Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death

Oral, Özlem and Öz-Arslan, Devrim and İtah, Zeynep and Naghavi, Atabak and Deveci, Remziye and Karaçalı, Sabire and Gözüaçık, Devrim (2012) Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death. Apoptosis, 17 (8). pp. 810-820. ISSN 1360-8185 (Print) 1573-675X (Online)

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Autophagy is an evolutionarily conserved mechanism contributing to cell survival under stress conditions including nutrient and growth factor deprivation. Connections and cross-talk between cell death mechanisms and autophagy is under investigation. Here, we describe Atg3, an essential regulatory component of autophagosome biogenesis, as a new substrate of caspase-8 during receptor-mediated cell death. Both, TNF-α- (tumor necrosis factor α) and TRAIL- (tumor necrosis factor-related apoptosis inducing ligand) induced cell death was accompanied by Atg3 cleavage and this event was inhibited by a pan-caspase inhibitor (zVAD) or a caspase-8-specific inhibitor (zIETD). Indeed, caspase-8 overexpression led to Atg3 degradation and this event depended on caspase-8 enzymatic activity. Mutation of the caspase-8 cleavage site on Atg3 abolished its cleavage both in vitro and in vivo, demonstrating that Atg3 was a direct target of caspase-8. Autophagy was inactive during apoptosis and blockage of caspases or overexpression of a non-cleavable Atg3 protein reestablished autophagic activity upon death receptor stimulation. In this system, autophagy was important for cell survival since inhibition of autophagy increased cell death. Therefore, Atg3 provides a novel link between apoptosis and autophagy during receptor-activated cell death.
Item Type: Article
Additional Information: DG is the corresponding author
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Engineering and Natural Sciences > Academic programs > Biological Sciences & Bio Eng.
Faculty of Engineering and Natural Sciences
Depositing User: Devrim Gözüaçık
Date Deposited: 04 Jul 2012 10:55
Last Modified: 31 Jul 2019 11:06

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