CD95 signaling via ceramide-rich membrane rafts

Clustering seems to be employed by many receptors for transmembrane signali ng. Here, we show that acid sphingomyelinase (ASM)-released ceramide is ess ential for clustering of CD95, In vitro and in vivo, extracellularly orient ated ceramide, released upon CD95-triggered translocation of ASM to the pla sma membrane outer surface, enabled clustering of CD95 in sphingo lipid-ric h membrane rafts and apoptosis induction. Whereas ASM deficiency, destructi on of rafts, or neutralization of surface ceramide prevented CD95 clusterin g and apoptosis, natural ceramide only rescued ASM-deficient cells. The dat a suggest CD95-mediated clustering by ceramide is prerequisite for signalin g and death.