Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β
Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β
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作者：
Nakagawa, T;Zhu, H;Yuan, JY
细胞凋亡或细胞自杀对正常发育和组织稳态很重要，但过多或过少的细胞凋亡也会导致疾病（1，2）。半胱氨酸蛋白酶家族，即所谓的半胱氨酸天冬氨酸蛋白酶，是程序性细胞死亡的关键介质（3），迄今已鉴定出14个家族成员。其中一些，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。其他的，如caspase-9（参考文献6），介导线粒体损伤后的凋亡信号。内质网（ER）中的应激也可导致细胞凋亡（7）。在这里，我们表明，caspase-12是本地化的ER和激活的ER应激，包括ER钙稳态的破坏和ER中多余的蛋白质的积累，但不是由膜或神经元靶向的凋亡信号。缺乏半胱天冬酶-12的小鼠对ER应激诱导的细胞凋亡具有抗性，但它们的细胞响应于其他死亡刺激而发生细胞凋亡。此外，我们发现，caspase-12缺陷的皮质神经元是有缺陷的淀粉样β蛋白诱导的细胞凋亡，但不是由星形孢菌素或营养因子剥夺。因此，半胱天冬酶-12介导ER特异性凋亡途径，并可能导致淀粉样蛋白β神经毒性。
Apoptosis, or cellular suicide, is important for normal development and tissue homeostasis, but too much or too Little apoptosis can also cause disease(1,2). The family of cysteine proteases, the so-called caspases, are critical mediators of programmed cell death(3), 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(7). 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-beta protein but not by staurosporine or trophic factor deprivation. Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-beta neurotoxicity.