SIRT1 regulates HIV transcription via Tat deacetylation

Sara Pagans, Angelika Pedal, Brian J. North, Katrin Kaehlcke, Brett L. Marshall, Alexander Dorr, Claudia Hetzer-Egger, Peter Henklein, Roy Frye, Michael W. McBurney, Henning Hruby, Manfred Jung, Eric Verdin, Melanie Ott

Research output: Contribution to journalArticlepeer-review

245 Scopus citations

Abstract

The human immunodeficiency virus (HIV) Tat protein is acetylated by the transcriptional coactivator p300, a necessary step in Tat-mediated transactivation. We report here that Tat is deacetylated by human sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent class III protein deacetylase in vitro and in vivo. Tat and SIRT1 coimmunoprecipitate and synergistically activate the HIV promoter. Conversely, knockdown of SIRT1 via small interfering RNAs or treatment with a novel small molecule inhibitor of the SIRT1 deacetylase activity inhibit Tatmediated transactivation of the HIV long terminal repeat. Tat transactivation is defective in SIRT1-null mouse embryonic fibroblasts and can be rescued by expression of SIRT1. These results support a model in which cycles of Tat acetylation and deacetylation regulate HIV transcription. SIRT1 recycles Tat to its unacetylated form and acts as a transcriptional coactivator during Tat transactivation. Copyright:

Original languageEnglish (US)
Article numbere41
Pages (from-to)210-220
Number of pages11
JournalPLoS Biology
Volume3
Issue number2
DOIs
StatePublished - Feb 2005
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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