Lipid metabolic circuits revealed by lipid visualization

Ceramide, the common precursor of sphingolipids, is a potent bioactive molecule with anti proliferative properties. Cellular ceramide levels are tightly controlled by enzymes that catalyze its production and disposal. After being synthesized in the Endoplasmic Reticulum ceramide is transported to the Golgi complex where it is converted to sphingomyelin and glycosphingolipids by Golgi resident enzymes. Thus, Golgi localized ceramide metabolism contributes to regulate its levels, and, by doing so, its cellular effects. A variety of cell stresses have been demonstrated to increase ceramide levels by impacting on ceramide synthesis, while little is known about the regulation of ceramide conversion into more complex sphingolipids at the Golgi complex. Here, we investigated the response of Golgi localized ceramide metabolizing machinery to increasing amounts of ceramide. By following this approach we uncovered a signalling cascade involving the PKD, PtdIns4P, and the oncogene GOLPH3, whose triggering leads to inecient ceramide consumption at the Golgi complex and, thus to ceramide accumulation and consequent cellular effects.