cBid, Bax and Bcl-xL exhibit opposite membrane remodeling activities.
cBid, Bax and Bcl-xL exhibit opposite membrane remodeling activities.
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DOI：
10.1038/cddis.2016.34
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发表时间：
2016-02-25
影响因子：
9
通讯作者：
García-Sáez AJ
中科院分区：
文献类型：
--
作者：
Bleicken S;Hofhaus G;Ugarte-Uribe B;Schröder R;García-Sáez AJ
Bcl-2家族蛋白在细胞凋亡过程中线粒体外膜通透和线粒体动力学调控中起着至关重要的作用。目前的模型认为Bax在线粒体形成环形孔，负责细胞色素c的释放，而Bcl-xL则抑制孔的形成。然而，Bcl-2蛋白如何调节线粒体裂变和融合仍然知之甚少。通过对单个囊泡水平的系统分析，我们发现cBid、Bax和Bcl-xL能够以不同的方式重塑膜。cBid和Bax诱导了囊泡大小的减小，除了膜通透性外，还可能与膜栓系、出芽和裂变有关。此外，它们优先位于高度弯曲的膜上。相比之下，Bcl-xL不仅平衡孔隙形成，还平衡膜萌发和裂变。我们的发现支持cBid和Bax诱导或稳定高弯曲膜的作用机制，包括非片层结构。这种分子活性降低了膜重塑的能量，而膜重塑是环形孔形成的必要步骤，也是膜裂变和融合的必要步骤，并提供了连接Bcl-2蛋白两种主要功能的共同机制。
The proteins of the Bcl-2 family have a crucial role in mitochondrial outer membrane permeabilization during apoptosis and in the regulation of mitochondrial dynamics. Current models consider that Bax forms toroidal pores at mitochondria that are responsible for the release of cytochrome c, whereas Bcl-xL inhibits pore formation. However, how Bcl-2 proteins regulate mitochondrial fission and fusion remains poorly understood. By using a systematic analysis at the single vesicle level, we found that cBid, Bax and Bcl-xL are able to remodel membranes in different ways. cBid and Bax induced a reduction in vesicle size likely related to membrane tethering, budding and fission, besides membrane permeabilization. Moreover, they are preferentially located at highly curved membranes. In contrast, Bcl-xL not only counterbalanced pore formation but also membrane budding and fission. Our findings support a mechanism of action by which cBid and Bax induce or stabilize highly curved membranes including non-lamellar structures. This molecular activity reduces the energy for membrane remodeling, which is a necessary step in toroidal pore formation, as well as membrane fission and fusion, and provides a common mechanism that links the two main functions of Bcl-2 proteins.