Involvement of FAN in TNF-induced apoptosis.
TNF-alpha is a pleiotropic cytokine activating several signaling pathways initiated at distinct intracellular domains of the TNF receptors. Although the C-terminal region is believed to be responsible for apoptosis induction, the functions of more membrane-proximal domains, including the domain that couples to neutral sphingomyelinase activation, are not yet fully elucidated. The roles of this region and of the associated adapter protein FAN (factor associated with neutral SMase activation) in the cytotoxic response to TNF have been investigated. We have now shown that stable expression in human fibroblasts of a dominant negative form of FAN abrogates TNF-induced ceramide generation from sphingomyelin hydrolysis and reduces caspase processing, thus markedly inhibiting TNF-triggered apoptosis. However, the cytotoxic responses to daunorubicin and exogenous ceramide remain unaltered, as do the TNF-induced p42/p44 MAPK activation and CD54 expression. Fibroblasts from FAN-knockout mice also proved to be resistant to TNF toxicity. These findings highlight the previously unrecognized role of the adapter protein FAN in signaling cell death induction by TNF.
Ségui
B
B
Institut National de la Santé et de la Recherche Médicale U466, Centre Hospitalier Universitaire Rangueil, Toulouse, France.
Cuvillier
O
O
Adam-Klages
S
S
Garcia
V
V
Malagarie-Cazenave
S
S
Lévêque
S
S
Caspar-Bauguil
S
S
Coudert
J
J
Salvayre
R
R
Krönke
M
M
Levade
T
T
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D002478:Cells, Cultured / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005799:Genes, Dominant; D006801:Humans; D006868:Hydrolysis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015290:Second Messenger Systems; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology* / Q000633:toxicity; D020298:U937 Cells
D000590:Amino Acid Chloromethyl Ketones; D015703:Antigens, CD; D002518:Ceramides; D015853:Cysteine Proteinase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C102036:NSMAF protein, human; C491112:Nsmaf protein, mouse; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D018799:Intercellular Adhesion Molecule-1; D019950:Mitogen-Activated Protein Kinase 1; D013108:Sphingomyelin Phosphodiesterase; D020169:Caspases; D003630:Daunorubicin