title: The Autophagy Machinery Controls Cell Death Switching between Apoptosis and Necroptosis.
abstract: Although autophagy controls cell death and survival, underlying mechanisms are poorly understood, and it is unknown whether autophagy affects only whether or not cells die or also controls other aspects of programmed cell death. MAP3K7 is a tumor suppressor gene associated with poor disease-free survival in prostate cancer. Here, we report that Map3k7 deletion in mouse prostate cells sensitizes to cell death by TRAIL (TNF-related apoptosis-inducing ligand). Surprisingly, this death occurs primarily through necroptosis, not apoptosis, due to assembly of the necrosome in association with the autophagy machinery, mediated by p62/SQSTM1 recruitment of RIPK1. The mechanism of cell death switches to apoptosis if p62-dependent recruitment of the necrosome to the autophagy machinery is blocked. These data show that the autophagy machinery can control the mechanism of programmed cell death by serving as a scaffold rather than by degrading cargo.
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Goodall
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Brent E
authors.initials: BE
authors.lastname: Fitzwalter
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Shadi
authors.initials: S
authors.lastname: Zahedi
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA; Department of Molecular and Cellular Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodriguez
authors.affiliation: Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Mulcahy-Levy
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO 80045, USA. Electronic address: andrew.thorburn@ucdenver.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D009336:Necrosis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000071187:Autophagy-Related Protein 5; D020930:MAP Kinase Kinase Kinases; D016601:RNA-Binding Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D000099151:MAP Kinase Kinase Kinase 7; C495773:Atg5 protein, mouse; C118585:P62 protein, human; C506251:Ripk1 protein, mouse