Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8.
We have recently shown that stimulation of TNF-R2 selectively enhances apoptosis induction by the death receptor TNF-R1. Here, we demonstrate that stimulation of CD30 or CD40 also leads to selective enhancement of TNF-R1-induced cell death. Enhancement of apoptosis was correlated with the depletion of endogenous TRAF2 within 1 to 6 hours. Selective prestimulation of TNF-R2 for several hours inhibited TNF-R2-induced activation of the anti-apoptotic NF-kappaB pathway up to 90% and dramatically enhanced apoptosis induction by this receptor. When both TNF-receptors were stimulated simultaneously, TNF-R1-induced NF-kappaB activation remained unaffected but TNF-R1-induced apoptosis was still significantly enhanced. Compared with FasL-induced cell death TNF-R1-induced activation of caspase-8 was significantly weaker and delayed. Costimulation or prestimulation of TNF-R2 enhanced caspase-8 processing. Life cell imaging and confocal microscopy revealed that both TNF-R1 and TNF-R2 recruited the anti-apoptotic factor cIAP1 in a TRAF2-dependent manner. Thus, TNF-R2 may compete with TNF-R1 for the recruitment of newly synthesized TRAF2-bound anti-apoptotic factors, thereby promoting the formation of a caspase-8-activating TNF-R1 complex. Hence, TNF-R2 triggering can interfere with TNF-R1-induced apoptosis by inhibition of NF-kappaB-dependent production of anti-apoptotic factors and by blocking the action of anti-apoptotic factors at the post-transcriptional level.
Fotin-Mleczek
Mariola
M
Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
Henkler
Frank
F
Samel
Dierk
D
Reichwein
Monica
M
Hausser
Angelika
A
Parmryd
Ingela
I
Scheurich
Peter
P
Schmid
Johannes A
JA
Wajant
Harald
H
D033962:Adaptor Protein Complex 2 / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics*; D005057:Eukaryotic Cells / Q000187:drug effects / Q000378:metabolism*; D053222:Fas Ligand Protein; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D017730:Ki-1 Antigen / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012208:Rhabdomyosarcoma; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; D018808:Transcription Factor AP-1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D033962:Adaptor Protein Complex 2; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D019013:CD40 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D017730:Ki-1 Antigen; D008562:Membrane Glycoproteins; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C494833:BIRC2 protein, human; D044767:Ubiquitin-Protein Ligases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases