Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO
Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO
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DOI：
10.1074/jbc.m207197200
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发表时间：
2003-03-21
影响因子：
4.8
通讯作者：
Yang, XL
中科院分区：
文献类型：
--
作者：
Hu, SM;Yang, XL
细胞凋亡抑制因子(IAPs)是细胞程序性死亡的重要调节因子。IAP阻止细胞凋亡的机制以前被认为是直接抑制caspase。哺乳动物IAP的功能在细胞凋亡过程中被细胞死亡诱导因子Smac/DIABLO所抵消。在这里，我们证明了cIAP1和cIAP2是Smac的E3泛素蛋白异肽连接酶(泛素连接酶)。CIAP在体内和体外刺激Smac的泛素化，导致Smac的降解。CIAP1和CIAP2与E2(泛素载体蛋白)泛素结合酶的重叠但不同的亚群相关。CIAP的底物依赖的E3活性是由其环结构域介导的，并且依赖于cIAP与Smac之间的特定相互作用。同样，果蝇IAP1也具有泛素连接酶活性，可介导果蝇细胞凋亡诱导剂GRIM和HID的降解。这些结果提示了一种新的保守机制，即IAP通过降解死亡诱导物来阻止细胞凋亡。
Inhibitors of apoptosis (IAPs) are crucial regulators of programmed cell death. The mechanism by which IAPs prevent apoptosis has previously been attributed to the direct inhibition of caspases. The function of mammalian IAPs is counteracted by cell death inducer second mitochondria-derived activator of caspases (Smac)/DIABLO during apoptosis. Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac. Similarly, Drosophila IAP1 also possesses ubiquitin ligase activity that mediates the degradation of the Drosophila apoptosis inducers Grim and HID. These results suggest a novel and conserved mechanism by which IAPs block apoptosis through the degradation of death inducers.