HIV-1 tat transactivator recruits p300 and CREB-binding protein histone acetyltransferases to the viral promoter.
In cells infected with HIV type 1 (HIV-1), the integrated viral promoter is present in a chromatin-bound conformation and is transcriptionally silent in the absence of stimulation. The HIV-1 Tat protein binds to a stem-loop structure at the 5' end of viral mRNA and relieves this inhibition by inducing a remodeling of the nucleosome arrangement downstream of the transcription-initiation site. Here we show that Tat performs this activity by recruiting to the viral long terminal repeat (LTR) the transcriptional coactivator p300 and the closely related CREB-binding protein (CBP), having histone acetyltransferase (HAT) activity. Tat associates with HAT activity in human nuclear extracts and binds to p300 and CBP both in vitro and in vivo. Integrity of the basic domain of Tat is essential for this interaction. By a quantitative chromatin immunoprecipitation assay we show that the delivery of recombinant Tat induces the association of p300 and CBP with the chromosomally integrated LTR promoter. Expression of human p300 in both human and rodent cells increases the levels of Tat transactivation of the integrated LTR. These results reinforce the evidence that p300 and CBP have a pivotal function at both cellular and viral promoters and demonstrate that they also can be recruited by an RNA-targeted activator. Additionally, these findings have important implications for the understanding of the mechanisms of HIV-1 latency and reactivation.
Marzio
G
G
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34012 Trieste, Italy.
Tyagi
M
M
Gutierrez
M I
MI
Giacca
M
M
D050882:CREB-Binding Protein; D002460:Cell Line; D015696:Gene Products, tat / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000821:virology*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000502:physiology*; D051548:Histone Acetyltransferases; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016662:Virus Integration; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D009687:Nuclear Proteins; D015534:Trans-Activators; D054322:tat Gene Products, Human Immunodeficiency Virus; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3