Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles.
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.
Schneider-Brachert
Wulf
W
Institute of Medical Microbiology and Hygiene, University of Regensburg, D-93053, Germany.
Tchikov
Vladimir
V
Neumeyer
Jens
J
Jakob
Marten
M
Winoto-Morbach
Supandi
S
Held-Feindt
Janka
J
Heinrich
Michael
M
Merkel
Oliver
O
Ehrenschwender
Martin
M
Adam
Dieter
D
Mentlein
Rolf
R
Kabelitz
Dieter
D
Schütze
Stefan
S
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
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