title: Regulation of de novo sphingolipid biosynthesis by the ORMDL proteins and sphingosine kinase-1.
abstract: Sphingolipids are a diverse set of structurally and metabolically related lipids that have numerous functions in cell structure and signaling. The regulation of these lipids is critical for normal cell function and disregulation has been implicated in pathophysiological conditions such as cancer and inflammation. Here we examine control of the initiating, and rate limiting, enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). We find that de novo synthesis of sphingolipid is stimulated by a number of cancer chemotherapeutics, suggesting that this may be an important aspect of their cytotoxic effects. The three ORMDL proteins are membrane proteins of the endoplasmic reticulum related to the yeast Orm proteins, which have been shown to be homeostatic regulators of SPT. We find that the ORMDL proteins are also negative regulators of SPT that transmit cellular levels of sphingolipids to SPT. The three isoforms have redundant functions in this system. The sphingosine kinases (sphingosine kinase-1 and -2) phosphorylate both sphingosine, which is released from ceramide, but also dihydrosphingosine, which is in the de novo biosynthetic pathway. We therefore examined the role of the sphingosine kinases in controlling de novo ceramide biosynthesis and find that sphingosine kinase-1 does indeed act as a negative regulator of this pathway. This establishes that sphingosine kinase, in addition to producing sphingosine-1-phosphate as a signaling molecule, also consumes dihydrosphingosine to regulate ceramide synthesis. Our studies demonstrate that there are multiple mechanisms of regulation of SPT and suggest that these regulators are important mediators of cell stress responses.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Siow
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky Lexington, Lexington, KY 40536, USA; Department of Veterans Affairs Medical Center, Lexington, KY, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky Lexington, Lexington, KY 40536, USA; Department of Veterans Affairs Medical Center, Lexington, KY, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.affiliation: James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA. Electronic address: b0watt01@louisville.edu.
authors.forename: Binks
authors.initials: B
authors.lastname: Wattenberg
mesh_terms: D000818:Animals; D002518:Ceramides / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008246:Lysophospholipids / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics; D000099157:Sphingosine Kinase
chemical_list: D002518:Ceramides; D008246:Lysophospholipids; D008565:Membrane Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C005682:safingol
keywords: Ceramide; ORMDL; Serine palmitoyltransferase; Sphingolipid; Sphingosine-1-phosphate