Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction.
Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction.
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DOI：
10.1016/j.freeradbiomed.2012.06.042
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发表时间：
2012-09-01
影响因子：
7.4
通讯作者：
Hinton, David R.
中科院分区：
文献类型：
--
作者：
Dou, Guorui;Sreekumar, Parameswaran G.;Spee, Christine;He, Shikun;Ryan, Stephen J.;Kannan, Ram;Hinton, David R.
关键词：
内质网（ER）应激与包括年龄相关性黄斑变性在内的几种病理状况有关。过度的ER应激启动细胞死亡级联反应，其部分通过线粒体功能障碍介导。在这里，我们确定αB晶体蛋白作为一个重要的调节ER应激诱导的细胞死亡。来自αB晶体蛋白（-/-）小鼠的视网膜色素上皮（RPE）细胞和用αB晶体蛋白siRNA转染的人RPE细胞更容易受到衣霉素诱导的ER应激的影响。ER应激介导的细胞死亡与活性氧水平升高、线粒体中谷胱甘肽耗竭、超氧化物歧化酶活性降低、细胞色素c释放增加以及半胱天冬酶3和4活化相关。ER应激信号抑制剂salubrinal和4-（2-aminoethyl）benzensulfonyl fluoride可减轻ER应激诱导的线粒体损伤和RPE凋亡。长期的内质网应激降低了αB晶状体蛋白的水平，从而加剧了线粒体功能障碍。过表达αB晶体蛋白通过减弱Bax、CHOP、线粒体通透性转换和切割的caspase 3的增加来保护RPE细胞免受ER应激诱导的凋亡。因此，这些数据共同表明，αB晶体蛋白在ER应激诱导的RPE凋亡过程中提供线粒体功能的关键保护。
Endoplasmic reticulum (ER) stress is linked to several pathological conditions including age-related macular degeneration. Excessive ER stress initiates cell death cascades which are mediated, in part, through mitochondrial dysfunction. Here, we identify αB crystallin as an important regulator of ER stress-induced cell death. Retinal pigment epithelial (RPE) cells from αB crystallin (−/−) mice, and human RPE cells transfected with αB crystallin siRNA, are more vulnerable to ER stress induced by tunicamycin. ER stress-mediated cell death is associated with increased levels of reactive oxygen species, depletion of glutathione in mitochondria, decreased superoxide dismutase activity, increased release of cytochrome c and activation of caspases 3 and 4. The ER stress signaling inhibitors, salubrinal and 4-(2-aminoethyl) benzenesulfonyl fluoride, decrease mitochondrial damage and reduce RPE apoptosis induced by ER stress. Prolonged ER stress decreases levels of αB crystallin, thus exacerbating mitochondrial dysfunction. Overexpression of αB crystallin protects RPE cells from ER stress-induced apoptosis by attenuating increases in Bax, CHOP, mitochondrial permeability transition, and cleaved caspase 3. Thus, these data collectively demonstrate that αB crystallin provides critical protection of mitochondrial function during ER stress-induced RPE apoptosis.
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影响因子：
3.6
作者：
Dasmahapatra G;Lembersky D;Rahmani M;Kramer L;Friedberg J;Fisher RI;Dent P;Grant S
通讯作者：
Grant S
影响因子：
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作者：
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4.4
作者：
Koyama, Yoshihisa;Matsuzaki, Shinsuke;Tohyama, Masaya
通讯作者：
Tohyama, Masaya
影响因子：
3.4
作者：
Ikesugi, Kengo;Yamamoto, Ryoko;Shinohara, Toshimichi
通讯作者：
Shinohara, Toshimichi
影响因子：
5
作者：
Kadono, Toshie;Zhang, Xiu Quan;Benjamin, Ivor J.
通讯作者：
Benjamin, Ivor J.