title: Death-receptor activation halts clathrin-dependent endocytosis.
abstract: Endocytosis is crucial for various aspects of cell homeostasis. Here, we show that proapoptotic death receptors (DRs) trigger selective destruction of the clathrin-dependent endocytosis machinery. DR stimulation induced rapid, caspase-mediated cleavage of key clathrin-pathway components, halting cellular uptake of the classic cargo protein transferrin. DR-proximal initiator caspases cleaved the clathrin adaptor subunit AP2alpha between functionally distinct domains, whereas effector caspases processed clathrin's heavy chain. DR5 underwent ligand-induced, clathrin-mediated endocytosis, suggesting that internalization of DR signaling complexes facilitates clathrin-pathway targeting by caspases. An endocytosis-blocking, temperature-sensitive dynamin-1 mutant attenuated DR internalization, enhanced caspase stimulation downstream of DRs, and increased apoptosis. Thus, DR-triggered caspase activity disrupts clathrin-dependent endocytosis, leading to amplification of programmed cell death.
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: David A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Peden
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Varfolomeev
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Klara
authors.initials: K
authors.lastname: Totpal
authors.affiliation: Cell Microscopy Center, Department of Cell Biology and Institute for Biomembranes, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.
authors.forename: Ann M
authors.initials: AM
authors.lastname: De Mazière
authors.affiliation: Cell Microscopy Center, Department of Cell Biology and Institute for Biomembranes, University Medical Center Utrecht, 3584CX, Utrecht, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Klumperman
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: David
authors.initials: D
authors.lastname: Arnott
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Pham
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and aa@gene.com scheller@gene.com.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scheller
authors.affiliation: *Departments of Research Administration, Molecular Oncology, and Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080; and aa@gene.com scheller@gene.com.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D016253:Microscopy, Immunoelectron; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D002966:Clathrin; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases