Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways
Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways
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DOI：
10.1172/jci38857
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发表时间：
2009-10-01
影响因子：
15.9
通讯作者：
Tabas, Ira
中科院分区：
文献类型：
--
作者：
Timmins, Jenelle M.;Ozcan, Lale;Tabas, Ira
内质网应激诱导的细胞凋亡涉及多种病理条件，但将内质网应激介导的信号转导到下游的凋亡通路的机制尚不清楚。利用人和小鼠细胞培养和内质网应激诱导的小鼠体内模型，我们已经证明了内质网应激产生的胞浆钙通过钙/钙调素依赖的蛋白激酶II-γ(CaMKII-γ)和JNK途径诱导Fas死亡受体的表达。值得注意的是，CaMKIIγ也参与了线粒体依赖性细胞凋亡的过程，包括线粒体细胞色素c的释放和线粒体膜电位的丧失。在一些与内质网应激相关的培养的人和小鼠细胞中也观察到依赖于CaMKII的凋亡，包括培养的巨噬细胞、内皮细胞和受到促凋亡的内质网应激的神经细胞。此外，全身内质网应激的WT小鼠表现出巨噬细胞线粒体功能障碍和凋亡、肾上皮细胞凋亡和肾功能障碍，而CaMKII伽玛缺乏小鼠的这些作用明显减弱。这些数据支持一个整合的模型，在该模型中，CaMKII是内质网应激与Fas和线粒体凋亡途径之间的统一纽带。我们的研究还揭示了我们认为CaMKII的一种新的促凋亡功能，即促进线粒体钙摄取。这些发现增加了CaMKII抑制剂在涉及内质网应激诱导细胞凋亡的病理环境中预防细胞凋亡的可能性。
ER stress-induced apoptosis is implicated in various pathological conditions, but the mechanisms linking ER stress-mediated signaling to downstream apoptotic pathways remain unclear. Using human and mouse cell culture and in vivo mouse models of ER stress-induced apoptosis, we have shown that cytosolic calcium resulting from ER stress induces expression of the Fas death receptor through a pathway involving calcium/calmodulin-dependent protein kinase II gamma (CaMKII gamma) and JNK. Remarkably, CaMKII gamma was also responsible for processes involved in mitochondrial-dependent apoptosis, including release of mitochondrial cytochrome c and loss of mitochondrial membrane potential. CaMKII-dependent apoptosis was also observed in a number of cultured human and mouse cells relevant to ER stress-induced pathology, including cultured macrophages, endothelial cells, and neuronal cells subjected to proapoptotic ER stress. Moreover, WT mice subjected to systemic ER stress showed evidence of macrophage mitochondrial dysfunction and apoptosis, renal epithelial cell apoptosis, and renal dysfunction, and these effects were markedly reduced in CaMKII gamma-deficient mice. These data support an integrated model in which CaMKII serves as a unifying link between ER stress and the Fas and mitochondrial apoptotic pathways. Our study also revealed what we believe to be a novel proapoptotic function for CaMKII, namely, promotion of mitochondrial calcium uptake. These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress-induced apoptosis.