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首页> 外文期刊>Nature >Caspase-12 mediates endoplasmicreticulum-specific apoptosis and cytotoxicity by amyloid-β
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Caspase-12 mediates endoplasmicreticulum-specific apoptosis and cytotoxicity by amyloid-β

机译：Caspase-12通过淀粉样β介导内质网特异性凋亡和细胞毒性

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摘要

Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too little apoptosis can also cause disease. The family of cysteine proteases, the so-called caspases, are critical mediators of programmed cell death, and thus far 14 family members have been identified. Some of these, such as caspase-8 (refs 4, 5), mediate signal transduction downstream of death receptors located on the plasma membrane. Others, such as caspase-9 (ref. 6), mediate apoptotic signals after mitochondrial damage. Stress in the endoplasmic reticulum (ER) can also result in apoptosis. Here we show that caspase-12 is localized to the ER and activated by ER stress, including disruption of ER calcium homeostasis and accumulation of excess proteins in ER, but not by membrane- or mitochondrial-targeted apoptotic signals. Mice that are deficient in caspase-12 are resistant to ER stress-induced apoptosis, but their cells undergo apoptosis in response to other death stimuli. Furthermore, we show that caspase-12-deficient cortical neurons are defective in apoptosis induced by amyloid-β protein but not by staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-β neurotoxicity.
机译：细胞凋亡或细胞自杀对于正常发育和组织稳态很重要，但细胞凋亡过多或过少也会引起疾病。半胱氨酸蛋白酶家族，即所谓的胱天蛋白酶，是程序性细胞死亡的关键介体，迄今已鉴定出14个家族成员。其中一些，例如caspase-8（参考文献4、5），介导位于质膜上的死亡受体下游的信号转导。其他诸如caspase-9（参考文献6）在线粒体损伤后介导凋亡信号。内质网（ER）的压力也可能导致细胞凋亡。在这里，我们显示caspase-12定位于ER并被ER应激激活，包括ER钙稳态的破坏和ER中多余蛋白质的积累，但不是膜或线粒体靶向的凋亡信号。缺乏caspase-12的小鼠对内质网应激诱导的凋亡具有抵抗力，但是它们的细胞会响应其他死亡刺激而发生凋亡。此外，我们表明缺乏caspase-12的皮质神经元在由淀粉样β蛋白诱导的凋亡中有缺陷，但不是由星形孢菌素或营养因子剥夺引起的。因此，caspase-12介导ER特异性凋亡途径，并可能导致淀粉样β神经毒性。

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