20. Shlomai A, Paran N, Shaul Y. PGC-1alpha controls hepatitis B virus through nutritional signals. Proc Natl Acad Sci U S A. 2006;103:16003–16008. doi: 10.1073/pnas.0607837103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Tang H, McLachlan A. Transcriptional regulation of hepatitis B virus by nuclear hormone receptors is a critical determinant of viral tropism. Proc Natl Acad Sci U S A. 2001;98:1841–1846. doi: 10.1073/pnas.98.4.1841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Terreni M, Valentini P, Liverani V, Gutierrez M I, Di Primio C, Di Fenza A, Tozzini V, Allouch A, Albanese A, Giacca M, Cereseto A. GCN5-dependent acetylation of HIV-1 integrase enhances viral integration. Retrovirology. 2010;7:18. doi: 10.1186/1742-4690-7-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tian Y, Chen W L, Ou J H. Effects of interferon-alpha/beta on HBV replication determined by viral load. PLoS Pathog. 2011;7:e1002159. doi: 10.1371/journal.ppat.1002159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wang Y, Li G, Goode J, Paz J C, Ouyang K, Screaton R, Fischer W H, Chen J, Tabas I, Montminy M. Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature. 2012;485:128–132. doi: 10.1038/nature10988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Yoon J C, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn C R, Granner D K, Newgard C B, Spiegelman B M. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001;413:131–138. doi: 10.1038/35093050. [DOI] [PubMed] [Google Scholar]

Articles from Virologica Sinica are provided here courtesy of Wuhan Institute of Virology, Chinese Academy of Sciences

RESOURCES