Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases
Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases
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DOI：
10.1093/emboj/18.19.5242
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发表时间：
1999-10-01
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;Leo, E;Reed, JC
几种人细胞凋亡抑制剂（IAP）家族蛋白通过在不需要IAP裂解的机制中直接抑制特异性半胱天冬酶而起作用。然而，在本研究中，我们证明内源性XIAP在肿瘤坏死因子家族成员Fas（CD 95）诱导的凋亡过程中被切割成两个片段，产生的两个片段包括杆状病毒抑制性重复序列（BIR）1和2结构域（BIR 1 -2）以及BIR 3和RING。BIR 1 -2片段的过表达抑制Fas诱导的细胞凋亡，尽管与全长XIAP相比效率显著降低。相反，BIR 3-环片段的过表达导致Fas-指导的凋亡的轻微增强。因此，XIAP的切割可能是细胞死亡程序绕过XIAP造成的抗凋亡屏障的一种机制。有趣的是，BIR 3-环片段的异位表达导致几乎完全的对Bar诱导的细胞凋亡的保护，使用纯化的重组蛋白揭示BIR 3-Ring是半胱天冬酶-9的特异性抑制剂，而BIR 1 -2对半胱天冬酶3和7具有特异性，因此，XIAP具有两种不同的半胱天冬酶抑制活性，这可以归因于XIAP内的不同结构域。这些数据可以解释为什么IAP进化为具有多个BIR结构域。
Several human inhibitor of apoptosis (IAP) family proteins function by directly inhibiting specific caspases in a mechanism that does not require IAP cleavage. In this study, however, we demonstrate that endogenous XIAP is cleaved into two fragments during apoptosis induced by the tumor necrosis factor family member Fas (CD95), The two fragments produced comprise the baculoviral inhibitory repeat (BIR) 1 and 2 domains (BIR1-2) and the BIR3 and RING (BIR3-Ring) domains of XIAP, Overexpression of the BIR1-2 fragment inhibits Fas-induced apoptosis, albeit at significantly reduced efficiency compared with full-length XIAP, In contrast, overexpression of the BIR3-Ring fragment results in a slight enhancement of Fas-directed apoptosis, Thus, cleavage of XIAP may be one mechanism by which cell death programs circumvent the anti-apoptotic barrier posed by XIAP, Interestingly, ectopic expression of the BIR3-Ring fragment resulted in nearly complete protection from Bar-induced apoptosis, Use of purified recombinant proteins revealed that BIR3-Ring is a specific inhibitor of caspase-9 whereas BIR1-2 is specific for caspases 3 and 7, Therefore XIAP possesses two different caspase inhibitory activities which can be attributed to distinct domains within XIAP, These data may provide an explanation for why IAPs have evolved with multiple BIR domains.