Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress
Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress
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DOI：
10.1074/jbc.m404272200
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发表时间：
2004-07-02
影响因子：
4.8
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Chan, SL;Fu, WM;Mattson, MP
在内质网（ER）应激反应中，细胞启动稳态和保护性反应，但也可以激活细胞死亡级联反应。一种名为Herp的54 kDa的内质网膜蛋白被鉴定为非神经元细胞中的应激反应蛋白。我们报道了疱疹存在于发育和成人大脑的神经元中，并且在神经元中受内质网应激的调节；亚致死水平的内质网应激可增加Herp水平，而高剂量的内质网应激可降低Herp水平并诱导细胞凋亡。在致死性内质网应激后，Herp蛋白水平的下降发生在线粒体功能障碍和细胞死亡之前，并由半胱天酶介导，该酶可产生30 kda的蛋白水解Herp片段。Herp中caspase裂解位点的突变增强了其内质网应激时的神经保护功能。虽然通过RNA干扰抑制Herp诱导使神经细胞对内质网应激诱导的凋亡敏感，但Herp的过表达通过稳定内质网Ca2+水平、保存线粒体功能和抑制caspase 3激活等机制促进存活。内质网应激诱导的JNK/c-Jun和caspase 12的激活被Herp降低，而内质网主要伴侣的诱导不受影响。Herp在内质网应激条件下阻止ER Ca2+过载，并且激动剂诱导的ER Ca2+释放被Herp减弱，这表明Herp在调节神经元Ca2+信号传导中起作用。通过稳定内质网Ca2+稳态和线粒体功能，Herp在内质网应激条件下具有神经保护功能。
In response to endoplasmic reticulum ( ER) stress, cells launch homeostatic and protective responses, but can also activate cell death cascades. A 54 kDa integral ER membrane protein called Herp was identified as a stress-responsive protein in non-neuronal cells. We report that Herp is present in neurons in the developing and adult brain, and that it is regulated in neurons by ER stress; sublethal levels of ER stress increase Herp levels, whereas higher doses decrease Herp levels and induce apoptosis. The decrease in Herp protein levels following a lethal ER stress occurs prior to mitochondrial dysfunction and cell death, and is mediated by caspases which generate a 30-kDa proteolytic Herp fragment. Mutagenesis of the caspase cleavage site in Herp enhances its neuroprotective function during ER stress. While suppression of Herp induction by RNA interference sensitizes neural cells to apoptosis induced by ER stress, overexpression of Herp promotes survival by a mechanism involving stabilization of ER Ca2+ levels, preservation of mitochondrial function and suppression of caspase 3 activation. ER stress-induced activation of JNK/c-Jun and caspase 12 are reduced by Herp, whereas induction of major ER chaperones is unaffected. Herp prevents ER Ca2+ overload under conditions of ER stress and agonist-induced ER Ca2+ release is attenuated by Herp suggesting a role for Herp in regulating neuronal Ca2+ signaling. By stabilizing ER Ca2+ homeostasis and mitochondrial functions, Herp serves a neuroprotective function under conditions of ER stress.