The organizing potential of sphingolipids in intracellular membrane transport

Eukaryotes are characterized by endomembranes that are connected by vesicul ar transport along secretory and endocytic pathways. The compositional diff erences between the various cellular membranes are maintained by sorting ev ents, and it has long been believed that sorting is based solely on protein -protein interactions. However, the central sorting station along the secre tory pathway is the Golgi apparatus, and this is the site of synthesis of t he sphingolipids. Sphingolipids are essential for eukaryotic life, and this review ascribes the sorting power of the Golgi to its capability to act as a distillation apparatus for sphingolipids and cholesterol. As Golgi ciste rnae mature, ongoing sphingolipid synthesis attracts endoplasmic reticulum- derived cholesterol and drives a fluid-fluid lipid phase separation that se gregates sphingolipids and sterols from unsaturated glycerolipids into late ral domains. While sphingolipid domains move forward, unsaturated glyceroli pids are retrieved by recycling vesicles budding from the sphingolipid-poor environment. We hypothesize that by this mechanism, the composition of the sphingolipid domains, and the surrounding membrane changes along the cis-t rans axis. At the same time the membrane thickens. These features are recog nized by a number of membrane proteins that as a consequence of partitionin g between domain and environment follow the domains but can enter recycling vesicles at any stage of the pathway. The interplay between protein- and l ipid-mediated sorting is discussed.