據(jù)一篇發(fā)表于9月21日J(rèn)ournal of Cell Biology的研究報告,，研究人員發(fā)現(xiàn)內(nèi)質(zhì)網(wǎng)(endoplasmic reticulum,ER)處于長期的脅迫下將導(dǎo)致儲存在內(nèi)質(zhì)網(wǎng)中的鈣離子釋放出來,，誘發(fā)細(xì)胞死亡,。
在壓力脅迫下，內(nèi)質(zhì)網(wǎng)中逐漸積累錯誤折疊的蛋白質(zhì),，而細(xì)胞自身可以通過放緩翻譯速度并增加正確折疊的蛋白質(zhì)產(chǎn)物來進(jìn)行矯正。但隨著壓力的持續(xù)影響，轉(zhuǎn)錄因子CHOP延長表達(dá)則會引起細(xì)胞凋亡,，這種細(xì)胞凋亡體系是由從內(nèi)質(zhì)網(wǎng)中釋放的鈣離子引發(fā)的，但到目前為止,，CHOP如何引發(fā)這一步還不得而知,。
研究人員對內(nèi)質(zhì)網(wǎng)中連接CHOP引入(CHOP induction)和鈣離子釋放的兩種蛋白質(zhì)ERO1-α氧化酶和鈣離子通道蛋白IP3R進(jìn)行研究。ERO1-α是CHOP轉(zhuǎn)錄后產(chǎn)物,，在缺失CHOP的細(xì)胞中ERO1-α再表達(dá)將引起細(xì)胞死亡,。另一方面，敲除到ERO1-α或IP3R基因可以防止鈣元素釋放和ER壓力下細(xì)胞的凋亡,。對胰島素抵抗的肥胖老鼠研究表明,，由于其經(jīng)受著內(nèi)質(zhì)網(wǎng)壓力脅迫，IP3R依賴性的鈣離子釋放量增加,。
研究人員認(rèn)為ERO1-α能夠氧化內(nèi)質(zhì)網(wǎng)腔,，促進(jìn)IP3R中關(guān)鍵的二硫鍵的形成，從而使該通道更加活躍,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
