Sphingolipid transport: rafts and translocators

Until some 15 years ago, sphingolipids were generally believed to protect the cell surface against harmful factors in the environment by forming a mechanically stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer. Furthermore, complex glycosphingolipids were found to be involved in specific functions like recognition and signaling (1). Whereas the first feature would depend on physical properties of the sphingolipids, the signaling functions involve specific interactions of the complex glycan structures on the glycosphingolipids with similar lipids on neighboring cells or with proteins. Since then, two findings have revolutionized the field. (i) Simple sphingolipid metabolites, like ceramide and sphingosine 1-phosphate, have been found to be important mediators in signaling cascades of apoptosis, proliferation, and stress responses (reviews by Hannun and Obeid (66) and Spiegel and Milstien (67)). (ii) It has been realized that ceramidebased lipids self-aggregate in cellular membranes to form a separate phase that is less fluid (liquid-ordered) than the bulk liquid-disordered phospholipids based on diacylglycerol. Sphingolipid-based microdomains or “rafts” were originally proposed to sort membrane proteins along the cellular pathways of membrane transport (2). Presently, most excitement focuses on their organizing functions in signal transduction (3). Sphingolipids are synthesized in the ER 1 and the Golgi but are enriched in plasma membrane and endosomes where they perform many of their functions. Thus, sphingolipids travel between organelles. Transport occurs via transport vesicles and via monomeric transport through the cytosol. Furthermore, some sphingolipids efficiently translocate across cellular membranes. That transport is not random is clear from the heterogeneous distribution of sphingolipids over the cell; sphingolipids are virtually absent from mitochondria and the ER but constitute 20 –35 mol % of the plasma membrane lipids (Table I). Furthermore, signaling pools of sphingolipids do not freely mix with pools of biosynthesis and degradation (reviews by Hannun and Obeid (66), Merrill (68), and Spiegel and Milstien (67)). The specificity in sphingolipid transport is the topic of the present review.