Caspase-2 permeabilizes the outer mitochondrial membrane and disrupts the binding of cytochrome c to anionic phospholipids
Caspase-2 permeabilizes the outer mitochondrial membrane and disrupts the binding of cytochrome c to anionic phospholipids
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DOI：
10.1074/jbc.c400374200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
Orrenius, S
中科院分区：
文献类型：
--
作者：
Enoksson, M;Robertson, JD;Orrenius, S
胱天蛋白酶是在细胞凋亡的执行中起核心作用的半胱氨酸蛋白酶。最近的证据表明，半胱天冬酶-2激活早期响应于遗传毒性应激，可以作为线粒体凋亡途径的上游调节剂。特别是，我们以前已经表明，完全加工的caspase-2可以透化线粒体外膜，并导致细胞色素c和Smac/DIABLO从这些细胞器释放。使用透化的细胞，分离的线粒体，和无蛋白质的脂质体，我们现在报告说，这种效果是直接的，既不依赖于其他蛋白质的存在或裂解，也不依赖于特定的磷脂组成的脂质体膜。有趣的是，半胱天冬酶-2也被证明破坏细胞色素c与阴离子磷脂，特别是心磷脂的相互作用，从而增强释放的血红素蛋白引起的线粒体与毛地黄皂苷或促凋亡蛋白Bax的治疗。结合，我们的数据表明，胱天蛋白酶-2具有无与伦比的能力，从事线粒体细胞凋亡途径，通过透化外线粒体膜和/或通过破坏与线粒体内膜细胞色素c的协会。
Caspases are cysteine proteases that play a central role in the execution of apoptosis. Recent evidence indicates that caspase-2 is activated early in response to genotoxic stress and can function as an upstream modulator of the mitochondrial apoptotic pathway. In particular, we have shown previously that fully processed caspase-2 can permeabilize the outer mitochondrial membrane and cause cytochrome c and Smac/DIABLO release from these organelles. Using permeabilized cells, isolated mitochondria, and protein-free liposomes, we now report that this effect is direct and depends neither on the presence or cleavage of other proteins nor on a specific phospholipid composition of the liposomal membrane. Interestingly, caspase-2 was also shown to disrupt the interaction of cytochrome c with anionic phospholipids, notably cardiolipin, and thereby enhance the release of the hemoprotein caused by treatment of mitochondria with digitonin or the proapoptotic protein Bax. Combined, our data suggest that caspase-2 possesses an unparalleled ability to engage the mitochondrial apoptotic pathway by permeabilizing the outer mitochondrial membrane and/or by breaching the association of cytochrome c with the inner mitochondrial membrane.