Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death.
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 α 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.
Faculty of Engineering and Natural Sciences, Biological Sciences and Bioengineering Program, Sabanci University, Orhanli-Tuzla, 34956, Istanbul, Turkey.
Ozlem
O
Oral
Devrim
D
Oz-Arslan
Zeynep
Z
Itah
Atabak
A
Naghavi
Remziye
R
Deveci
Sabire
S
Karacali
Devrim
D
Gozuacik
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D053181:Caspase 8 / Q000378:metabolism*; D061945:Caspase Inhibitors; D002470:Cell Survival; D017124:Conserved Sequence; D003513:Cycloheximide / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism*
D000071183:Autophagy-Related Proteins; D061945:Caspase Inhibitors; D009842:Oligopeptides; D011500:Protein Synthesis Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D003513:Cycloheximide; D044763:Ubiquitin-Conjugating Enzymes; C505530:CASP8 protein, human; D053181:Caspase 8; C455621:ATG3 protein, human