ER stress triggers apoptosis by activating BH3-only protein Bim
ER stress triggers apoptosis by activating BH3-only protein Bim
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DOI：
10.1016/j.cell.2007.04.027
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发表时间：
2007-06-29
期刊：
影响因子：
64.5
通讯作者：
Strasser, Andreas
中科院分区：
文献类型：
--
作者：
Puthalakath, Hamsa;O'Reilly, Lorraine A.;Strasser, Andreas
由错误折叠的蛋白质或细胞毒性药物引起的内质网（ER）应激可以杀死细胞，尽管该途径的激活与某些退行性疾病的病因学有关，但其机制尚未解决。Bim是Bcl-2家族的一个促凋亡基因，在细胞因子缺乏或某些应激刺激诱导的细胞凋亡中起重要作用。它的促凋亡活性可以通过多种转录或翻译后机制来调节，例如ERK介导的磷酸化，促进其遍在化和蛋白酶体降解。我们发现，Bim是必不可少的ER应激诱导的细胞凋亡在不同范围的细胞类型，无论是在文化和整个动物。ER应激通过两种新的途径激活Bim，包括蛋白磷酸酶2A介导的去磷酸化，这阻止了其泛素化和蛋白酶体降解以及CHOP-C/EBP α介导的直接转录诱导。这些结果定义了ER应激诱导细胞凋亡的分子机制，并确定了ER应激相关疾病的治疗干预靶点。
Endoplasmic reticulum ( ER) stress caused by misfolded proteins or cytotoxic drugs can kill cells and although activation of this pathway has been implicated in the etiology of certain degenerative disorders its mechanism remains unresolved. Bim, a proapoptotic BH3-onlymember of the Bcl-2 family is required for initiation of apoptosis induced by cytokine deprivation or certain stress stimuli. Its proapoptotic activity can be regulated by several transcriptional or posttranslational mechanisms, such as ERK-mediated phosphorylation, promoting its ubiquitination and proteasomal degradation. We found that Bim is essential for ER stress-induced apoptosis in a diverse range of cell types both in culture and within the whole animal. ER stress activates Bim through two novel pathways, involving protein phosphatase 2A-mediated dephosphorylation, which prevents its ubiquitination and proteasomal degradation and CHOP-C/EBP alpha-mediated direct transcriptional induction. These results define the molecular mechanisms of ER stress-induced apoptosis and identify targets for therapeutic intervention in ER stress-related diseases.