期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 27, 页码 18323-18333出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.020891
关键词
-
资金
- American Federation on Aging Research
The endoplasmic reticulum (ER) is a key organelle regulating intracellular Ca2+ homeostasis. Oxidants and mitochondria-derived free radicals can target ER-based Ca2+ regulatory proteins and cause uncontrolled Ca2+ release that may contribute to protracted ER stress and apoptosis. Several ER stress proteins have been suggested to counteract the deregulation of ER Ca2+ homeostasis and ER stress. Here we showed that knockdown of Herp, an ubiquitin-like domain containing ER stress protein, renders PC12 and MN9D cells vulnerable to 1-methyl-4-phenylpyridinium-induced cytotoxic cell death by a mechanism involving up-regulation of CHOP expression and ER Ca2+ depletion. Conversely, Herp overexpression confers protection by blocking 1-methyl-4-phenylpyridinium-induced CHOP upregulation, ER Ca2+ store depletion, and mitochondrial Ca2+ accumulation in a manner dependent on a functional ubiquitin-proteasomal protein degradation pathway. Deletion of the ubiquitin-like domain of Herp or treatment with a proteasomal inhibitor abolished the central function of Herp in ER Ca2+ homeostasis. Thus, elucidating the underlying molecular mechanism(s) whereby Herp counteracts Ca2+ disturbances will provide insights into the molecular cascade of cell death in dopaminergic neurons and may uncover novel therapeutic strategies to prevent and ameliorate Parkinson disease progression.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据