Institute of Molecular Biosciences, University of Graz, Graz, Austria.
EMBO J. 2011 Jun 14;30(14):2779-92. doi: 10.1038/emboj.2011.197.
Mitochondrial outer membrane permeabilization is a watershed event in the process of apoptosis, which is tightly regulated by a series of pro- and anti-apoptotic proteins belonging to the BCL-2 family, each characteristically possessing a BCL-2 homology domain 3 (BH3). Here, we identify a yeast protein (Ybh3p) that interacts with BCL-X(L) and harbours a functional BH3 domain. Upon lethal insult, Ybh3p translocates to mitochondria and triggers BH3 domain-dependent apoptosis. Ybh3p induces cell death and disruption of the mitochondrial transmembrane potential via the mitochondrial phosphate carrier Mir1p. Deletion of Mir1p and depletion of its human orthologue (SLC25A3/PHC) abolish stress-induced mitochondrial targeting of Ybh3p in yeast and that of BAX in human cells, respectively. Yeast cells lacking YBH3 display prolonged chronological and replicative lifespans and resistance to apoptosis induction. Thus, the yeast genome encodes a functional BH3 domain that induces cell death through phylogenetically conserved mechanisms.
线粒体膜通透性的改变是细胞凋亡过程中的一个关键事件，这个过程受到一系列促凋亡和抗凋亡蛋白的严格调控，这些蛋白都具有 BCL-2 同源结构域 3（BH3）。在这里，我们鉴定出一种酵母蛋白（Ybh3p），它与 BCL-X(L)相互作用并具有功能性 BH3 结构域。在受到致死性损伤时，Ybh3p 易位到线粒体并引发 BH3 结构域依赖性凋亡。Ybh3p 通过线粒体磷酸盐载体 Mir1p 诱导细胞死亡和破坏线粒体跨膜电位。Mir1p 的缺失和其人类同源物（SLC25A3/PHC）的消耗分别消除了应激诱导的 Ybh3p 在酵母和 BAX 在人细胞中线粒体靶向作用。缺乏 YBH3 的酵母细胞表现出延长的酵母细胞的chronological 和 replicative 寿命以及对凋亡诱导的抗性。因此，酵母基因组编码了一种功能性 BH3 结构域，它通过进化保守的机制诱导细胞死亡。
