Regulation of survivin stability by the aryl hydrocarbon receptor-interacting protein
Regulation of survivin stability by the aryl hydrocarbon receptor-interacting protein
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DOI：
10.1074/jbc.m603175200
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发表时间：
2006-08-25
影响因子：
4.8
通讯作者：
Altieri, Dario C.
中科院分区：
文献类型：
--
作者：
Kang, Byoung Heon;Altieri, Dario C.
Survivin是IAP（inhibitor of apoptosis）家族的一个多功能成员，但其在保护细胞免于死亡和调节细胞分裂中的分子相互作用尚未完全阐明。在蛋白质组学筛选，以确定新的生存素结合的合作伙伴，我们发现，芳香烃受体相互作用蛋白（AIP）直接与生存素在体外和在体内的免疫共沉淀实验。这种相互作用是由AIP的羧基末端介导的，AIP包含三个tetratricopeptide基序，并涉及Survivin的羧基末端卷曲螺旋，其中Asp 142在AIP识别中起关键作用。仅缺乏Asp 142的存活素突变体不能结合AIP，并且在由蛋白酶体抑制剂逆转的反应中表现出体内加速降解。通过短干扰RNA或通过肽基模拟生存素AIP复合物的竞争急性敲低AIP使细胞中的生存素水平不稳定，具有增强的凋亡，但细胞周期进展没有变化。因此，AIP调节存活素稳定性，从而提高细胞抗凋亡阈值。生存素-AIP复合物可能影响细胞对环境毒素的异生素反应，并在细胞死亡调节过程中参与亚细胞伴侣蛋白的运输。
Survivin is a multifunctional member of the IAP ( inhibitor of apoptosis) family, but its molecular interactions in protection from cell death and regulation of cell division have not been completely elucidated. In a proteomics screening to identify novel survivin-binding partners, we found that the aryl hydrocarbon receptor-interacting protein (AIP) directly associates with survivin in vitro and in co-immunoprecipitation experiments in vivo. This interaction is mediated by the carboxyl-terminal end of AIP, which contains three tetratricopeptide motifs, and involves the carboxyl terminus coiled coil in survivin with critical roles of Asp142 in AIP recognition. A survivin mutant lacking only Asp142 fails to bind AIP and exhibits accelerated degradation in vivo in a reaction reversed by a proteasome inhibitor. Acute knock-down of AIP by short interference RNA or competition of the survivin AIP complex by peptidyl mimicry destabilizes survivin levels in cells, with enhanced apoptosis but no changes in cell cycle progression. Therefore, AIP regulates survivin stability, thus elevating a cellular anti-apoptotic threshold. The survivin-AIP complex may influence the cellular xenobiotic response to environmental toxin(s) and contribute to subcellular chaperone trafficking during cell death regulation.