Abstract
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.
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Acknowledgements
JG, CN and GM are supported by LTU PhD scholarship and this project was funded by an Australian National Health and Medical Research Council Project grant APP1085328 (to HP).
Author contributions
JG, MD, CN, IJ, GM and GB conducted the experiments. AK, DS, MJ and DH generated the CRISPR knockout cell lines. MJ, DH, AP, JP and HP designed the experiments and MD, JG and HP wrote the manuscript.
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Edited by G Melino
Supplementary Information accompanies this paper on Cell Death and Differentiation website
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Glab, J., Doerflinger, M., Nedeva, C. et al. DR5 and caspase-8 are dispensable in ER stress-induced apoptosis. Cell Death Differ 24, 944–950 (2017). https://doi.org/10.1038/cdd.2017.53
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DOI: https://doi.org/10.1038/cdd.2017.53
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