Abstract
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 β-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–eIF2α 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.
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Abbreviations
- ER stress:
-
endoplasmic reticulum stress
- UPR:
-
unfolded protein response
- AATF:
-
apoptosis antagonizing transcription factor
- WFS1:
-
Wolfram syndrome 1 gene
- AKT1:
-
v-akt murine thymoma viral oncogene homolog 1
- STAT3:
-
signal transducer and activator of transcription 3
- JNK:
-
c-Jun N-terminal kinase
- ERAD:
-
endoplasmic reticulum-associated protein degradation
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Acknowledgements
We thank E Campeau for providing lentiviral expression systems; MR Green, KL Lipson, C Kakiuchi, R Ghosh, and Y Okawa for helpful discussions; K Sargent and L Leehy for technical assistance. Research in the laboratory of F Urano was supported by an NIH R01DK067493 grant, a grant from the Diabetes and Endocrinology Research Center at the University of Massachusetts Medical School (DK032520), a Juvenile Diabetes Research Foundation Regular Grant, and an Iacocca Foundation/Juvenile Diabetes Research Foundation joint grant.
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Ishigaki, S., Fonseca, S., Oslowski, C. et al. AATF mediates an antiapoptotic effect of the unfolded protein response through transcriptional regulation of AKT1. Cell Death Differ 17, 774–786 (2010). https://doi.org/10.1038/cdd.2009.175
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DOI: https://doi.org/10.1038/cdd.2009.175
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