Intracellular nucleotides act as critical prosurvival factors by binding to cyctochrome c and inhibiting apoptosome
Intracellular nucleotides act as critical prosurvival factors by binding to cyctochrome c and inhibiting apoptosome
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DOI：
10.1016/j.cell.2006.05.026
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发表时间：
2006-06-30
期刊：
影响因子：
64.5
通讯作者：
Tang, Dean G.
中科院分区：
文献类型：
--
作者：
Chandra, Dhyan;Bratton, Shawn B.;Tang, Dean G.
细胞色素（CC）启动的Apaf-1核糖体形成是细胞凋亡的关键起始事件。该过程可以通过向细胞裂解物中加入CC和ATP或dATP在体外重构。生理水平的核苷酸，通常在高mM浓度下，如何影响核糖体激活仍不清楚。在这里，我们表明，生理水平的核苷酸抑制CC启动的溶酶体形成和caspase-9的激活直接结合到CC上的几个关键的赖氨酸残基，从而防止CC与Apaf-1的相互作用。我们发现，在各种凋亡系统中，caspase激活之前或伴随着整体细胞内NTP池的减少。微量注射核苷酸抑制，而实验减少NTP池增强CC和凋亡刺激诱导的细胞死亡。因此，我们的研究结果表明，细胞内的核苷酸代表关键的促生存因子，作为天然抑制剂的tagosome的形成和障碍，细胞必须克服的核苷酸障碍进行细胞凋亡细胞死亡。
Cytochromec(CC)-initiated Apaf-1 apoptosome formation represents a key initiating event in apoptosis. This process can be reconstituted in vitro with the addition of CC and ATP or dATP to cell lysates. How physiological levels of nucleotides, normally at high mM concentrations, affect apoptosome activation remains unclear. Here we show that physiological levels of nucleotides inhibit the CC-initiated apoptosome formation and caspase-9 activation by directly binding to CC on several key lysine residues and thus preventing CC interaction with Apaf-1. We show that in various apoptotic systems caspase activation is preceded or accompanied by decreases in overall intracellular NTP pools. Microinjection of nucleotides inhibits whereas experimentally reducing NTP pools enhances both CC and apoptotic stimuli-induced cell death. Our results thus suggest that the intracellular nucleotides represent critical prosurvival factors by functioning as natural inhibitors of apoptosome formation and a barrier that cells must overcome the nucleotide barrier to undergo apoptosis cell death.