Journal
APOPTOSIS
Volume 17, Issue 8, Pages 810-820Publisher
SPRINGER
DOI: 10.1007/s10495-012-0735-0
Keywords
Apoptosis; Autophagy; Death receptor; TNF-alpha; TRAIL; Caspase-8; Cell survival
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Funding
- The Scientific and Technological Research Council of Turkey (TUBITAK) [107T153, 2218]
- EMBO Strategical Development and Installations Grant (EMBO-SDIG) [1449]
- Sabanci University
- Turkish Academy of Sciences (TUBA) GEBIP Award
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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, tumor necrosis factor alpha and 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.
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