Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

Abstract

IntroductionBioactive lipids, derived from metabolism of plasma membrane lipids, are important mediators of cellular communication in vertebrates. The appearance of bioactive lipid receptors in the vertebrate genomes (1) was coincident with the increased complexity of circulatory, immune, and nervous systems in evolution, suggesting that vertebrates began to use extracellular signaling of lipid mediators for the regulation of sophisticated organ systems. This Review will focus on the lysosphingolipid sphingosine-1-phosphate (S1P) and how the basic understanding of its metabolism, transport, and signaling functions has revealed its role in the pathogenesis of various diseases and allowed rational therapeutic strategies to advance. S1P metabolismSphingosine, the precursor substrate for the synthesis of S1P, is derived by the hydrolysis of ceramide during the sequential degradation of plasma membrane glycosphingolipids and sphingomyelin (refs. 2, 3, and Figure 1). Even though this occurs in various cell compartments, the bulk of sphingosine is generated by degradation in lysosomes. Indeed, the prominence of this lysosomal catabolism pathway is illustrated by the severity of the sphingolipidoses, a family of genetic disorders in which sphingolipid metabolites accumulate (4). The catabolically generated sphingosine is phosphorylated by either of two sphingosine kinases, SPHK1 and SPHK2, to produce S1P. SPHK1 is largely cytoplasmic and can acutely associate with the plasma membranes (5), phagosomes (6), and endosomal vesicles (7), whereas SPHK2 is present cytoplasmically but is predominately in the nucleus (8).While not strictly required for cellular viability (9), the formation of S1P is essential for organismal development (10). The viability of the single Sphk KO mice (10, 11) indicates that the isozymes can partially compensate for each other during development but have nonoverlapping functions. Once formed intracellularly, S1P takes one of three pathways (Figure 1). In one, the sphingosine moiety of S1P is recycled through ceramide synthesis after dephosphorylation by S1P-specific ER phosphatases, SGPP1 and SGPP2 (12, 13). In some mammalian cells, this pathway can account for greater than half of complex sphingolipid synthesis (14).In a second pathway, S1P is irreversibly degraded by S1P lyase, another ER-resident enzyme, into phosphoethanolamine and hexadecenal (15). This reaction facilitates transfer of substrate from the sphingolipid to the glycerolipid pathway via the conversion of hexadecenal by fatty aldehyde dehydrogenase to hexadecanoate, a precursor of palmitoyl-CoA (16), and by the utilization of phosphoethanolamine for phosphatidylethanolamine synthesis (17, 18).In the third pathway, intracellular S1P is released to the extracellular environment, a process that is highly efficient in rbc (19-21), platelets (22), and endothelial cells (19)(20)(21). A specific S1P transporter, SPNS2, is used in endothelial cells for S1P secretion (23). The precise secretion mechanism in rbc has not been established, but ...

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