S-palmitoylation represents a novel mechanism regulating the mitochondrial targeting of BAX and initiation of apoptosis.
S-palmitoylation represents a novel mechanism regulating the mitochondrial targeting of BAX and initiation of apoptosis.
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DOI：
10.1038/cddis.2014.17
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发表时间：
2014-02-13
影响因子：
9
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中科院分区：
文献类型：
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凋亡性细胞死亡的内在途径主要由BCL-2相关的X（BAX）蛋白通过线粒体外膜（mtDNA）的透化和伴随的细胞色素c释放到胞质溶胶中来介导。在健康的非凋亡细胞中，BAX主要定位于胞质溶胶中，并在胞质溶胶和线粒体之间表现出动态穿梭循环。因此，与线粒体的初始关联代表了使BAX能够插入到M0 M中的关键调节步骤，促进细胞色素c的释放并最终导致细胞凋亡。然而，BAX如何与MOMs相关联的分子模式以及细胞调控机制是否控制这一过程的分子模式知之甚少。在这里，我们表明，在原代组织和培养的细胞中，与MOMs和促凋亡作用的BAX的协会是由其在Cys-126的S-棕榈酰化。BAX棕榈酰化的缺乏减少了BAX线粒体易位、BAX寡聚化、半胱天冬酶活性和凋亡。此外，在培养的健康细胞中特异性棕榈酰转移酶的异位表达增加BAX S-棕榈酰化并加速细胞凋亡，而恶性肿瘤细胞显示与其减少的BAX介导的促细胞凋亡活性一致的减少的BAX S-棕榈酰化。我们的研究结果表明，S-palmitoylation的BAX在Cys 126是一个关键的调控过程中的BAX介导的细胞凋亡。
The intrinsic pathway of apoptotic cell death is mainly mediated by the BCL-2-associated X (BAX) protein through permeabilization of the mitochondrial outer membrane (MOM) and the concomitant release of cytochrome c into the cytosol. In healthy, non-apoptotic cells, BAX is predominantly localized in the cytosol and exhibits a dynamic shuttle cycle between the cytosol and the mitochondria. Thus, the initial association with mitochondria represents a critical regulatory step enabling BAX to insert into MOMs, promoting the release of cytochrome c and ultimately resulting in apoptosis. However, the molecular mode of how BAX associates with MOMs and whether a cellular regulatory mechanism governs this process is poorly understood. Here we show that in both primary tissues and cultured cells, the association with MOMs and the proapoptotic action of BAX is controlled by its S-palmitoylation at Cys-126. A lack of BAX palmitoylation reduced BAX mitochondrial translocation, BAX oligomerization, caspase activity and apoptosis. Furthermore, ectopic expression of specific palmitoyl transferases in cultured healthy cells increases BAX S-palmitoylation and accelerates apoptosis, whereas malignant tumor cells show reduced BAX S-palmitoylation consistent with their reduced BAX-mediated proapoptotic activity. Our findings suggest that S-palmitoylation of BAX at Cys126 is a key regulatory process of BAX-mediated apoptosis.
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影响因子：
7.8
作者：
Goping, I S;Gross, A;Lavoie, J N;Nguyen, M;Jemmerson, R;Roth, K;Korsmeyer, S J;Shore, G C
通讯作者：
Shore, G C
影响因子：
64.5
作者：
Chipuk JE;McStay GP;Bharti A;Kuwana T;Clarke CJ;Siskind LJ;Obeid LM;Green DR
通讯作者：
Green DR
影响因子：
16
作者：
Dumitru, Raluca;Gama, Vivian;Fagan, B. Matthew;Bower, Jacquelyn J.;Swahari, Vijay;Pevny, Larysa H.;Deshmukh, Mohanish
通讯作者：
Deshmukh, Mohanish
影响因子：
11.4
作者：
Feig, Christine;Tchikov, Vladimir;Peter, Marcus E.
通讯作者：
Peter, Marcus E.
影响因子：
7.8
作者：
Abrami, Laurence;Leppla, Stephen H;van der Goot, F Gisou
通讯作者：
van der Goot, F Gisou