Regulation of death receptor signaling and apoptosis by ceramide.

Ceramide has been shown to be critically involved in many forms of apoptosis including death triggered by receptors, e.g. CD95 or the tumor necrosis factor receptor, during development, or stress. Stress stimuli that employ ceramide to induce apoptosis include irradiation, heat shock or UV-light. The release of ceramide by these stimuli is mediated by the acid sphingomyelinase (ASM), an enzyme that is rapidly activated by many apoptotic stimuli. Studies on CD95 may serve as paradigm for the regulation of the ASM and showed that stimulation via this receptor triggers a rapid translocation of the ASM from intracellular stores onto the extracellular leaflet of the cell membrane. This seems to be mediated by a fusion of ASM containing vesicles with the cell membrane resulting in cell surface exposure of the ASM. Surface ASM releases ceramide from sphingomyelin that rapidly forms ceramide-enriched platforms in the cell membrane. These ceramide-enriched membrane domains serve as signaling platforms that cluster receptor molecules and transmit the apoptotic stimuli into the cell. Identical mechanisms seem to be operative in the signaling of apoptosis by other death receptors or stress suggesting a general role of ceramide-enriched platforms in apoptosis.