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

• Published in: Apoptosis (London) Vol. 17; no. 8; pp. 810 - 820
• Main Authors: Oral, Ozlem, Oz-Arslan, Devrim, Itah, Zeynep, Naghavi, Atabak, Deveci, Remziye, Karacali, Sabire, Gozuacik, Devrim
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-08-2012; Springer Nature B.V
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Autophagy; Autophagy-Related Proteins; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Caspase 8 - metabolism; Caspase Inhibitors; Cell Biology; Cell death; Cell Survival; Conserved Sequence; Cycloheximide - pharmacology; Enzymatic activity; Humans; Jurkat Cells; Molecular Sequence Data; Mortality; Oligopeptides - pharmacology; Oncology; Original Paper; Protein Synthesis Inhibitors - pharmacology; Proteolysis; Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TNF-Related Apoptosis-Inducing Ligand - physiology; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factor-alpha - physiology; Ubiquitin-Conjugating Enzymes - chemistry; Ubiquitin-Conjugating Enzymes - metabolism; Virology; Caspase-8; TRAIL; Cell survival; TNF-α; Death receptor; Autophagy; Apoptosis
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-012-0735-0

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.