Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2
Apoptosis-associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2
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DOI：
10.1093/emboj/20.23.6627
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发表时间：
2001-12-03
期刊：
影响因子：
11.4
通讯作者：
Martin, SJ
中科院分区：
文献类型：
--
作者：
Adrain, C;Creagh, EM;Martin, SJ
Smac/DIABLO是一种线粒体蛋白，可能通过中和凋亡抑制蛋白IAP家族的一个或多个成员来增强某些形式的凋亡。Smac已经显示出在由UV或γ辐射触发的细胞凋亡期间退出线粒体并进入胞质溶胶。在这里，我们报告说，Smac/DIABLO出口从线粒体到胞质溶胶引起的细胞毒性药物和DNA损伤，以及连接的CD 95死亡受体。在Bcl-2过表达细胞中，Smac/DIABLO的线粒体外排对各种促凋亡剂的反应受到了深刻的抑制。因此，除了调节凋亡相关的线粒体细胞色素c的释放，Bcl-2还调节Smac的释放，这表明这两种分子可能通过相同的途径逃逸。然而，而细胞应激相关的线粒体细胞色素c的释放在很大程度上是半胱天冬酶的独立性，释放Smac/ DIABLO在响应相同的刺激被阻止的广谱半胱天冬酶抑制剂。这表明，线粒体中与凋亡相关的细胞色素c和Smac/ DIABLO释放不是通过相同的机制发生的。相反，Smac/DIABLO从线粒体流出是一种半胱天冬酶催化的事件，发生在细胞色素c释放的下游。
Smac/DIABLO is a mitochondrial protein that potentiates some forms of apoptosis, possibly by neutralizing one or more members of the IAP family of apoptosis inhibitory proteins. Smac has been shown to exit mitochondria and enter the cytosol during apoptosis triggered by UV- or gamma -irradiation. Here, we report that Smac/DIABLO export from mitochondria into the cytosol is provoked by cytotoxic drugs and DNA damage, as well as by ligation of the CD95 death receptor. Mitochondrial efflux of Smac/DIABLO, in response to a variety of pro-apoptotic agents, was profoundly inhibited in Bcl-2-overexpressing cells. Thus, in addition to modulating apoptosis-associated mitochondrial cytochrome c release, Bcl-2 also regulates Smac release, suggesting that both molecules may escape via the same route. However, whereas cell stress-associated mitochondrial cytochrome c release was largely caspase independent, release of Smac/ DIABLO in response to the same stimuli was blocked by a broad-spectrum caspase inhibitor. This suggests that apoptosis-associated cytochrome c and Smac/ DIABLO release from mitochondria do not occur via the same mechanism. Rather, Smac/DIABLO efflux from mitochondria is a caspase-catalysed event that occurs downstream of cytochrome c release.