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.
|Number of pages||13|
|Journal||Advances in Biological Regulation|
|State||Published - Jan 1 2015|
Bibliographical noteFunding Information:
This work was supported by a grant from the Kentucky Lung Cancer Research Program , by a Fellowship from the James Graham Brown Cancer Center to D.S. and by funds from the James Graham Brown Cancer Center, from the Center for Environmental Genomics and Integrative Biology , and the Clinical and Translational Research Pilot program and Bridge Grant Program of the University of Louisville School of Medicine to B.W. A.J.M. and M.S. were supported by grants from the National Institutes of Health and Veterans Administration ( NIH 5P42ES007380-16 VA , BX00184-01 ), and work utilized resources from the Lexington Veterans Affairs Medical Center.
© 2014 Elsevier Ltd.
- Serine palmitoyltransferase
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Cancer Research