SIRT1 regulates HIV transcription via Tat deacetylation

• Published in: PLoS biology Vol. 3; no. 2; p. e41
• Main Authors: Pagans, Sara, Pedal, Angelika, North, Brian J, Kaehlcke, Katrin, Marshall, Brett L, Dorr, Alexander, Hetzer-Egger, Claudia, Henklein, Peter, Frye, Roy, McBurney, Michael W, Hruby, Henning, Jung, Manfred, Verdin, Eric, Ott, Melanie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2005; Public Library of Science (PLoS)
• Subjects: Acetylation; Base Sequence; Cell Biology; DNA Primers; Enzymes; Gene Expression Regulation, Viral; Gene Products, tat - metabolism; Histone Deacetylases - genetics; HIV - genetics; HIV/AIDS; Human immunodeficiency virus; Humans; Infectious Diseases; Kinases; Molecular Biology/Structural Biology; Molecular Sequence Data; Proteins; Sirtuin 1; Sirtuins - genetics; tat Gene Products, Human Immunodeficiency Virus; Transcription, Genetic; Viral infections; Virology; Viruses; United States > US; Sirtuins; tat Gene Products, Human Immunodeficiency Virus; Gene Products, tat; Humans; Molecular Sequence Data; Histone Deacetylases; DNA Primers; HIV; Gene Expression Regulation, Viral; Sirtuin 1; Base Sequence; Transcription, Genetic; Acetylation
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0030041

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 Tat-mediated 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.