Brès Vanessa, Tagami Hideaki, Péloponèse Jean-Marie, Loret Erwan, Jeang Kuan-Teh, Nakatani Yoshihiro, Emiliani Stephane, Benkirane Monsef, Kiernan Rosemary E
Laboratoire de Virologie Moléculaire et Transfert de Gène, Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France.
EMBO J. 2002 Dec 16;21(24):6811-9. doi: 10.1093/emboj/cdf669.
The HIV-1 transactivator protein, Tat, is an atypical transcriptional activator that functions through binding, not to DNA, but to a short leader RNA, TAR. Although details of its functional mechanism are still unknown, emerging findings suggest that Tat serves primarily to adapt co-activator complexes such as p300, PCAF and P-TEFb to the HIV-1 long terminal repeat. Hence, an understanding of how Tat interacts with these cofactors is crucial. It has recently been shown that acetylation at a single lysine, residue 50, regulated the association of Tat with PCAF. Here, we report that in the absence of Tat acetylation, PCAF binds to amino acids 20-40 within Tat. Interestingly, acetylation of Tat at Lys28 abrogates Tat-PCAF interaction. Acetylation at Lys50 creates a new site for binding to PCAF and dictates the formation of a ternary complex of Tat-PCAF-P-TEFb. Thus, differential lysine acetylation of Tat coordinates the interactions with its co-activators, cyclin T1 and PCAF. Our results may help in understanding the ordered recruitment of Tat co-activators to the HIV-1 promoter.
HIV-1反式激活蛋白Tat是一种非典型转录激活因子，它不是通过与DNA结合，而是与一段短的前导RNA（TAR）结合来发挥作用。尽管其功能机制的细节仍不清楚，但新出现的研究结果表明，Tat主要作用是使诸如p300、PCAF和P-TEFb等共激活复合物适应HIV-1长末端重复序列。因此，了解Tat如何与这些辅因子相互作用至关重要。最近有研究表明，单个赖氨酸残基50的乙酰化调节了Tat与PCAF的结合。在此，我们报告，在没有Tat乙酰化的情况下，PCAF与Tat内的20-40位氨基酸结合。有趣的是，Tat在赖氨酸28处的乙酰化消除了Tat与PCAF的相互作用。赖氨酸50处的乙酰化产生了一个与PCAF结合的新位点，并决定了Tat-PCAF-P-TEFb三元复合物的形成。因此，Tat不同赖氨酸残基的乙酰化协调了其与共激活因子细胞周期蛋白T1和PCAF的相互作用。我们的结果可能有助于理解Tat共激活因子向HIV-1启动子的有序募集。
