Glab Jason A, Doerflinger Marcel, Nedeva Christina, Jose Irvin, Mbogo George W, Paton James C, Paton Adrienne W, Kueh Andrew J, Herold Marco J, Huang David Cs, Segal David, Brumatti Gabriella, Puthalakath Hamsa
Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, Kingsbury Drive, Melbourne, VIC 3086, Australia.
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Cell Death Differ. 2017 May;24(5):944-950. doi: 10.1038/cdd.2017.53. Epub 2017 Apr 14.
The endoplasmic reticulum (ER) stress response constitutes cellular reactions triggered by a wide variety of stimuli that disturb folding of proteins, often leading to apoptosis. ER stress-induced apoptotic cell death is thought to be an important contributor to many human pathological conditions. The molecular mechanism of this apoptosis process has been highly controversial with both the receptor and the mitochondrial pathways being implicated. Using knockout mouse models and RNAi-mediated gene silencing in cell lines, our group and others had demonstrated the importance of the mitochondrial apoptotic pathway in ER stress-induced cell death, particularly the role of the pro-apoptotic BH3-only BCL-2 family members, BIM and PUMA. However, a recent report suggested a central role for the death receptor, DR5, activated in a ligand-independent manner, and the initiator caspase, caspase-8, in ER stress-induced cell death. This prompted us to re-visit our previous observations and attempt to reproduce the newly published findings. Here we report that the mitochondrial apoptotic pathway, activated by BH3-only proteins, is essential for ER stress-induced cell death and that, in contrast to the previous report, DR5 as well as caspase-8 are not required for this process.
内质网（ER）应激反应是由多种干扰蛋白质折叠的刺激引发的细胞反应，常导致细胞凋亡。内质网应激诱导的凋亡性细胞死亡被认为是许多人类病理状况的一个重要促成因素。这种凋亡过程的分子机制一直存在高度争议，涉及受体途径和线粒体途径。利用基因敲除小鼠模型以及细胞系中RNAi介导的基因沉默技术，我们团队和其他研究团队已证明线粒体凋亡途径在内质网应激诱导的细胞死亡中具有重要性，尤其是促凋亡的仅含BH3结构域的BCL-2家族成员BIM和PUMA的作用。然而，最近的一份报告表明，死亡受体DR5以非配体依赖的方式被激活，以及起始半胱天冬酶caspase-8在内质网应激诱导的细胞死亡中起核心作用。这促使我们重新审视我们之前的观察结果，并试图重现新发表的研究发现。在此我们报告，由仅含BH3结构域的蛋白质激活的线粒体凋亡途径对于内质网应激诱导的细胞死亡至关重要，并且与之前的报告相反，该过程不需要DR5以及caspase-8。
