Modulation of Eg5 activity contributes to mitotic spindle checkpoint activation and Tat-mediated apoptosis in CD4-positive T-lymphocytes
Modulation of Eg5 activity contributes to mitotic spindle checkpoint activation and Tat-mediated apoptosis in CD4-positive T-lymphocytes
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DOI：
10.1002/path.4333
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发表时间：
2014-06-01
影响因子：
7.3
通讯作者：
Zhou, Jun
中科院分区：
文献类型：
--
作者：
Liu, Min;Li, Dengwen;Zhou, Jun
达特是人类免疫缺陷病毒1型（HIV-1）的反式激活因子，是介导HIV-1感染患者中CD 4阳性T淋巴细胞损失的主要参与者之一，这主要是由于达特触发细胞凋亡的能力。然而，这一过程背后的分子事件仍然难以捉摸。在这项研究中，我们提供的证据表明，达特相互作用与Eg 5，微管相关的马达蛋白，变构调节ATP酶的活性Eg 5通过影响ADP释放的酶的活性中心。达特的这种作用损害有丝分裂纺锤体的形成并激活纺锤体检查点，从而阻断有丝分裂时的细胞周期进程并导致细胞凋亡。进一步的研究表明，达特羧基末端的赖氨酸85对于其与Eg 5的相互作用以及因此其对Eg 5活性、有丝分裂进程和凋亡的影响是关键的。这些发现确定达特作为Eg 5的病毒调节剂，并提供了新的见解达特介导的CD 4阳性T淋巴细胞减少的作用机制。版权所有（c）2014大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Tat, the transactivation factor of human immunodeficiency virus type 1 (HIV-1), represents one of the major players mediating the loss of CD4-positive T-lymphocytes in HIV-1-infected patients, primarily due to the ability of Tat to trigger apoptosis. However, the molecular events underlying this process remain elusive. In this study, we provide evidence that Tat interacts with Eg5, a microtubule-associated motor protein, and allosterically modulates the ATPase activity of Eg5 by affecting ADP release from the enzyme's active centre. This action of Tat impairs the formation of the mitotic spindle and activates the spindle checkpoint, thereby blocking cell cycle progression at mitosis and leading to apoptosis. Further studies reveal that lysine 85 in the carboxyl terminus of Tat is critical for its interaction with Eg5 and hence its effects on Eg5 activity, mitotic progression, and apoptosis. These findings identify Tat as a viral regulator of Eg5 and provide novel insights into the mechanisms of action of Tat in mediating the reduction of CD4-positive T-lymphocytes. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.