HIV-1 Tat transcriptional activity is regulated by acetylation

• Published in: The EMBO journal 1999-11, Vol.18 (21), p.6106-6118
• Main Authors: Kiernan, Rosemary E., Vanhulle, Caroline, Schiltz, Lou, Adam, Emmanuelle, Xiao, Hua, Maudoux, Frédéric, Calomme, Claire, Burny, Arsène, Nakatani, Yoshihiro, Jeang, Kuan-Teh, Benkirane, Monsef, Van Lint, Carine
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Acetylation; Acetyltransferases - metabolism; AIDS/HIV; Animals; Cell Cycle Proteins - metabolism; Cyclin T; Cyclins - metabolism; Gene Expression Regulation, Viral - genetics; Gene Products, tat - genetics; Gene Products, tat - metabolism; Histone Acetyltransferases; HIV Long Terminal Repeat - genetics; HIV-1 - genetics; HIV-1 Tat; Human immunodeficiency virus 1; Humans; Mice; Mutation; p300; p300-CBP Transcription Factors; p300/CBP-associated factor; p300/CBP-associating factor; PCAF; Positive Transcriptional Elongation Factor B; Promoter Regions, Genetic; Protein-Serine-Threonine Kinases - metabolism; RNA, Viral - metabolism; RNA-Binding Proteins - metabolism; Saccharomyces cerevisiae Proteins; Synergism; tat Gene Products, Human Immunodeficiency Virus; Transcription Factors; Transcription, Genetic; transcriptional activity; trichostatin A; Viral Proteins - metabolism
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/18.21.6106

The human immunodeficiency virus (HIV) trans‐ activator protein, Tat, stimulates transcription from the viral long‐terminal repeats (LTR) through an RNA hairpin element, trans ‐activation responsive region (TAR). We and others have shown that trans ‐activator protein (Tat)‐associated histone acetyltransferases (TAHs), p300 and p300/CBP‐associating factor (PCAF), assist functionally in the activation of chromosomally integrated HIV‐1 LTR. Here, we show that p300 and PCAF also directly acetylate Tat. We defined two sites of acetylation located in different functional domains of Tat. p300 acetylated Lys50 in the TAR RNA binding domain, while PCAF acetylated Lys28 in the activation domain of Tat. In support of a functional role for acetylation in vivo , histone deacetylase inhibitor (trichostatin A) synergized with Tat in transcriptional activation of the HIV‐1 LTR. Synergism was TAR‐dependent and required the intact presence of both Lys28 and Lys50. Mechanistically, acetylation at Lys28 by PCAF enhanced Tat binding to the Tat‐associated kinase, CDK9/P‐TEFb, while acetylation by p300 at Lys50 of Tat promoted the dissociation of Tat from TAR RNA that occurs during early transcription elongation. These data suggest that acetylation of Tat regulates two discrete and functionally critical steps in transcription, binding to an RNAP II CTD‐kinase and release of Tat from TAR RNA.