据一篇发表于9月21日Journal of Cell Biology的研究报告，研究人员发现内质网(endoplasmic reticulum,ER)处于长期的胁迫下将导致储存在内质网中的钙离子释放出来，诱发细胞死亡。
在压力胁迫下，内质网中逐渐积累错误折叠的蛋白质，而细胞自身可以通过放缓翻译速度并增加正确折叠的蛋白质产物来进行矫正。但随着压力的持续影响，转录因子CHOP延长表达则会引起细胞凋亡，这种细胞凋亡体系是由从内质网中释放的钙离子引发的，但到目前为止，CHOP如何引发这一步还不得而知。
研究人员对内质网中连接CHOP引入(CHOP induction)和钙离子释放的两种蛋白质ERO1-α氧化酶和钙离子通道蛋白IP3R进行研究。ERO1-α是CHOP转录后产物，在缺失CHOP的细胞中ERO1-α再表达将引起细胞死亡。另一方面，敲除到ERO1-α或IP3R基因可以防止钙元素释放和ER压力下细胞的凋亡。对胰岛素抵抗的肥胖老鼠研究表明，由于其经受着内质网压力胁迫，IP3R依赖性的钙离子释放量增加。
研究人员认为ERO1-α能够氧化内质网腔，促进IP3R中关键的二硫键的形成，从而使该通道更加活跃。（生物谷Bioon.com）
生物谷推荐原始出处：
The Journal of Cell Biology doi:10.1083/jcb.200904060
Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis
Gang Li1, Marco Mongillo2,4, King-Tung Chin5, Heather Harding5, David Ron5, Andrew R. Marks2,4, and Ira Tabas1,2,3,4
1 Department of Medicine, 2 Department of Physiology and Cellular Biophysics, 3 Department of Pathology and Cell Biology, and 4 Clyde and Helen Wu Center for Molecular Cardiology, Columbia University, New York, NY 10032 5 Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016
Endoplasmic reticulum (ER) stress–induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1- (ER oxidase 1 ). In ER-stressed cells, ERO1- is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1- suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1- or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1- in Chop–/– macrophages restores ER stress–induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop–/– mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-–IP3R pathway.
