IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases
IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases
复制标题
DOI：
10.1093/emboj/17.8.2215
复制
发表时间：
1998-04-15
期刊：
影响因子：
11.4
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Deveraux, QL;Roy, N;Reed, JC
凋亡抑制因子（IAP）基因产物在从昆虫到人类的多种物种中调节程序性细胞死亡中起着进化上保守的作用。人XIAP、cIAP 1和cIAP 2是细胞死亡蛋白酶的半胱天冬酶家族的至少两个成员的直接抑制剂：半胱天冬酶-3和半胱天冬酶-7。在此，我们比较了IAP干扰细胞溶质提取物中半胱天冬酶-3和其它效应物半胱天冬酶的活化的机制，其中半胱天冬酶的活化由半胱天冬酶-8（通过TNF家族受体的连接激活的近端蛋白酶）或细胞色素c启动，这些研究表明，XIAP、cIAP 1和cIAP 2可以通过阻断细胞色素c诱导的caspase-9的活化来阻止caspase-3、-6和-7的蛋白水解过程，相反，这些IAP家族蛋白不能阻止caspase-8诱导的caspase-3的蛋白水解活化;然而，它们随后直接抑制活性半胱天冬酶-3，从而阻断下游凋亡事件，例如半胱天冬酶的进一步激活。这些发现表明IAP可以通过抑制不同的半胱天冬酶来抑制不同的凋亡途径，并将半胱天冬酶原-9鉴定为IAP介导的凋亡抑制的新靶点。
Inhibitor of apoptosis (IAP) gene products play an evolutionarily conserved role in regulating programmed cell death in diverse species ranging from insects to humans. Human XIAP, cIAP1 and cIAP2 are direct inhibitors of at least two members of the caspase family of cell death proteases: caspase-3 and caspase-7, Here we compared the mechanism by which IAPs interfere with activation of caspase-3 and other effector caspases in cytosolic extracts where caspase activation was initiated by caspase-8, a proximal protease activated by ligation of TNF-family receptors, or by cytochrome c, which is released from mitochondria into the cytosol during apoptosis, These studies demonstrate that XIAP, cIAP1 and cIAP2 can prevent the proteolytic processing of pro-caspases -3, -6 and -7 by blocking the cytochrome c-induced activation of procaspase-9, In contrast, these IAP family proteins did not prevent caspase-8-induced proteolytic activation of pro-caspase-3; however, they subsequently inhibited active caspase-3 directly, thus blocking downstream apoptotic events such as further activation of caspases, These findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis.