Abstract
The human immunodeficiency virus type-1 trans-activator Tat is a transcription factor that activates the HIV-1 promoter through binding to the trans-activation-responsive region (TAR) localized at the 5'-end of all viral transcripts. We and others have recently shown that Tat is directly acetylated at lysine 28, within the activation domain, and lysine 50, in the TAR RNA binding domain, by Tat-associated histone acetyltransferases p300, p300/CBP-associating factor, and hGCN5. Here, we show that mutation of acetyl-acceptor lysines to arginine or glutamine affects virus replication. Interestingly, mutation of lysine 28 and lysine 50 differentially affected Tat trans-activation of integrated versus nonintegrated long terminal repeat. Our results highlight the importance of lysine 28 and lysine 50 of Tat in virus replication and Tat-mediated trans-activation.
Highlights
The primary function attributed to Tat is its role in Human immunodeficiency virus type-1 (HIV-1) promoter activation
Tat interacts with cyclin T1 to recruit positive transcription elongation factor b to the HIV-1 trans-activationresponsive region (TAR) element and to stimulate elongation of transcripts originating from the viral long terminal repeat (LTR) [32, 33]
We have recently shown that Tat lysine 28, within the activation domain, and lysine 50, within the RNA binding domain, are targeted for acetylation by p300/ CBP-associating factor (PCAF) and p300, respectively
Summary
The primary function attributed to Tat is its role in HIV-1 promoter activation. Tat is an atypical transcriptional activator that functions through binding, not to DNA, but to a short leader RNA, trans-activation responsive region (TAR) localized at the 5Ј termini of all viral transcripts (14 –16). Mutation of Tat Acetyl-acceptor Lysines Affects HIV-1 Replication—HIV-1 Tat is essential for virus replication and is a potent trans-activator of viral gene expression [20]. Mutation of acetyl-acceptor residues Lys28 and Lys50 to alanine reduces Tat-mediated trans-activation of the HIV-1 promoter in transient transfection assays [40].
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