title: Atg4D at the interface between autophagy and apoptosis.
abstract: The Atg4 family of endopeptidases regulates autophagosome biogenesis by priming newly synthesized Atg8 to enable covalent attachment of phosphatidylethanolamine, and by delipidating Atg8 at the lysosomal fusion step. Control of Atg4 activity is therefore crucial, although little is known about how these molecules are regulated in living cells. We have found that one human Atg4 family member (Atg4D) is cleaved at DEVD(63)K by caspase-3 during apoptosis. Importantly, our studies suggest that native Atg4D is enzymatically inactive, but gains GABARAP-L1 priming/delipidation activity following caspase cleavage. Caspase-cleaved Atg4D is also highly cytotoxic; however, toxicity is not due to enhanced autophagy, but is mediated by a putative C-terminal BH3 domain, and is associated with transient recruitment of Atg4D to mitochondria.
authors.affiliation: Cell Biology Laboratories, Department of Biochemistry, University of Bristol, Bristol, UK.
authors.forename: Virginie M S
authors.initials: VM
authors.lastname: Betin
authors.forename: Jon D
authors.initials: JD
authors.lastname: Lane
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; C543490:ATG4D protein, human; D003546:Cysteine Endopeptidases