AATF mediates anti-apoptotic effect of the unfolded protein response through transcriptional regulation of AKT1

Endoplasmic reticulum (ER) stress-mediated cell death plays an important role in the pathogenesis of chronic diseases including diabetes and neurodegeneration. Although pro-apoptotic programs activated by ER stress have been extensively studied, identification and characterization of anti-apoptotic programs that counteract ER stress is currently incomplete. Through the gene expression profiling of β-cells lacking WFS1, a causative gene for Wolfram syndrome, we have discovered a novel anti-apoptotic 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 anti-apoptotic activities in response to ER stress. We show that AATF is induced by ER stress through the PERK-eIF2α pathway and transcriptionally activates the Akt1 gene through 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 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 anti-apoptotic program relevant to treatment for diseases caused by ER stress-mediated cell death.