Seminars

Cells routinely synthesize ceramides in the endoplasmic reticulum (ER) as precursors for sphingolipids to form an impermeable plasma membrane. As ceramides are engaged in apoptotic pathways, cells would need to monitor their levels closely to avoid killing themselves during sphingolipid biosynthesis. How this is accomplished remains to be established. In mammals, the bulk of newly-synthesized ceramides is converted to sphingomyelin (SM) by a SM synthase (SMS) in the Golgi. Using a bioinformatics-based cloning strategy in yeast, we identified the Golgi-resident enzyme and discovered a multiplicity of SMS genes in the human genome. We found that one of the SMS family members, SMSr, is not a conventional synthase, but serves a role as ceramide sensor in the ER. Disrupting sensor function causes a rise in ER ceramides and their flow into mitochondria, triggering a mitochondrial pathway of apoptosis. SMSr itself is a target of the apoptotic machinery and loses its ability to suppress ceramide accumulation and cell death following caspase-mediated proteolysis. In sum, cells acquired SMSr as ceramide sensor to protect themselves against the inherent danger of sphingolipid biosynthesis. Unraveling the mechanism by which SMSr monitors and adjusts ER ceramide levels may disclose new avenues for controlling the fate of diseased cells.
＊＊References＊＊
Vacaru AM, et al. (2009) Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER. J. Cell Biol. 185:1013-1027