Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis
Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis
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DOI：
10.1101/gad.1097903
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发表时间：
2003-06-15
影响因子：
10.5
通讯作者：
Du, CY
中科院分区：
文献类型：
--
作者：
Yang, QH;Church-Hajduk, R;Du, CY
Omi/HtrA 2是一种线粒体丝氨酸蛋白酶，其在细胞凋亡期间释放到胞质溶胶中以拮抗细胞凋亡抑制剂（IAP）并促成半胱天冬酶非依赖性细胞死亡。在这里，我们证明Omi/HtrA 2在体外直接切割各种IAP，并且切割效率由其IAP结合基序AVPS决定。IAP如c-IAP 1的切割显著降低其抑制和泛素化半胱天冬酶的能力。与Smac/DIABLO的化学计量抗IAP活性相反，Omi/HtrA 2对c-IAP 1的裂解是催化的和不可逆的，从而更有效地灭活IAP并促进半胱天冬酶活性。通过RNA干扰消除内源性Omi可消除c-IAP 1裂解并使细胞对TRAIL诱导的凋亡脱敏。此外，裂解位点突变体c-IAP 1的过表达使细胞对TRAIL诱导的半胱天冬酶活化更具抗性。Omi对IAP的切割不依赖于半胱天冬酶。综上所述，这些结果表明，与Smac/DIABLO不同，Omi/HtrA 2对IAP的催化裂解是其不可逆地抑制IAP并促进凋亡的关键机制。
Omi/HtrA2 is a mitochondrial serine protease that is released into the cytosol during apoptosis to antagonize inhibitors of apoptosis (IAPs) and contribute to caspase-independent cell death. Here, we demonstrate that Omi/HtrA2 directly cleaves various IAPs in vitro, and the cleavage efficiency is determined by its IAP-binding motif, AVPS. Cleavage of IAPs such as c-IAP1 substantially reduces its ability to inhibit and ubiquitylate caspases. In contrast to the stoichiometric anti-IAP activity by Smac/DIABLO, Omi/HtrA2 cleavage of c-IAP1 is catalytic and irreversible, thereby more efficiently inactivating IAPs and promoting caspase activity. Elimination of endogenous Omi by RNA interference abolishes c-IAP1 cleavage and desensitizes cells to apoptosis induced by TRAIL. In addition, overexpression of cleavage-site mutant c-IAP1 makes cells more resistant to TRAIL-induced caspase activation. This IAP cleavage by Omi is independent of caspase. Taken together, these results indicate that unlike Smac/DIABLO, Omi/HtrA2's catalytic cleavage of IAPs is a key mechanism for it to irreversibly inactivate IAPs and promote apoptosis.