TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase.
Sphingomyelinase (SMase) activation and ceramide generation have emerged as an important signaling pathway transducing diverse biological effects of cytokine receptors like p55 tumor necrosis factor (TNF) receptor or Fas. Here we describe the TNF-dependent activation of acid SMase (A-SMase) through the p55 TNF receptor-associated proteins TRADD and FADD. Overexpression of TRADD and FADD in 293 cells did not change basal activity of A-SMase but enhanced TNF-induced stimulation of A-SMase. Other TNF R55-associated proteins like TRAF2 and RIP, which were reported to mediate TNF R55-mediated activation of nuclear factor kappaB, did not affect activation of A-SMase. Caspase inhibitors markedly reduced A-SMase activity, suggesting the involvement of an ICE-like protease in TRADD/FADD-mediated activation of A-SMase. Overexpression of caspase-8/a (FLICE/MACH) or caspase-10/b (FLICE2) did not change A-SMase activity, suggesting that TRADD/FADD-mediated activation of A-SMase involves a yet to be defined caspase-like protease distinct from caspase-8/a or -10/b.
Schwandner
R
R
Institute of Immunology, Christian-Albrechts University of Kiel, Brunswiker Strasse 4, 24105 Kiel, Germany.
Wiegmann
K
K
Bernardo
K
K
Kreder
D
D
Kronke
M
M
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D053200:Fas-Associated Death Domain Protein; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007700:Kinetics; D011506:Proteins / Q000502:physiology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015843:Serpins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D011506:Proteins; D015843:Serpins; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D013108:Sphingomyelin Phosphodiesterase; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; C105036:interleukin 1beta-converting enzyme 2