Adrain C, Creagh E M, Martin S J
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
EMBO J. 2001 Dec 3;20(23):6627-36. doi: 10.1093/emboj/20.23.6627.
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.
Smac/DIABLO是一种线粒体蛋白，它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细胞凋亡。研究表明，在紫外线或γ射线诱导的细胞凋亡过程中，Smac会离开线粒体进入细胞质。在此，我们报告，细胞毒性药物、DNA损伤以及CD95死亡受体的连接均可引发Smac/DIABLO从线粒体向细胞质的输出。在过表达Bcl-2的细胞中，响应多种促凋亡因子时，Smac/DIABLO的线粒体外排受到显著抑制。因此，除了调节与细胞凋亡相关的线粒体细胞色素c释放外，Bcl-2还调节Smac的释放，这表明这两种分子可能通过相同途径释放。然而，虽然与细胞应激相关的线粒体细胞色素c释放很大程度上不依赖于半胱天冬酶，但广谱半胱天冬酶抑制剂可阻断在相同刺激下Smac/DIABLO的释放。这表明与细胞凋亡相关的细胞色素c和Smac/DIABLO从线粒体的释放并非通过相同机制。相反，Smac/DIABLO从线粒体的外排是一个由半胱天冬酶催化的事件，发生在细胞色素c释放之后。
