Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
J Biol Chem. 2010 Jan 8;285(2):1081-8. doi: 10.1074/jbc.M109.072322. Epub 2009 Oct 29.
Apoptosis is controlled by a signaling equilibrium between prosurvival and proapoptotic pathways, such that unwanted apoptosis is avoided, but when required it occurs rapidly and efficiently. Many apoptosis regulators display dual roles, depending upon whether a cell has received an apoptotic stimulus or not. Here, we identify a novel and unexpected function for X-linked inhibitor of apoptosis (XIAP) that occurs when apoptosis is triggered under physiological conditions. We show that in response to loss of survival signals provided by cell adhesion, endogenous XIAP translocates from the cytosol into a mitochondrial 400-kDa complex and that this occurs very early in the apoptosis process. Membrane-associated XIAP induces mitochondrial outer membrane permeabilization leading to cytochrome c and Smac release, which is dependent on Bax and Bak. Thus, although XIAP suppresses apoptosis in healthy cells, our data indicate that XIAP may contribute to it in response to a proapoptotic signal such as loss of extracellular matrix-dependent survival signaling. We suggest that, as with Bcl-2 family proteins, more diverse functions for XIAP exist than previously identified. Moreover, switching the function of proteins from anti- to proapoptotic forms may be a common theme in the efficient execution of cell death.
细胞凋亡受存活信号和凋亡信号通路之间的信号平衡调控，这样可以避免非必要的细胞凋亡，但当需要时，细胞凋亡会迅速而有效地发生。许多凋亡调控因子具有双重作用，这取决于细胞是否接收到凋亡刺激。在这里，我们发现了一种新的、意想不到的 X 连锁凋亡抑制蛋白（XIAP）的功能，这种功能发生在生理条件下触发细胞凋亡时。我们发现，当细胞黏附提供的存活信号丢失时，内源性 XIAP 从细胞质易位到线粒体 400 kDa 复合物中，这发生在细胞凋亡过程的早期。膜结合的 XIAP 诱导线粒体外膜通透性增加，导致细胞色素 c 和 Smac 的释放，这依赖于 Bax 和 Bak。因此，尽管 XIAP 在健康细胞中抑制细胞凋亡，但我们的数据表明，当细胞外基质依赖的存活信号丢失等促凋亡信号出现时，XIAP 可能会促进细胞凋亡。我们认为，与 Bcl-2 家族蛋白一样，XIAP 的功能比以前确定的更为多样化。此外，将蛋白质的功能从抗凋亡形式切换为促凋亡形式可能是细胞死亡有效执行的一个共同主题。
