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Regulation of caspase-12 during endoplasmic reticulum stress-induced

内质网应激诱导过程中 caspase-12 的调节

基本信息

批准号：
16601005
负责人：
MORISHIMA Nobuhiro
金额：
$ 2.37万
依托单位：
RIKEN
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16601005/
关键词：
apoptosis ER stress caspase-12 Bcl-xL Bim オスパーゼ12 Bcl-2ファミリー

项目摘要

Endoplasmic reticulum (ER) stress activates caspase12 in murine cells, triggering the ER stress-specific cascade for implementation of apoptosis. In C2C12 murine myoblast cells, activation of the cascade occurs without release of cytochrome c from mitochondria, suggesting that the cascade is independent of mitochondrial damage. Stable overexpression of Bcl-xL in C2C12 cells suppressed activation of caspase-12 and apoptosis. In ER stressed cells, but not in normal cells, Bcl-xL was co-immunoprecipitated with Bim, a proapoptotic member of the Bcl-2 family, suggesting that Bcl-xL sequesters Bim, thereby inhibiting the apoptotic signaling. Fractionation of C2C12 cells revealed that ER stress led to translocation of Bim from a dynein-rich compartment to the ER, while stable overexpression of Bcl-xL suppressed accumulation of Bim on the ER. Although the toxic effect of Bim had been previously observed only at the mitochondrial outer membrane, overexpression of a Bim derivative, Bim(ER), targeted at the surface of the ER led to apoptosis. A C2C12 transfectant overexpressing the caspa-se12 suppressor protein was resistant to Bim (ER), suggesting that the toxic effect of Bim on the ER is dependent on activation of caspase-12. Knockdown of Bim by RNAi provided cells resistant to ER stress. These results suggest that translocation of Bim to the ER in response to ER stress is an important step towards activation of caspase-12 and initiation of the ER stress-specific caspase cascade. Recently, the involvement of Bax and Bak in ER stress-induced apoptosis has been suggested. According to the model, conformational changes and oligomerization of Bax/Bak probably causes activation of caspase-12, although a trigger for Bax/Bak activation has not been identified. Our data demonstrate that Bim is a candidate for the molecular link between ER stress and Bax/Bak activation.

内质网(ER)应激激活小鼠细胞中的caspase12，触发内质网应激特异的级联反应，实现细胞凋亡。在C2C12小鼠成肌细胞中，级联的激活不会从线粒体释放细胞色素c，这表明该级联不依赖于线粒体的损伤。Bclxl在C2C12细胞中的稳定过表达抑制了caspase-12的激活和细胞凋亡。在内质网应激细胞中，Bcl-xL与Bim共沉淀，Bim是Bim家族中的促凋亡成员，提示在内质网应激的细胞中，Bim与Bcl-xl结合，从而抑制细胞的凋亡信号。C2C12细胞的分级显示，内质网应激导致Bim从一个富含动力蛋白的隔室转移到内质网，而稳定的Bim过表达抑制了Bim在内质网上的积聚。尽管Bim的毒性作用以前只在线粒体外膜观察到，但针对内质网表面的Bim衍生物Bim(ER)过表达可导致细胞凋亡。过量表达Caspa-SE12抑制蛋白的C2C12转染体对Bim(ER)具有抗性，提示Bim对ER的毒性作用依赖于Caspase-12的激活。通过RNAi敲除Bim使细胞对内质网应激产生抵抗。这些结果表明，Bim在内质网应激反应中移位到内质网是激活caspase-12和启动内质网应激特异性caspase级联的重要一步。最近，Bax和Bak被认为参与了内质网应激诱导的细胞凋亡。根据该模型，Bax/Bak的构象变化和寡聚化可能导致caspase-12的激活，尽管还没有确定Bax/Bak激活的触发因素。我们的数据表明，Bim是内质网应激和Bax/Bak激活之间的分子联系的候选者。