Intracellular K+ inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release
Intracellular K+ inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release
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DOI：
10.1038/sj.cdd.4402221
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发表时间：
2007-12-01
影响因子：
12.4
通讯作者：
Park, I-S
中科院分区：
文献类型：
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作者：
Karki, P.;Seong, C.;Park, I-S
细胞离子稳态，主要是钾离子（K⁺）稳态，被认为是细胞凋亡的关键调节因素。在细胞凋亡刺激下细胞内K⁺外流，以及高浓度细胞外K⁺抑制细胞凋亡，或者K⁺通道阻滞剂抑制这种外流后所产生的效果，都确立了K⁺在启动细胞凋亡机制中的关键作用。一些相反的观察结果报道，细胞内K⁺浓度的抗凋亡作用是抑制细胞色素c从线粒体释放的结果，但确切的抑制机制仍不清楚。然而，我们在此表明，细胞凋亡过程中K⁺外流受阻并不影响细胞色素c从线粒体释放，但仍完全抑制了包含凋亡蛋白酶激活因子1（Apaf - 1）、细胞色素c、半胱天冬酶 - 9（caspase - 9）及其他辅助成分的凋亡小体的形成。由于这一事件，半胱天冬酶原 - 9、 - 3、 - 8及其他与死亡相关的蛋白质未被加工处理。此外，生理浓度的K⁺还在不同程度上抑制了纯化的半胱天冬酶 - 8或 - 9对半胱天冬酶原 - 3的加工处理，抑制了纯化的DNA断裂因子40（DFF40）/ caspase - activated DNase（CAD）对核小体DNA的断裂作用以及对核断裂的影响。总之，这些发现表明，K⁺外流不仅是凋亡小体形成的必要条件，也是下游细胞凋亡信号转导通路所必需的。
Cellular ionic homeostasis, fundamentally K+ homeostasis, has been implicated as a critical regulator of apoptosis. The intracellular K+ efflux on apoptotic insult and suppression of apoptosis by high concentration of extracellular K+ or after inhibition of this efflux by K+ channel blockers have established the crucial role of K+ in turning on the apoptotic machinery. Several contrasting observations have reported the antiapoptotic effect of intracellular K+ concentration to be the result of inhibition of cytochrome c release from mitochondria, but the exact inhibitory mechanism remains obscure. However, here we show the blockage of K+ efflux during apoptosis did not affect cytochrome c release from the mitochondria, still completely inhibited the formation of the apoptosome comprising Apaf-1, cytochrome c, caspase-9 and other accessories. As a consequence of this event, procaspase-9, -3, -8 and other death-related proteins were not processed. Furthermore, physiological concentrations of K+ also inhibited the processing of procaspase-3 by purified caspase-8 or -9, the nucleosomal DNA fragmentation by purified DFF40/CAD and the nuclear fragmentation to varying extents. Altogether, these findings suggest that the efflux of K+ is prerequisite not only for the formation of the apoptosome but also for the downstream apoptotic signal-transduction pathways.