Sphingosine-1-phosphate rheostat (ceramide -> sphingosine -> S1P -> exit)

The "sphingolipid rheostat" is the interconversion of the bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P), whose relative levels set the balance between cell death/growth arrest (ceramide, sphingosine) and survival/proliferation/migration (S1P). Ceramide is hydrolysed to sphingosine plus a free fatty acid by ceramidases: the alkaline ceramidases ACER1 (ER, skin), ACER2 (Golgi) and ACER3 (ER/Golgi, broadly expressed) act here, complementing the acid (ASAH1, lysosomal) and neutral (ASAH2) ceramidases curated elsewhere. Sphingosine is then phosphorylated with ATP to S1P by the sphingosine kinases SPHK1 (cytosolic, translocating to the plasma membrane; pro-survival/pro-inflammatory) and SPHK2 (nuclear/ER/mitochondrial; its nuclear S1P inhibits HDAC1/2). S1P has two fates. It is reversibly dephosphorylated back to sphingosine by the ER S1P phosphatases SGPP1 and SGPP2 (recycling sphingosine for re-acylation to ceramide and damping S1P signalling), or it is IRREVERSIBLY cleaved by the PLP-dependent ER lyase SGPL1 to (2E)-hexadecenal + phosphoethanolamine — the sole exit from sphingolipid metabolism, which also builds the tissue-to-blood S1P gradient that governs lymphocyte egress. Inherited defects illustrate the pathway's importance: ACER3 childhood leukodystrophy and SGPL1 sphingosine-phosphate-lyase insufficiency syndrome (steroid-resistant nephrotic syndrome with adrenal insufficiency); the S1P axis is also the target of the immunomodulator fingolimod (FTY720, an SPHK2 substrate).