CHOP/GADD153 在内质网应激介导细胞凋亡中的研究进展

内质网(endoplasmic reticulum,ER)广泛存在于真核细胞中,是负责细胞中分泌性蛋白合成和折叠的细胞器。20世纪70年代开始发现了许多干扰内质网功能的因素可直接或间接使内质网中未折叠的蛋白质堆积,使细胞处于应激状态(ER stress),细胞通过未折叠蛋白质反应(unfolded protein response,UPR)来适应内质网应激。未折叠蛋白质反应途径(UPR pathway)是一种信号转导途径,最早在酵母中阐明。近年来对哺乳动物细胞未折叠蛋白质反应途径的研究也获得了重要成果。毒性、缺氧、病毒感染等不良刺激可使细胞内环境的稳态受到破坏,诱发一系列内质网应激反应(ER stress)来维持细胞的正常功能。当细胞受到持续而强烈的刺激时,不能缓解内质网应激状态,细胞会走向凋亡。近年来的研究发现,CHOP/GADD153作为一种前凋亡分子,在内质网应激介导的细胞凋亡中发挥着重要作用,参与肿瘤、阿尔茨海默、糖尿病等诸多疾病的发生和发展过程。

Advances of Insights into the Roles of CHOP-induced Apoptosis in ER Stress

Endoplasmic reticulum (ER) widely exists in eukaryotes and functions as an essential synthesis and folding manufactory of secretory proteins. Perturbations of ER homeostasis adversely indulge in protein folding and cause endoplasmic reticulum stress (ER stress) when the cell suffers from the adverse environment such as toxicity, ischemia, virus infection, pH changes and so on. All the above factors can result in an accumulation of unfolded or misfolded protein in the ER lumen, namely ER stress. To adapt to the occurrence of ER stress, cells can sense these stresses and activate highly conversed stress responses to them through translational attenuation, up-regulation of the genes for ER chaperones and related proteins and degradation of unfolded proteins by quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in various diseases such as neurodegenerative disorders, metabolic diseases and tumors. One of the significantly important but unclear components of the ER stress-mediated apoptosis pathway is CHOP (C/EBP homologous protein), also defined as growth arrest-and DNA damage-inducible gene 153 (GADD153). According to the current research progress of CHOP-mediated apoptosis in ER stress and in diseases including neurodegenerative disorders, metabolic diseases and tumors, we summarize the current researches and investigations of the roles of CHOP/GADD153 in ER Stress in the following categories.