Siow Deanna, Sunkara Manjula, Morris Andrew, Wattenberg Binks
James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA.
Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky Lexington, Lexington, KY 40536, USA; Department of Veterans Affairs Medical Center, Lexington, KY, USA.
Adv Biol Regul. 2015 Jan;57:42-54. doi: 10.1016/j.jbior.2014.09.002. Epub 2014 Sep 17.
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.
鞘脂是一组结构和代谢相关的多样化脂质，在细胞结构和信号传导中具有多种功能。这些脂质的调节对于正常细胞功能至关重要，而调节异常与癌症和炎症等病理生理状况有关。在这里，我们研究了鞘脂生物合成起始和限速酶——丝氨酸棕榈酰转移酶（SPT）的调控。我们发现许多癌症化疗药物会刺激鞘脂的从头合成，这表明这可能是它们细胞毒性作用的一个重要方面。三种ORMDL蛋白是与酵母Orm蛋白相关的内质网膜蛋白，已被证明是SPT的稳态调节因子。我们发现ORMDL蛋白也是SPT的负调节因子，可将细胞内鞘脂水平传递给SPT。这三种同工型在该系统中具有冗余功能。鞘氨醇激酶（鞘氨醇激酶-1和-2）可磷酸化从神经酰胺释放的鞘氨醇以及从头生物合成途径中的二氢鞘氨醇。因此，我们研究了鞘氨醇激酶在控制神经酰胺从头生物合成中的作用，发现鞘氨醇激酶-1确实是该途径的负调节因子。这表明鞘氨醇激酶除了产生作为信号分子的鞘氨醇-1-磷酸外，还消耗二氢鞘氨醇来调节神经酰胺合成。我们的研究表明，SPT存在多种调节机制，并且这些调节因子是细胞应激反应的重要介质。
