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Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions

Shane Deegan, Svetlana Saveljeva, Susan E Logue, Karolina Pakos-Zebrucka, Sanjeev Gupta, Peter Vandenabeele UGent, Mathieu Bertrand UGent and Afshin Samali (2014) AUTOPHAGY. 10(11). p.1921-1936
abstract
Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
autophagy, caspase, endoplasmic reticulum stress, unfolded protein response, ENDOPLASMIC-RETICULUM STRESS, CELL-DEATH, CYTOCHROME-C, BCL-2 FAMILY, CASPASE-8, ACTIVATION, ASSAYS, ROLES, CHAIN, FADD, apoptosis, autophagic cell death
journal title
AUTOPHAGY
Autophagy
volume
10
issue
11
pages
1921 - 1936
Web of Science type
Article
Web of Science id
000348314200005
JCR category
CELL BIOLOGY
JCR impact factor
11.753 (2014)
JCR rank
15/184 (2014)
JCR quartile
1 (2014)
ISSN
1554-8627
DOI
10.4161/15548627.2014.981790
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
5818591
handle
http://hdl.handle.net/1854/LU-5818591
date created
2015-01-26 16:48:47
date last changed
2016-12-19 15:41:32
@article{5818591,
  abstract     = {Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.},
  author       = {Deegan, Shane and Saveljeva, Svetlana and Logue, Susan E and Pakos-Zebrucka, Karolina and Gupta, Sanjeev and Vandenabeele, Peter and Bertrand, Mathieu and Samali, Afshin},
  issn         = {1554-8627},
  journal      = {AUTOPHAGY},
  keyword      = {autophagy,caspase,endoplasmic reticulum stress,unfolded protein response,ENDOPLASMIC-RETICULUM STRESS,CELL-DEATH,CYTOCHROME-C,BCL-2 FAMILY,CASPASE-8,ACTIVATION,ASSAYS,ROLES,CHAIN,FADD,apoptosis,autophagic cell death},
  language     = {eng},
  number       = {11},
  pages        = {1921--1936},
  title        = {Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions},
  url          = {http://dx.doi.org/10.4161/15548627.2014.981790},
  volume       = {10},
  year         = {2014},
}

Chicago
Deegan, Shane, Svetlana Saveljeva, Susan E Logue, Karolina Pakos-Zebrucka, Sanjeev Gupta, Peter Vandenabeele, Mathieu Bertrand, and Afshin Samali. 2014. “Deficiency in the Mitochondrial Apoptotic Pathway Reveals the Toxic Potential of Autophagy Under ER Stress Conditions.” Autophagy 10 (11): 1921–1936.
APA
Deegan, S., Saveljeva, S., Logue, S. E., Pakos-Zebrucka, K., Gupta, S., Vandenabeele, P., Bertrand, M., et al. (2014). Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions. AUTOPHAGY, 10(11), 1921–1936.
Vancouver
1.
Deegan S, Saveljeva S, Logue SE, Pakos-Zebrucka K, Gupta S, Vandenabeele P, et al. Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions. AUTOPHAGY. 2014;10(11):1921–36.
MLA
Deegan, Shane, Svetlana Saveljeva, Susan E Logue, et al. “Deficiency in the Mitochondrial Apoptotic Pathway Reveals the Toxic Potential of Autophagy Under ER Stress Conditions.” AUTOPHAGY 10.11 (2014): 1921–1936. Print.