TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced "acidic" sphingomyelin breakdown.
In this paper, we describe a phospholipid transmission pathway mediating tumor necrosis factor (TNF) activation of the nuclear transcription factor kappa B (NF-kappa B). Central to this TNF signaling route is the second messenger-like molecule ceramide, which is generated by sphingomyelin (SM) breakdown catalyzed by a sphingomyelinase (SMase). SMase activation is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-specific phospholipase C (PC-PLC). The functional coupling of these two C type phospholipases is revealed by D609, a selective inhibitor of PC-PLC. SMase itself, or SMase-inducing regimens such as exogenous PLC or synthetic DAGs, induces NF-kappa B activation at pH 5.0, suggesting the operation of an acidic SMase. A model is proposed in which a TNF-responsive PC-PLC via DAG couples to an acidic SMase, resulting in the generation of ceramide, which eventually triggers rapid induction of nuclear NF-kappa B activity.
Schütze
S
S
Institut für Medizinische Mikrobiologie und Hygiene, Technische Universität München, Germany.
Potthoff
K
K
Machleidt
T
T
Berkovic
D
D
Wiegmann
K
K
Krönke
M
M
D001483:Base Sequence; D002518:Ceramides / Q000494:pharmacology; D004075:Diglycerides / Q000494:pharmacology; D007526:Isoelectric Point; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010713:Phosphatidylcholines / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000502:physiology*
D002518:Ceramides; D004075:Diglycerides; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D010713:Phosphatidylcholines; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; D010738:Type C Phospholipases; D013108:Sphingomyelin Phosphodiesterase