University of Massachusetts Medical School, Worcester, 01605-2324, USA.
Cell Death Differ. 2010 May;17(5):774-86. doi: 10.1038/cdd.2009.175. Epub 2009 Nov 13.
Endoplasmic reticulum (ER) stress-mediated cell death has an important role in the pathogenesis of chronic diseases, including diabetes and neurodegeneration. Although proapoptotic programs activated by ER stress have been extensively studied, identification and characterization of antiapoptotic programs that counteract ER stress are currently incomplete. Through the gene expression profiling of beta-cells lacking Wolfram syndrome 1 gene (WFS1), a causative gene for Wolfram syndrome, we discovered a novel antiapoptotic gene of the unfolded protein response (UPR), apoptosis antagonizing transcription factor (AATF). Here, we study the regulation of AATF, identify its target genes, and determine the basis for its antiapoptotic activities in response to ER stress. We show that AATF is induced by ER stress through the PERK-eIF2alpha pathway and transcriptionally activates the v-akt murine thymoma viral oncogene homolog 1 (AKT1) gene through signal transducer and activator of transcription 3 (Stat3), which sustains Akt1 activation and promotes cell survival. Ectopic expression of AATF or a constitutively active form of AKT1 confers on cells resistance to ER stress-mediated cell death, whereas RNAi-mediated knockdown of AATF or AKT1 renders cells sensitive to ER stress. We also discovered a positive crosstalk between the AATF and WFS1 signaling pathways. Thus, WFS1 deficiency or AATF deficiency mediates a self-perpetuating cycle of cell death. Our results reveal a novel antiapoptotic program relevant to the treatment of diseases caused by ER stress-mediated cell death.
内质网（ER）应激介导的细胞死亡在包括糖尿病和神经退行性变在内的慢性疾病发病机制中起重要作用。尽管已广泛研究了由 ER 应激激活的促凋亡程序，但目前仍不完全清楚拮抗 ER 应激的抗凋亡程序的鉴定和特征。通过缺乏沃尔夫拉姆综合征 1 基因（WFS1）的β细胞的基因表达谱分析，WFS1 是沃尔夫拉姆综合征的致病基因，我们发现了未折叠蛋白反应（UPR）的一种新型抗凋亡基因，凋亡拮抗转录因子（AATF）。在这里，我们研究了 AATF 的调节，鉴定了其靶基因，并确定了其在应对 ER 应激时的抗凋亡活性的基础。我们表明，AATF 通过 PERK-eIF2alpha 途径被 ER 应激诱导，并通过信号转导和转录激活因子 3（Stat3）转录激活 v-akt 鼠胸腺病毒癌基因同源物 1（AKT1）基因，从而维持 Akt1 激活并促进细胞存活。AATF 的异位表达或 AKT1 的组成性激活形式赋予细胞对 ER 应激介导的细胞死亡的抗性，而 AATF 或 AKT1 的 RNAi 介导的敲低使细胞对 ER 应激敏感。我们还发现了 AATF 和 WFS1 信号通路之间的正交互作用。因此，WFS1 缺乏或 AATF 缺乏介导了细胞死亡的自我维持循环。我们的结果揭示了与治疗由 ER 应激介导的细胞死亡引起的疾病相关的新型抗凋亡程序。
