TNFR80-dependent enhancement of TNFR60-induced cell death is mediated by TNFR-associated factor 2 and is specific for TNFR60.
Costimulation of TNFR80 can strongly enhance TNFR60-induced cell death. In this study, we show that this enhancement is TNFR60 selective, as neither TNF-related apoptosis-inducing ligand/Apo2 ligand-, Apo1/Fas-, ceramide-, nor daunorubicin-mediated cell death was affected by costimulation of TNFR80. We further demonstrate that TNFR-associated factor 2 (TRAF2) is critically involved in both negative and positive regulation of TNF-induced cell death. Overexpression of TRAF2 and of a TRAF2 mutant, deficient in nuclear factor-kappaB activation, selectively desensitized and enhanced, respectively, TNFR60-induced cell death in HeLa cells. However, upon costimulation of TNFR80, which mediates activation of nuclear factor-kappaB and the c-Jun amino-terminal kinase via TRAF2, TNF-induced cell death is drastically enhanced in parental and TRAF2-transfected, but not in TRAF2 (87-501)-transfected cells. These data point to a critical role of TRAF2 in the apoptotic TNFR cross talk, whereby the TNFR80-dependent enhancement of TNFR60-induced cell death is due to TNFR80-mediated negative regulation of TRAF2 function(s). An interference with TRAF2 function was confirmed independently by analysis of c-Jun amino-terminal kinase activation via TNFR60 upon prestimulation of TNFR80. We propose that the apoptotic TNFR cross talk is based on TNFR80-mediated abrogation of antiapoptotic TRAF2-dependent signaling pathways initiated by TNFR60, but not Apo1/Fas or the apoptotic TNF-related apoptosis-inducing ligand receptors.
Weiss
T
T
Institute of Cell Biology and Immunology, University of Stuttgart, Germany.
Grell
M
M
Siemienski
K
K
Mühlenbeck
F
F
Dürkop
H
H
Pfizenmaier
K
K
Scheurich
P
P
Wajant
H
H
D000276:Adjuvants, Immunologic / Q000502:physiology*; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002518:Ceramides / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006367:HeLa Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D002518:Ceramides; D008024:Ligands; D008562:Membrane Glycoproteins; C101338:PSMD2 protein, human; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D003630:Daunorubicin