title: SIRT1 regulates HIV transcription via Tat deacetylation.
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 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.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, San Francisco, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Pagans
authors.forename: Angelika
authors.initials: A
authors.lastname: Pedal
authors.forename: Brian J
authors.initials: BJ
authors.lastname: North
authors.forename: Katrin
authors.initials: K
authors.lastname: Kaehlcke
authors.forename: Brett L
authors.initials: BL
authors.lastname: Marshall
authors.forename: Alexander
authors.initials: A
authors.lastname: Dorr
authors.forename: Claudia
authors.initials: C
authors.lastname: Hetzer-Egger
authors.forename: Peter
authors.initials: P
authors.lastname: Henklein
authors.forename: Roy
authors.initials: R
authors.lastname: Frye
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Henning
authors.initials: H
authors.lastname: Hruby
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
mesh_terms: D000107:Acetylation; D001483:Base Sequence; D017931:DNA Primers; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000378:metabolism*; D006678:HIV / Q000235:genetics*; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics*; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D017931:DNA Primers; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases
references.citation: Gene. 2001 Nov 14;279(1):1-16
references.pmid: 11722841
references.citation: EMBO J. 1998 Dec 1;17(23):7056-65
references.pmid: 9843510
references.citation: Mol Cell. 2002 Mar;9(3):575-86
references.pmid: 11931765
references.citation: J Biol Chem. 2002 Apr 12;277(15):12632-41
references.pmid: 11812793
references.citation: EMBO J. 2002 May 15;21(10):2383-96
references.pmid: 12006491
references.citation: EMBO J. 2002 Jun 3;21(11):2715-23
references.pmid: 12032084
references.citation: J Cell Biol. 2002 Aug 19;158(4):647-57
references.pmid: 12186850
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13653-8
references.pmid: 12374852
references.citation: J Biol Chem. 2002 Nov 22;277(47):45099-107
references.pmid: 12297502
references.citation: Mol Cell Biol. 2003 Jan;23(1):38-54
references.pmid: 12482959
references.citation: Biochem Biophys Res Commun. 2003 Jan 31;301(1):250-7
references.pmid: 12535671
references.citation: Mol Cell. 2003 Feb;11(2):437-44
references.pmid: 12620231
references.citation: Biochem J. 2003 Mar 15;370(Pt 3):737-49
references.pmid: 12429021
references.citation: Curr Opin Cell Biol. 2003 Apr;15(2):164-71
references.pmid: 12648672
references.citation: EMBO J. 1999 Nov 1;18(21):6106-18
references.pmid: 10545121
references.citation: Science. 1999 Nov 12;286(5443):1368-71
references.pmid: 10558993
references.citation: Curr Biol. 1999 Dec 16-30;9(24):1489-92
references.pmid: 10607594
references.citation: Mol Cell. 1999 Nov;4(5):725-34
references.pmid: 10619020
references.citation: Nature. 2000 Feb 17;403(6771):795-800
references.pmid: 10693811
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5807-11
references.pmid: 10811920
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6658-63
references.pmid: 10841563
references.citation: J Virol. 2000 Aug;74(15):6790-9
references.pmid: 10888618
references.citation: Virology. 2000 Nov 25;277(2):278-95
references.pmid: 11080476
references.citation: Nature. 2000 Nov 16;408(6810):377-81
references.pmid: 11099047
references.citation: Biochem Biophys Res Commun. 2000 Nov 30;278(3):685-90
references.pmid: 11095969
references.citation: EMBO J. 2001 Mar 15;20(6):1353-62
references.pmid: 11250901
references.citation: Nature. 2001 May 24;411(6836):494-8
references.pmid: 11373684
references.citation: J Biol Chem. 2001 Jul 27;276(30):28179-84
references.pmid: 11384967
references.citation: Science. 2001 Aug 31;293(5535):1653-7
references.pmid: 11533489
references.citation: Cell. 2001 Oct 19;107(2):137-48
references.pmid: 11672522
references.citation: Cell. 2001 Oct 19;107(2):149-59
references.pmid: 11672523
references.citation: EMBO J. 2003 Apr 15;22(8):1868-77
references.pmid: 12682019
references.citation: Trends Genet. 2003 May;19(5):286-93
references.pmid: 12711221
references.citation: EMBO J. 2003 May 1;22(9):2156-66
references.pmid: 12727882
references.citation: Mol Cell. 2003 Jul;12(1):51-62
references.pmid: 12887892
references.citation: Mol Cell. 2003 Jul;12(1):167-76
references.pmid: 12887902
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10794-9
references.pmid: 12960381
references.citation: J Biol Chem. 2003 Oct 31;278(44):43041-50
references.pmid: 12930829
references.citation: J Biol Chem. 2003 Dec 26;278(52):52773-82
references.pmid: 14534292
references.citation: Mol Cell. 2004 Jan 30;13(2):179-90
references.pmid: 14759364
references.citation: Cell. 2004 Feb 20;116(4):551-63
references.pmid: 14980222
references.citation: Science. 2004 Mar 26;303(5666):2011-5
references.pmid: 14976264
references.citation: Genome Biol. 2004;5(5):224
references.pmid: 15128440
references.citation: EMBO J. 2004 Jun 16;23(12):2369-80
references.pmid: 15152190
references.citation: Nature. 2004 Jun 17;429(6993):771-6
references.pmid: 15175761
references.citation: Science. 2004 Jul 16;305(5682):390-2
references.pmid: 15205477
references.citation: Mol Cell. 2004 Oct 8;16(1):93-105
references.pmid: 15469825
references.citation: Cell. 1985 Jul;41(3):813-23
references.pmid: 2988790
references.citation: Nature. 1987 Dec 3-9;330(6147):489-93
references.pmid: 2825027
references.citation: Nature. 1988 Jul 14;334(6178):165-7
references.pmid: 3386755
references.citation: Genes Dev. 1989 Mar;3(3):265-82
references.pmid: 2542124
references.citation: Genes Dev. 1990 Aug;4(8):1365-73
references.pmid: 2227414
references.citation: Science. 1996 Apr 12;272(5259):263-7
references.pmid: 8602510
references.citation: EMBO J. 1996 Mar 1;15(5):1112-20
references.pmid: 8605881
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6377-81
references.pmid: 8692823
references.citation: Science. 1997 Mar 7;275(5305):1481-5
references.pmid: 9045614
references.citation: Nat Biotechnol. 1997 Sep;15(9):871-5
references.pmid: 9306402
references.citation: Genes Dev. 1997 Oct 15;11(20):2622-32
references.pmid: 9334325
references.citation: Genes Dev. 1997 Dec 15;11(24):3327-40
references.pmid: 9407026
references.citation: J Virol. 1998 Feb;72(2):1666-70
references.pmid: 9445075
references.citation: Cell. 1998 Feb 20;92(4):451-62
references.pmid: 9491887
references.citation: Genes Dev. 1998 Nov 15;12(22):3512-27
references.pmid: 9832504
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15113-8
references.pmid: 11752457