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Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response

V Pagliarini, Ellen Wirawan UGent, A Romagnoli, F Ciccosanti, G Lisi, Saskia Lippens UGent, F Cecconi, GM Fimia, Peter Vandenabeele UGent and M Corazzari, et al. (2012) CELL DEATH AND DIFFERENTIATION. 19(9). p.1495-1504
abstract
Under stress conditions, pro-survival and pro-death processes are concomitantly activated and the final outcome depends on the complex crosstalk between these pathways. In most cases, autophagy functions as an early-induced cytoprotective response, favoring stress adaptation by removing damaged subcellular constituents. Moreover, several lines of evidence suggest that autophagy inactivation by the apoptotic machinery is a crucial event for cell death execution. Here we show that apoptotic stimuli induce a rapid decrease in the level of the autophagic factor Activating Molecule in Beclin1-Regulated Autophagy (Ambra1). Ambra1 degradation is prevented by concomitant inhibition of caspases and calpains. By both in vitro and in vivo approaches, we demonstrate that caspases are responsible for Ambra1 cleavage at the D482 site, whereas calpains are involved in complete Ambra1 degradation. Finally, we show that Ambra1 levels are critical for the rate of apoptosis induction. RNA interference-mediated Ambra1 downregulation further sensitizes cells to apoptotic stimuli, while Ambra1 overexpression and, more efficiently, a caspase non-cleavable mutant counteract cell death by prolonging autophagy induction. We conclude that Ambra1 is an important target of apoptotic proteases resulting in the dismantling of the autophagic machinery and the accomplishment of the cell death program.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ATAXIN-7, CALPAIN, CASPASE-8, INVOLVEMENT, BECLIN-1, PROTEINS, IN-VITRO, MECHANISM, MEDIATED CLEAVAGE, PROGRAMMED CELL-DEATH, calpains, caspases, Ambra1, autophagy, apoptosis
journal title
CELL DEATH AND DIFFERENTIATION
Cell Death Differ.
volume
19
issue
9
pages
1495 - 1504
Web of Science type
Article
Web of Science id
000307650300008
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
8.371 (2012)
JCR rank
26/288 (2012)
JCR quartile
1 (2012)
ISSN
1350-9047
DOI
10.1038/cdd.2012.27
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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
3009479
handle
http://hdl.handle.net/1854/LU-3009479
date created
2012-10-09 10:20:59
date last changed
2014-05-12 11:01:16
@article{3009479,
  abstract     = {Under stress conditions, pro-survival and pro-death processes are concomitantly activated and the final outcome depends on the complex crosstalk between these pathways. In most cases, autophagy functions as an early-induced cytoprotective response, favoring stress adaptation by removing damaged subcellular constituents. Moreover, several lines of evidence suggest that autophagy inactivation by the apoptotic machinery is a crucial event for cell death execution. Here we show that apoptotic stimuli induce a rapid decrease in the level of the autophagic factor Activating Molecule in Beclin1-Regulated Autophagy (Ambra1). Ambra1 degradation is prevented by concomitant inhibition of caspases and calpains. By both in vitro and in vivo approaches, we demonstrate that caspases are responsible for Ambra1 cleavage at the D482 site, whereas calpains are involved in complete Ambra1 degradation. Finally, we show that Ambra1 levels are critical for the rate of apoptosis induction. RNA interference-mediated Ambra1 downregulation further sensitizes cells to apoptotic stimuli, while Ambra1 overexpression and, more efficiently, a caspase non-cleavable mutant counteract cell death by prolonging autophagy induction. We conclude that Ambra1 is an important target of apoptotic proteases resulting in the dismantling of the autophagic machinery and the accomplishment of the cell death program.},
  author       = {Pagliarini, V and Wirawan, Ellen and Romagnoli, A and Ciccosanti, F and Lisi, G and Lippens, Saskia and Cecconi, F and Fimia, GM and Vandenabeele, Peter and Corazzari, M and Piacentini, M},
  issn         = {1350-9047},
  journal      = {CELL DEATH AND DIFFERENTIATION},
  keyword      = {ATAXIN-7,CALPAIN,CASPASE-8,INVOLVEMENT,BECLIN-1,PROTEINS,IN-VITRO,MECHANISM,MEDIATED CLEAVAGE,PROGRAMMED CELL-DEATH,calpains,caspases,Ambra1,autophagy,apoptosis},
  language     = {eng},
  number       = {9},
  pages        = {1495--1504},
  title        = {Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response},
  url          = {http://dx.doi.org/10.1038/cdd.2012.27},
  volume       = {19},
  year         = {2012},
}

Chicago
Pagliarini, V, Ellen Wirawan, A Romagnoli, F Ciccosanti, G Lisi, Saskia Lippens, F Cecconi, et al. 2012. “Proteolysis of Ambra1 During Apoptosis Has a Role in the Inhibition of the Autophagic Pro-survival Response.” Cell Death and Differentiation 19 (9): 1495–1504.
APA
Pagliarini, V., Wirawan, E., Romagnoli, A., Ciccosanti, F., Lisi, G., Lippens, S., Cecconi, F., et al. (2012). Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response. CELL DEATH AND DIFFERENTIATION, 19(9), 1495–1504.
Vancouver
1.
Pagliarini V, Wirawan E, Romagnoli A, Ciccosanti F, Lisi G, Lippens S, et al. Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response. CELL DEATH AND DIFFERENTIATION. 2012;19(9):1495–504.
MLA
Pagliarini, V, Ellen Wirawan, A Romagnoli, et al. “Proteolysis of Ambra1 During Apoptosis Has a Role in the Inhibition of the Autophagic Pro-survival Response.” CELL DEATH AND DIFFERENTIATION 19.9 (2012): 1495–1504. Print.