SIRT1 regulates HIV transcription via Tat deacetylation.
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.
Pagans
Sara
S
Gladstone Institute of Virology and Immunology, University of California, San Francisco, USA.
Pedal
Angelika
A
North
Brian J
BJ
Kaehlcke
Katrin
K
Marshall
Brett L
BL
Dorr
Alexander
A
Hetzer-Egger
Claudia
C
Henklein
Peter
P
Frye
Roy
R
McBurney
Michael W
MW
Hruby
Henning
H
Jung
Manfred
M
Verdin
Eric
E
Ott
Melanie
M
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
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
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