HIV-1 tat protein concomitantly down-regulates apical caspase-10 and up-regulates c-FLIP in lymphoid T cells: A potential molecular mechanism to escape TRAIL cytotoxicity
HIV-1 tat protein concomitantly down-regulates apical caspase-10 and up-regulates c-FLIP in lymphoid T cells: A potential molecular mechanism to escape TRAIL cytotoxicity
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DOI：
10.1002/jcp.20252
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发表时间：
2005-06-01
影响因子：
5.6
通讯作者：
Zauli, G
中科院分区：
文献类型：
--
作者：
Gibellini, D;Re, MC;Zauli, G
在这项研究中，我们发现HIV-1血清阳性患者中人类免疫缺陷病毒I型(HIV-1)RNA的量与血浆TRAIL水平之间存在正相关。鉴于先前已证实HIV-1 Tat蛋白Lip调节单核细胞中TRAIL的表达，而表达Tat的淋巴细胞对TRAIL的细胞毒性更具抵抗力，我们接下来研究了Tat对顶端caspase-8和-10表达/活性的影响，这两个蛋白在TRAIL和c-flip介导细胞凋亡的初始阶段起着关键作用。稳定表达野生型(HIV-1)Tat基因的Jurkat淋巴母细胞人T细胞株与对照组和突变的(Cys22)非功能Tat基因的Jurkat淋巴母细胞系相比，caspase-8的表达水平正常，但caspase-10的mRNA和蛋白水平显著降低。瞬时转染携带TAT基因的载体后，caspase-10的表达/活性显著降低。此外，在TAT表达的细胞中，c-FLIPL和c-Flips亚型在mRNA和蛋白水平均较对照细胞上调。综上所述，这些结果为解释表达TAT的Jurkat细胞对TRAIL诱导的细胞凋亡以及可能对其他死亡诱导配体的抗性提供了分子基础。(C)2004年Wiley-Liss公司
In this study, we showed the existence of a positive correlation between the amount of human immunodeficiency virus-type I (HIV-1) RNA in HIV-1 seropositive subjects and the plasma levels of TRAIL. Since it has been previously demonstrated that HIV-1 Tat protein Lip-regulates the expression of TRAIL in monocytic cells whereas tat-expressing lymphoid cells are more resistant to TRAIL cytotoxicity, we next investigated the effect of Tat on the expression/activity of both apical caspase-8 and -10, which play a key role in mediating the initial phases of apoptosis by TRAIL, and c-FLIP. Jurkat lymphoblastoid human T cell lines stably transfected with a plasmid expressing wild-type (HIV-1) tat gene showed normal levels of caspase-8 but significantly decreased levels of caspase-10 at both mRNA and protein levels with respect to Jurkat transfected with the control plasmid or with a mutated (cys22) non-functional tat cDNA. A significant decrease of caspase-10 expression/activity was also observed in transient transfection experiments with plasmid carrying tat cDNA. Moreover, c-FLIPL and c-FLIPS isoforms were up-regulated in tat-expressing cells at both mRNA and protein level in comparison with control cells. Taken together, these results provide a molecular basis to explain the resistance of tat-expressing Jurkat cells to apoptosis induced by TRAIL and, possibly, to other death-inducing ligands. (c) 2004 Wiley-Liss, Inc.