MAP-1 is a mitochondrial effector of Bax
MAP-1 is a mitochondrial effector of Bax
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DOI：
10.1073/pnas.0503524102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Yu, VC
中科院分区：
文献类型：
--
作者：
Tan, KO;Fu, NY;Yu, VC
凋亡刺激诱导Bax的构象变化，并触发其从细胞质到线粒体的易位。在组装成线粒体膜后，Bax通过一系列事件启动死亡程序，最终释放细胞色素c等促凋亡因子。尽管已知Bax是整合多种死亡信号的关键因素之一，但Bax在线粒体中的作用机制仍存在争议。我们以前已经确定调亡蛋白-1（MAP-1）作为一种凋亡相关蛋白，但其与Bax在促进凋亡调节中的功能关系仍有待建立。在这项研究中，我们表明，MAP-1是一个关键的线粒体效应Bax。MAP-1是一种富含Bax的蛋白质，仅在细胞凋亡诱导时与Bax结合，这与线粒体释放细胞色素c相一致。减少哺乳动物细胞系中MAP-11水平的小干扰RNA赋予选择性抑制MAP-11介导的细胞凋亡。稳定表达MAP-11小干扰RNA的哺乳动物细胞对多种凋亡刺激具有抗性，从而触发凋亡性死亡以及诱导Bax的构象变化和易位。与MAP-1缺陷型细胞类似，MAP-1缺陷型细胞表现出侵袭性的非贴壁依赖性生长。值得注意的是，在MAP-1敲低细胞中，重组Bax或tBid介导的细胞色素c从分离的线粒体的释放显著受损。我们认为MAP-11是Bax的直接线粒体靶点。
Apoptotic stimuli induce conformational changes in Bax and trigger its translocation from cytosol to mitochondria. Upon assembling into the mitochondrial membrane, Bax initiates a death program through a series of events, culminating in the release of apoptogenic factors such as cytochrome c. Although it is known that Bax is one of the key factors for integrating multiple death signals, the mechanism by which Bax functions in mitochondria remains controversial. We have previously identified modulator of apoptosis-1 (MAP-1) as a Bax-associating protein, but its functional relationship with Bax in contributing to apoptosis regulation remains to be established. In this study, we show that MAP-1 is a critical mitochondrial effector of Bax. MAP-1 is a mitochondria-enriched protein that associates with Bax only upon apoptotic induction, which coincides with the release of cytochrome c from mitochondria. Small interfering RNAs that diminish MAP-11 levels in mammalian cell lines confer selective inhibition of Bax-mediated apoptosis. Mammalian cells with stable expression of MAP-11 small interfering RNAs are resistant to multiple apoptotic stimuli in triggering apoptotic death as well as in inducing conformation change and translocation of Bax. Similar to Bax-deficient cells, MAP-1-deficient cells exhibit aggressive anchorage-independent growth. Remarkably, recombinant Bax- or tBid-mediated release of cytochrome c from isolated mitochondria is significantly compromised in the MAP-1 knockdown cells. We propose that MAP-11 is a direct mitochondrial target of Bax.