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. Author manuscript; available in PMC: 2015 Feb 8.
Published in final edited form as: Nature. 2014 Jun 5;510(7503):58–67. doi: 10.1038/nature13475

Figure 2. Subcellular compartmentalization of sphingolipid metabolism.

Figure 2

De novo ceramide (Cer) synthesis takes place in the endoplasmic reticulum (ER). Cer is delivered by ceramide transport protein (CERT) or vesicular transport to the Golgi for synthesis of ceramide-1-phosphate (C1P) (by ceramide kinase, CERK), sphingomyelin (SM), and glucosylceramide (GluCer). Four-phosphate adaptor protein 2 (FAPP2) then transports GluCer to the trans-Golgi for biosynthesis of complex glycosphingolipids (GSLs). SM and GSLs are delivered to the plasma membrane by vesicular transport and C1P by a C1P-specific transfer protein (CPTP). For signalling at the plasma membrane, sphingomyelinase (SMase), ceramidase (CDase), and sphingosine kinases (SphK) produce the bioactive metabolites Cer, sphingosine (Sph) and sphingosine-1-phosphate (S1P), respectively. S1P is then transported across the membrane. Membrane sphingolipids are internalized by the endocytic pathway and in the lysosome they are degraded by acidic forms of SMase, glycosidase (GCase) and CDase. The Sph formed can be metabolized to glycerolipids after phosphorylation by SphKs (probably SphK1) and cleavage by S1P lyase (SPL) or reutilized for sphingolipid synthesis in the salvage pathway. In the nucleus, SphK2-produced S1P inhibits histone deacetylases.