HIV-1 Tat protein enhances microtubule polymerization.
HIV-1 Tat protein enhances microtubule polymerization.
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DOI：
10.1186/1742-4690-2-5
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发表时间：
2005-02-03
期刊：
影响因子：
3.3
通讯作者：
Loret EP
中科院分区：
文献类型：
--
作者：
de Mareuil J;Carre M;Barbier P;Campbell GR;Lancelot S;Opi S;Esquieu D;Watkins JD;Prevot C;Braguer D;Peyrot V;Loret EP
HIV 感染和进展为 AIDS 的特点是 T 细胞耗竭，这可能部分是由于 Tat 与微管蛋白结合而导致细胞外 HIV 编码的 Tat 蛋白介导的细胞凋亡。微管是微管蛋白聚合物，对于细胞结构和分裂至关重要。靶向微管的分子可诱导细胞凋亡，是有效的抗癌药物。我们研究了三种 Tat 变体对微管蛋白聚合的影响：来自快速进展者 (RP) 患者的 Tat HxB2 和 Tat Eli，以及来自高度暴露但持续血清阴性 (HEPS) 患者的 Tat Oyi。我们比较了这些 Tat 变体和对应于 Tat 序列不同部分的肽与紫杉醇（一种针对微管的抗癌药物）对微管蛋白聚合的影响。我们证明 Tat，特别是残基 38-72，可以直接增强微管蛋白聚合。我们证明，Tat 还可以直接触发线粒体途径诱导 T 细胞凋亡，如体外分离的线粒体释放细胞色素 c 所示。这些结果表明Tat直接作用于微管聚合，并为细胞外Tat介导的T细胞凋亡机制提供了见解。
HIV infection and progression to AIDS is characterized by the depletion of T cells, which could be due, in part, to apoptosis mediated by the extra-cellular HIV-encoded Tat protein as a consequence of Tat binding to tubulin. Microtubules are tubulin polymers that are essential for cell structure and division. Molecules that target microtubules induce apoptosis and are potent anti-cancer drugs. We studied the effect on tubulin polymerization of three Tat variants: Tat HxB2 and Tat Eli from patients who are rapid progressors (RP) and Tat Oyi from highly exposed but persistently seronegative (HEPS) patients. We compared the effect on tubulin polymerization of these Tat variants and peptides corresponding to different parts of the Tat sequence, with paclitaxel, an anti-cancer drug that targets microtubules. We show that Tat, and specifically, residues 38–72, directly enhance tubulin polymerization. We demonstrate that Tat could also directly trigger the mitochondrial pathway to induce T cell apoptosis, as shown in vitro by the release of cytochrome c from isolated mitochondria. These results show that Tat directly acts on microtubule polymerization and provide insights into the mechanism of T cell apoptosis mediated by extra-cellular Tat.