Guo Bin, Zhai Dayong, Cabezas Edelmira, Welsh Kate, Nouraini Shahrzad, Satterthwait Arnold C, Reed John C
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature. 2003 May 22;423(6938):456-61. doi: 10.1038/nature01627. Epub 2003 May 4.
Bax (Bcl2-associated X protein) is an apoptosis-inducing protein that participates in cell death during normal development and in various diseases. Bax resides in an inactive state in the cytosol of many cells. In response to death stimuli, Bax protein undergoes conformational changes that expose membrane-targeting domains, resulting in its translocation to mitochondrial membranes, where Bax inserts and causes release of cytochrome c and other apoptogenic proteins. It is unknown what controls conversion of Bax from the inactive to active conformation. Here we show that Bax interacts with humanin (HN), an anti-apoptotic peptide of 24 amino acids encoded in mammalian genomes. HN prevents the translocation of Bax from cytosol to mitochondria. Conversely, reducing HN expression by small interfering RNAs sensitizes cells to Bax and increases Bax translocation to membranes. HN peptides also block Bax association with isolated mitochondria, and suppress cytochrome c release in vitro. Notably, the mitochondrial genome contains an identical open reading frame, and the mitochondrial version of HN can also bind and suppress Bax. We speculate therefore that HN arose from mitochondria and transferred to the nuclear genome, providing a mechanism for protecting these organelles from Bax.
Bax（Bcl2相关X蛋白）是一种诱导凋亡的蛋白，在正常发育及多种疾病过程中参与细胞死亡。在许多细胞的胞质溶胶中，Bax处于无活性状态。响应死亡刺激时，Bax蛋白会发生构象变化，暴露出靶向膜的结构域，导致其转运至线粒体膜，Bax插入线粒体膜并引起细胞色素c和其他凋亡蛋白的释放。目前尚不清楚是什么控制着Bax从无活性构象向活性构象的转变。在此我们表明，Bax与人类in（HN）相互作用，HN是哺乳动物基因组中编码的一种24个氨基酸的抗凋亡肽。HN可阻止Bax从胞质溶胶转运至线粒体。相反，通过小干扰RNA降低HN表达会使细胞对Bax敏感，并增加Bax向膜的转运。HN肽还可阻断Bax与分离线粒体的结合，并在体外抑制细胞色素c的释放。值得注意的是，线粒体基因组包含一个相同的开放阅读框，线粒体版本的HN也能结合并抑制Bax。因此我们推测，HN起源于线粒体并转移至核基因组，为保护这些细胞器免受Bax影响提供了一种机制。
