Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2
Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2
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DOI：
10.1093/hmg/ddi195
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Nishimura, M
中科院分区：
文献类型：
--
作者：
Wang, HQ;Nakaya, Y;Nishimura, M
早老素1和2 （PS1/2）是家族性阿尔茨海默病（FAD）的致病分子，是主要定位于内质网（ER）和高尔基体的多通道跨膜蛋白。含有PS1/2的异质蛋白复合物被认为参与多种功能，包括由其t分泌酶活性介导的膜内蛋白水解。先前的研究表明PS1/2也参与凋亡细胞死亡的调控，尽管其潜在机制尚不清楚。在这里，我们证明了FKBP38，一个居住在线粒体膜上的亲免疫蛋白家族成员，是一个真正的ps1 /2相互作用蛋白。PS1/2和FKBP38与抗凋亡Bcl-2形成大分子复合物。PS1/2促进FKBP38和Bcl-2的降解，并将这些蛋白隔离在内质网/高尔基区室中，从而通过不依赖于γ分泌酶的机制抑制FKBP38介导的Bcl-2的线粒体靶向。因此，PS1/2通过拮抗FKBP38的抗凋亡功能而增加细胞凋亡的易感性。相反，caspase处理的PS1/2的c端片段通过废除全长PS1/2的活性将BcI-2重新分配到线粒体，从而产生显性负性抗凋亡作用。在培养细胞和ps1敲入突变体小鼠大脑中，fad相关的PS1/2突变体比野生型PS1/2更有效地减少线粒体BcI-2，从而增强促凋亡活性。这些结果表明，PS1/2和FKBP38之间的竞争调控线粒体介导的细胞凋亡的亚细胞靶向Bcl-2的新的分子机制。PS1/2的促凋亡活性过高可能在FAD的发病机制中起作用。
Presenilins 1 and 2 (PS1/2), causative molecules for familial Alzheimer's disease (FAD), are multipass transmembrane proteins localized predominantly in the endoplasmic reticulum (ER) and Golgi apparatus. Heteromeric protein complexes containing PS1/2 are thought to participate in several functions, including intramembrane proteolysis mediated by their T-secretase activities. Previous studies have shown that PS1/2 are also involved in the regulation of apoptotic cell death, although the underlying mechanism remains unknown. Here, we demonstrate that FKBP38, an immunophilin family member residing in the mitochondrial membrane, is an authentic PS1/2-interacting protein. PS1/2 and FKBP38 form macromolecular complexes together with anti-apoptotic Bcl-2. PS1/2 promote the degradation of FKBP38 and Bcl-2 and sequester these proteins in the ER/Golgi compartments, thereby inhibiting FKBP38-mediated mitochondrial targeting of Bcl-2 via a gamma-secretase-independent mechanism. Thus, PS1/2 increase the susceptibility to apoptosis by antagonizing the anti-apoptotic function of FKBP38. In contrast, C-terminal fragments of caspase-processed PS1/2 redistribute BcI-2 to the mitochondria by abrogating the activity of full-length PS1/2, resulting in a dominant-negative anti-apoptotic effect. In cultured cells and mutant PS1-knockin mice brains, FAD-linked PS1/2 mutants enhance the pro-apoptotic activity by causing a more efficient reduction in mitochondrial BcI-2 than wild-type PS1/2. These results suggest a novel molecular mechanism for the regulation of mitochondria-mediated apoptosis by competition between PS1/2 and FKBP38 for subcellular targeting of Bcl-2. Excessive pro-apoptotic activity of PS1/2 may play a role in the pathogenesis of FAD.