Humanin peptide suppresses apoptosis by interfering with Bax activation
Humanin peptide suppresses apoptosis by interfering with Bax activation
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DOI：
10.1038/nature01627
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发表时间：
2003-05-22
期刊：
影响因子：
64.8
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Guo, B;Zhai, DY;Reed, JC
Bax(Bcl2相关X蛋白)是一种凋亡诱导蛋白，参与细胞在正常发育和各种疾病中的死亡[1]。Bax在许多细胞的胞浆中以非活性状态存在。作为对死亡刺激的反应，Bax蛋白经历了暴露膜靶向结构域的构象变化，导致其移位到线粒体膜，在那里Bax插入并导致细胞色素c和其他促凋亡蛋白的释放(2)。目前尚不清楚是什么控制了Bax从非活性构象到活性构象的转换。在这里，我们发现Bax与人蛋白(HN)相互作用，人蛋白(HN)是一种在哺乳动物基因组中编码的由24个氨基酸组成的抗凋亡多肽(3，4)。HN阻止Bax从胞浆到线粒体的移位。相反，通过小干扰RNA减少HN的表达会增加细胞对Bax的敏感性，并增加Bax向膜的移位。HN多肽还可阻断Bax与分离的线粒体的结合，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架，线粒体版本的HN也可以结合和抑制Bax。因此，我们推测HN起源于线粒体并转移到核基因组，为保护这些细胞器免受Bax的伤害提供了一种机制。
Bax (Bcl2-associated X protein) is an apoptosis-inducing protein that participates in cell death during normal development and in various diseases(1). 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(2). 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(3,4). 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.