The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis
The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis
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DOI：
10.1074/jbc.m406195200
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发表时间：
2004-11-12
影响因子：
4.8
通讯作者：
Loret, EP
中科院分区：
文献类型：
--
作者：
Campbell, GR;Pesquier, E;Loret, EP
人类免疫缺陷病毒(HIV)感染和发展为艾滋病的特征是CD4(+)T细胞耗尽。HIV-1感染导致未感染的旁观者细胞的凋亡，并直接杀死感染了HIV的细胞。这在一定程度上是由HIV-1Tat蛋白介导的，Tat蛋白由病毒感染的细胞分泌，并由未感染的细胞吸收。我们从两名临床上被归类为快速进展者或长期生存者的乌干达患者身上化学合成了两个86个残基的D亚型TAT蛋白，UG05RP和UG11LTS，非保守突变主要位于谷氨酰胺富集区。CD揭示了结构的异质性，这转化为不同的反式激活和凋亡效应。CD数据分析和分子模拟表明，在快速进展型患者如TAT MAL和TAT UG05RP的D亚型TAT蛋白中观察到的短α-螺旋在UG11LTS中不存在。我们发现TAT UG05RP在其反式激活作用和通过线粒体途径结合微管蛋白而诱导细胞凋亡方面比TAT UGUG11LTS更有效。TAT的谷氨酰胺富集区似乎参与了TAT介导的T细胞凋亡。
Human immunodeficiency virus (HIV) infection and the progression to AIDS are characterized by the depletion of CD4(+) T-cells. HIV-1 infection leads to apoptosis of uninfected bystander cells and the direct killing of HIV-infected cells. This is mediated, in part, by the HIV-1 Tat protein, which is secreted by virally infected cells and taken up by uninfected cells. We chemically synthesized two 86-residue subtype D Tat proteins, Ug05RP and Ug11LTS, from two Ugandan patients who were clinically categorized as either rapid progressor or long-term survivor, with non-conservative mutations located essentially in the glutamine-rich region. Structural heterogeneities were revealed by CD, which translate into differing trans-activational and apoptotic effects. CD data analysis and molecular modeling indicated that the short alpha-helix observed in subtype D Tat proteins from rapid progressor patients such as Tat Mal and Tat Ug05RP is not present in Ug11LTS. We show that Tat Ug05RP is more efficient than Tat Ug11LTS in its trans-activational role and in inducing apoptosis in binding tubulin via the mitochondrial pathway. The glutamine-rich region of Tat appears to be involved in the Tat-mediated apoptosis of T-cells.