Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions.
Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions.
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DOI：
10.4161/15548627.2014.981790
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发表时间：
2014
期刊：
影响因子：
13.3
通讯作者：
Samali A
中科院分区：
文献类型：
--
作者：
Deegan S;Saveljeva S;Logue SE;Pakos-Zebrucka K;Gupta S;Vandenabeele P;Bertrand MJ;Samali A
内质网（ER）应激诱导的细胞死亡通常与线粒体凋亡途径的激活有关，其特征是CYCS（细胞色素c，体细胞）释放、凋亡体形成和半胱天冬酶激活，从而导致细胞死亡。在本研究中，我们证明，在内质网应激条件下，缺乏 CASP9/caspase-9 或 BAX 和 BAK1（因此线粒体凋亡途径有缺陷）的细胞仍会经历与 caspase 激活相关的延迟形式的细胞死亡，因此揭示了另一种应激诱导的 caspase 激活途径的存在。我们确定 CASP8/caspase-8 是该 caspase 级联中的顶端蛋白酶，并发现关键自噬基因 ATG5 或 ATG7 的敲低会影响 CASP8 激活和细胞死亡诱导，强调自噬在激活这种新型 ER 应激诱导死亡途径中的关键作用。与此相符，我们鉴定了由 ATG5、FADD 和 pro-CASP8 组成的蛋白质复合物，其组装与 caspase 激活和细胞死亡诱导一致。总之，我们的结果揭示了在线粒体凋亡途径有缺陷的内质网应激细胞中自噬的潜在毒性，并提出了一种模型，其中自噬体作为促进 pro-CASP8 激活的平台。化疗耐药是癌症治疗中的一个常见问题，通常是由关键线粒体死亡效应蛋白的下调引起的。另一种应激诱导的细胞凋亡途径，例如本文描述的途径，可能对于解决癌细胞的化学耐药性问题特别重要。
Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.