Mechanism and importance of mitochondrial import of BH3-only proteins during apoptosis

细胞凋亡过程中 BH3-only 蛋白线粒体输入的机制和重要性

• 批准号: 63014790
• 负责人: Professor Dr. Georg Häcker
• 金额: --
• 依托单位: Department für Medizinische Mikrobiologie, Virologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/63014790?language=en
• 关键词: Mechanism; importance; mitochondrial; import; BH3

The release of cytochrome c from a cell’s mitochondria is a key step in mitochondrial apoptosis. Although it is clear that the members of the Bcl-2 protein family regulate cytochrome c-release, it is still under dispute how this is achieved. Two models are presently discussed in the literature; both agree that the BH3-only group of Bcl-2 family proteins trigger the release, which then depends on the BH3-only protein dependent activation of the Bcl-2 family proteins Bax and Bak. However, the models are in almost complete disagreement as to the molecular occurrences. We have recently found that mitochondrial import/insertion of the BH3-only protein BimS into the outer mitochondrial membrane is essential for its pro-apoptotic function in yeast and mammalian models of mitochondrial apoptosis. In this project, we aim at understanding the molecular details and the general importance of mitochondrial import of BH3-only proteins for apoptosis. Mitochondrial insertion of the known BH3-only proteins and requirement of the mitochondrial import machinery will be tested. The question whether the activation of Bax and Bak relies on BH3-only protein import to the same degree will be analysed. The hypothesis will further be tested that mitochondrial insertion of BH3-only proteins is the trigger of mitochondrial translocation and thus activation of Bax. Finally, mitochondrial insertion of BH3-only proteins in cells undergoing apoptosis will be investigated.

细胞色素c从细胞线粒体的释放是线粒体凋亡的关键步骤。虽然Bcl-2蛋白家族的成员调节细胞色素c的释放是很清楚的，但这是如何实现的仍然存在争议。目前在文献中讨论了两种模型;两者都同意Bcl-2家族蛋白的仅BH 3基团触发释放，其然后取决于Bcl-2家族蛋白Bax和巴克的仅BH 3蛋白依赖性活化。然而，这些模型在分子发生方面几乎完全不一致。我们最近发现，线粒体进口/插入的BH 3-唯一的蛋白质BimS到线粒体外膜是必不可少的，其促凋亡的功能，在酵母和哺乳动物模型的线粒体凋亡。在这个项目中，我们的目标是了解分子的细节和一般的重要性，线粒体进口的BH 3蛋白的细胞凋亡。将测试已知的仅BH 3蛋白的线粒体插入和线粒体输入机制的要求。将分析Bax和巴克的激活是否在相同程度上依赖于仅BH 3的蛋白质输入的问题。该假设将被进一步测试，即BH 3-only蛋白的线粒体插入是线粒体易位的触发器，从而激活Bax。最后，将研究在经历细胞凋亡的细胞中仅BH 3蛋白的线粒体插入。

项目成果

BH3-only proteins are tail-anchored in the outer mitochondrial membrane and can initiate the activation of Bax

• DOI: 10.1038/cdd.2012.9
• 发表时间: 2012-02
• 期刊: Cell Death and Differentiation
• 影响因子: 12.4
• 作者: Florian Wilfling;Florian Wilfling;A. Weber;S. Potthoff;F. Vögtle;C. Meisinger;Stefan A. Paschen;Georg Häcker