title: Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles.
abstract: The molecular regulation of the recruitment of initial signaling complexes at the TNF-R1 is poorly defined. We demonstrate here that within minutes internalized TNF-R1 (TNF receptosomes) recruits TRADD, FADD, and caspase-8 to establish the "death-inducing signaling complex" (DISC). In addition, we identified the TNF-R1 internalization domain (TRID) required for receptor endocytosis and provide evidence that TNF-R1 internalization, DISC formation, and apoptosis are inseparable events. Analyzing cell lines expressing an internalization-deficient receptor (TNF-R1 DeltaTRID) revealed that recruitment of RIP-1 and TRAF-2 to TNF-R1 occurred at the level of the plasma membrane. In contrast, aggregation of TRADD, FADD, and caspase-8 to establish the TNF-R1-associated DISC is critically dependent on receptor endocytosis. Furthermore, fusion of TNF receptosomes with trans-Golgi vesicles results in activation of acid sphingomyelinase and cathepsin D. Thus, TNF receptosomes establish the different TNF signaling pathways by compartmentalization of plasma membrane-derived endocytic vesicles harboring the TNF-R1-associated DISC.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Regensburg, D-93053, Germany.
authors.forename: Wulf
authors.initials: W
authors.lastname: Schneider-Brachert
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tchikov
authors.forename: Jens
authors.initials: J
authors.lastname: Neumeyer
authors.forename: Marten
authors.initials: M
authors.lastname: Jakob
authors.forename: Supandi
authors.initials: S
authors.lastname: Winoto-Morbach
authors.forename: Janka
authors.initials: J
authors.lastname: Held-Feindt
authors.forename: Michael
authors.initials: M
authors.lastname: Heinrich
authors.forename: Oliver
authors.initials: O
authors.lastname: Merkel
authors.forename: Martin
authors.initials: M
authors.lastname: Ehrenschwender
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
authors.forename: Rolf
authors.initials: R
authors.lastname: Mentlein
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000502:physiology* / Q000648:ultrastructure; D053200:Fas-Associated Death Domain Protein; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins; D006056:Golgi Apparatus / Q000502:physiology / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008854:Microscopy, Electron; D041681:NIH 3T3 Cells; D011233:Precipitin Tests; D011506:Proteins / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism* / Q000648:ultrastructure; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000502:physiology*; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; D053319:Tumor Necrosis Factor Decoy Receptors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D020298:U937 Cells
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D058851:GPI-Linked Proteins; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D047888:Receptors, Tumor Necrosis Factor, Type I; D053199:TNF Receptor-Associated Death Domain Protein; D047990:TNF Receptor-Associated Factor 1; C108661:TNFRSF10C protein, human; C481226:Tradd protein, mouse; D053319:Tumor Necrosis Factor Decoy Receptors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases