HIV-1 Tat transcriptional activity is regulated by acetylation

Citation
Re. Kiernan et al., HIV-1 Tat transcriptional activity is regulated by acetylation, EMBO J, 18(21), 1999, pp. 6106-6118
Citations number
67
Categorie Soggetti
Molecular Biology & Genetics
Journal title
EMBO JOURNAL
ISSN journal
02614189 → ACNP
Volume
18
Issue
21
Year of publication
1999
Pages
6106 - 6118
Database
ISI
SICI code
0261-4189(19991101)18:21<6106:HTTAIR>2.0.ZU;2-Z
Abstract
The human immunodeficiency virus (HIV) transactivator protein, Tat, stimula tes transcription from the viral long-terminal repeats (LTR) through an RNA hairpin element, trans-activation responsive region (TAR). We and others h ave shown that trans-activator protein (Tat)-associated histone acetyltrans ferases (TAHs), p300 and p300/CBP-associating factor (PCAF), assist functio nally in the activation of chromosomally integrated HIV-1 LTR. Here, we sho w that p300 and PCAF also directly acetylate Tat. We defined two sites of a cetylation located in different functional domains of Tat. p300 acetylated Lys50 in the TAR RNA binding domain, while PCAF acetylated Lys28 in the act ivation domain of Tat. In support of a functional role for acetylation irt vivo, histone deacetylase inhibitor (trichostatin A) synergized with Tat in transcriptional activation of the HIV-1 LTR. Synergism was TAR-dependent a nd required the intact presence of both Lys28 and Lys50. Mechanistically, a cetylation at Lys28 by PCAF enhanced Tat binding to the Tat-associated kina se, CDK9/P-TEFb, while acetylation by p300 at Lys50 of Tat promoted the dis sociation of Tat from TAR RNA that occurs during early transcription elonga tion. These data suggest that acetylation of Tat regulates two discrete and functionally critical steps in transcription, binding to an RNAP II CTD-ki nase and release of Tat from TAR RNA.