Kang Byoung Heon, Altieri Dario C
Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
J Biol Chem. 2006 Aug 25;281(34):24721-7. doi: 10.1074/jbc.M603175200. Epub 2006 Jun 27.
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 Asp(142) in AIP recognition. A survivin mutant lacking only Asp(142) 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.
生存素是凋亡抑制蛋白（IAP）家族的多功能成员，但其在保护细胞免于死亡及调节细胞分裂过程中的分子相互作用尚未完全阐明。在一项旨在鉴定新型生存素结合伴侣的蛋白质组学筛选中，我们发现芳烃受体相互作用蛋白（AIP）在体外及体内的共免疫沉淀实验中均可直接与生存素结合。这种相互作用由AIP的羧基末端介导，该末端包含三个四肽重复基序，且涉及生存素中的羧基末端卷曲螺旋结构，其中天冬氨酸（Asp142）在AIP识别中起关键作用。仅缺失Asp142的生存素突变体无法与AIP结合，并在体内表现出加速降解，而蛋白酶体抑制剂可逆转这一反应。通过短干扰RNA急性敲低AIP或通过肽模拟物竞争生存素 - AIP复合物会使细胞内生存素水平不稳定，导致细胞凋亡增加，但细胞周期进程无变化。因此，AIP调节生存素的稳定性，从而提高细胞的抗凋亡阈值。生存素 - AIP复合物可能影响细胞对环境毒素的外源性反应，并在细胞死亡调节过程中促进亚细胞伴侣的转运。
