Department of Medicine, Columbia University, New York, NY 10032, USA.
J Cell Biol. 2010 Dec 13;191(6):1113-25. doi: 10.1083/jcb.201006121. Epub 2010 Dec 6.
Endoplasmic reticulum (ER)-induced apoptosis and oxidative stress contribute to several chronic disease processes, yet molecular and cellular mechanisms linking ER stress and oxidative stress in the setting of apoptosis are poorly understood and infrequently explored in vivo. In this paper, we focus on a previously elucidated ER stress-apoptosis pathway whose molecular components have been identified and documented to cause apoptosis in vivo. We now show that nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX) and NOX-mediated oxidative stress are induced by this pathway and that apoptosis is blocked by both genetic deletion of the NOX subunit NOX2 and by the antioxidant N-acetylcysteine. Unexpectedly, NOX and oxidative stress further amplify CCAAT/enhancer binding protein homologous protein (CHOP) induction through activation of the double-stranded RNA-dependent protein kinase (PKR). In vivo, NOX2 deficiency protects ER-stressed mice from renal cell CHOP induction and apoptosis and prevents renal dysfunction. These data provide new insight into how ER stress, oxidative stress, and PKR activation can be integrated to induce apoptosis in a pathophysiologically relevant manner.
内质网（ER）诱导的细胞凋亡和氧化应激与几种慢性疾病过程有关，但 ER 应激与细胞凋亡过程中氧化应激之间的分子和细胞机制在体内尚不清楚，也很少被探索。在本文中，我们重点介绍了一个先前阐明的 ER 应激-细胞凋亡途径，其分子成分已被确定，并被证明在体内引起细胞凋亡。我们现在表明，烟酰胺腺嘌呤二核苷酸磷酸还原型氧化酶（NOX）和 NOX 介导的氧化应激是由该途径诱导的，细胞凋亡可以通过 NOX 亚基 NOX2 的基因缺失和抗氧化剂 N-乙酰半胱氨酸来阻断。出乎意料的是，NOX 和氧化应激通过双链 RNA 依赖性蛋白激酶 (PKR) 的激活进一步放大 CCAAT/增强子结合蛋白同源蛋白 (CHOP) 的诱导。在体内，NOX2 缺陷可保护 ER 应激小鼠免受肾细胞 CHOP 诱导和细胞凋亡，并防止肾功能障碍。这些数据为 ER 应激、氧化应激和 PKR 激活如何以生理相关的方式整合诱导细胞凋亡提供了新的见解。
