title: Autophagy controls the kinetics and extent of mitochondrial apoptosis by regulating PUMA levels.
abstract: Macroautophagy is thought to protect against apoptosis; however, underlying mechanisms are poorly understood. We examined how autophagy affects canonical death receptor-induced mitochondrial outer membrane permeabilization (MOMP) and apoptosis. MOMP occurs at variable times in a population of cells, and this is delayed by autophagy. Additionally, autophagy leads to inefficient MOMP, after which some cells die through a slower process than typical apoptosis and, surprisingly, can recover and divide afterward. These effects are associated with p62/SQSTM1-dependent selective autophagy causing PUMA levels to be kept low through an indirect mechanism whereby autophagy affects constitutive levels of PUMA mRNA. PUMA depletion is sufficient to prevent the sensitization to apoptosis that occurs when autophagy is blocked. Autophagy can therefore control apoptosis via a key regulator that makes MOMP faster and more efficient, thus ensuring rapid completion of apoptosis. This identifies a molecular mechanism whereby cell-fate decisions can be determined by autophagy.
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Thorburn
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Andrysik
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Staskiewicz
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Gump
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Maycotte
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109-8059, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Espinosa
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: andrew.thorburn@ucdenver.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins