GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation
GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation
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DOI：
10.1016/j.cell.2007.03.045
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发表时间：
2007-06-01
期刊：
影响因子：
64.5
通讯作者：
Green, Douglas R.
中科院分区：
文献类型：
--
作者：
Colell, Anna;Ricci, Jean-Ehrland;Green, Douglas R.
在进行细胞凋亡的细胞中，线粒体外膜通透性(MOMP)之后，释放的细胞色素c促进了paspase的激活。尽管caspase介导了细胞的凋亡表型，但caspase的抑制通常不足以维持MOMP后的生存；相反，细胞经历了caspase非依赖性的细胞死亡(CICD)。因此，MOMP可能代表了细胞死亡的一个承诺点。在这里，我们确定甘油醛-3-磷酸脱氢酶(GAPDH)是CICD的关键调节因子。在半胱氨酸天冬氨酸氨基转移酶激活被阻断的情况下，表达GAPDH的细胞在MOMP后保留了其克隆形成能力。GAPDH介导的CICD对细胞的保护涉及糖酵解和核功能的增加，该功能与Atg12表达的增加相关，并被其取代。与此一致的是，对CICD的保护反映了自噬的增加和对自噬的依赖，与线粒体质量的一过性减少相关。因此，GAPDH介导糖酵解的升高和增强的自噬，共同保护细胞免受CICD的影响。
In cells undergoing apoptosis, mitochondrial outer-membrane permeabilization (MOMP) is followed by paspase activation promoted by released cytochrome c. Although caspases mediate the apoptotic phenotype, caspase inhibition is generally not sufficient for survival following MOMP; instead cells undergo a "caspase-independent cell death" (CICD). Thus, MOMP may represent a point of commitment to cell death. Here, we identify glyceraidehyde-3-phosphate dehydrogenase (GAPDH) as a critical regulator of CICD. GAPDH-expressing cells preserved their clonogenic potential following MOMP, provided that caspase activation was blocked. GAPDHmediated protection of cells from CICD involved an elevation in glycolysis and a nuclear function that correlated with and was replaced by an increase in Atg12 expression. Consistent with this, protection from CICD reflected an increase in and a dependence upon autophagy, associated with a transient decrease in mitochondrial mass. Therefore, GAPDH mediates an elevation in glycolysis and enhanced autophagy that cooperate to protect cells from CICD.