Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis.
Autophagy is an important catabolic process with roles in cell survival and cell death. It sequesters cytosol and organelles within double-membrane autophagosomes that deliver their contents to lysosomes for degradation. Autophagosome biogenesis is coordinated by the autophagy-related protein 4 (Atg4) family of C54 endopeptidases (Atg4A-Atg4D). These enzymes prime and then ... later delipidate the autophagosome marker, Atg8. Here, we show that one family member, Atg4D, is cleaved by caspase-3 in vitro and in apoptotic cells. Atg4D is a poor priming and delipidation enzyme in vitro, but truncated DeltaN63 Atg4D displays increased activity against the Atg8 paralogue, gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAP-L1). In living cells, DeltaN63 Atg4D stimulates the delipidation of GABARAP-L1, whereas siRNA silencing of the gene expressing Atg4D abrogates GABARAP-L1 autophagosome formation and sensitises cells to starvation and staurosporine-induced cell death. Interestingly, Atg4D overexpression induces apoptosis, which is preceded by the caspase-independent recruitment of Atg4D to mitochondria and is facilitated by a putative C-terminal Bcl-2 homology 3 (BH3) domain. Atg4D also acquires affinity for damaged mitochondria in cells treated with hydrogen peroxide. These data suggest that Atg4D is an autophagy regulator that links mitochondrial dysfunction with apoptosis.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Apoptosis, Autophagy, Caspase 3, Cysteine Endopeptidases, HeLa Cells, Humans, Hydrogen Peroxide, Lipid Metabolism, Microtubule-Associated Proteins, Mitochondria, Molecular Sequence Data, Mutation, Oxidative Stress, Protein Structure, Tertiary, RNA Interference, Signal Transduction, Staurosporine, Stress, Physiological, Time Factors, Transfection
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Apoptosis, Autophagy, Caspase 3, Cysteine Endopeptidases, HeLa Cells, Humans, Hydrogen Peroxide, Lipid Metabolism, Microtubule-Associated Proteins, Mitochondria, Molecular Sequence Data, Mutation, Oxidative Stress, Protein Structure, Tertiary, RNA Interference, Signal Transduction, Staurosporine, Stress, Physiological, Time Factors, Transfection
J. Cell. Sci.
Date: Jul. 15, 2009
PubMed ID: 19549685
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