Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14850, USA.
J Biol Chem. 2010 Apr 30;285(18):13694-703. doi: 10.1074/jbc.M109.085340. Epub 2010 Mar 2.
Stress in the endoplasmic reticulum (ER) plays an important causal role in the pathogenesis of several chronic diseases such as Alzheimer, Parkinson, and diabetes mellitus. Insight into the genetic determinants responsible for ER homeostasis will greatly facilitate the development of therapeutic strategies for the treatment of these debilitating diseases. Suppressor enhancer Lin12 1 like (SEL1L) is an ER membrane protein and was thought to be involved in the quality control of secreted proteins. Here we show that the mice homozygous mutant for SEL1L were embryonic lethal. Electron microscopy studies revealed a severely dilated ER in the fetal liver of mutant embryos, indicative of alteration in ER homeostasis. Consistent with this, several ER stress responsive genes were significantly up-regulated in the mutant embryos. Mouse embryonic fibroblast cells deficient in SEL1L exhibited activated unfolded protein response at the basal state, impaired ER-associated protein degradation, and reduced protein secretion. Furthermore, markedly increased apoptosis was observed in the forebrain and dorsal root ganglions of mutant embryos. Taken together, our results demonstrate an essential role for SEL1L in protein quality control during mouse embryonic development.
内质网（ER）中的应激在几种慢性疾病（如阿尔茨海默病、帕金森病和糖尿病）的发病机制中起着重要的因果作用。深入了解负责 ER 动态平衡的遗传决定因素将极大地促进治疗这些使人衰弱的疾病的治疗策略的发展。抑制增强子 Lin12 1 样（SEL1L）是一种内质网膜蛋白，被认为参与分泌蛋白的质量控制。在这里，我们发现 SEL1L 纯合突变的小鼠是胚胎致死的。电子显微镜研究显示突变胚胎的胎肝中 ER 严重扩张，表明 ER 动态平衡发生改变。与此一致，突变胚胎中几种 ER 应激反应基因显著上调。缺乏 SEL1L 的小鼠胚胎成纤维细胞在基础状态下表现出未折叠蛋白反应激活、内质网相关蛋白降解受损和蛋白质分泌减少。此外，突变胚胎的前脑和背根神经节中观察到明显增加的细胞凋亡。总之，我们的结果表明 SEL1L 在小鼠胚胎发育过程中的蛋白质质量控制中起着至关重要的作用。
