Sphingolipids in the eukaryotic stress response

The metabolism of sphingolipids is now appreciated to be highly regulated. The diverse enzymes of sphingolipid metabolism regulate levels of several candidate intra- and intercellular messengers including ceramide, sphingosine, and sphingosine-1 -phosphate. In mammalian cells as well as in S. cerevisiae, ceramide accumulates in response to a diverse set of extracellular stimuli and stress agents, including cytokines (such as tumor necrosis factor a), heat, or chemotherapeutic agents. The modulation of intracellular levels of ceramide in turn regulates the responses of cells to stress; including effects on cell senescence, cell cycle progression, and apoptosis. Also, studies in S. cerevisiae support an essential role for sphingolipids in the response of this organism to heat and possibly other Stressors. Finally, evolving mechanistic insight supports a role for these pathways in stress responses. As an example, the direct effects of glutathione (GSH) on neutral sphingomyelinase illustrate an important mechanism in regulating ceramide formation in response to oxidative stress and other stimuli that modulate intracellular levels of glutathione. The study of sphingolipid metabolism and function is providing novel insight into mechanisms of stress response and growth regulation.