Lipid Metabolism

ReseaRch highlights

Deletion of Sac1 increases levels of sphingolipid precursors, but, as the Orm proteins and Sac1 bind to serine palmitoyltransferase independently, the authors suggest that they negatively regulate its function by distinct mechanisms. The identification of several phosphorylated Orm species, and the use of the serine palmitoyltransferase inhibitor myriocin, provided further mechanistic clues. Comparisons of growth rate and metabolite levels between Orm1- and Orm2-deleted and wild-type yeast, with or without lipid metabOlism myriocin, indicated that cells use progressive inactivation of Orm1 and Orm2 to maintain sphingolipid output as serine palmitoyltransferase Orm SPOTS demand activity is inhibited. Inactivation of Strongly conserved but of unknown of double mutants to identify path- Orm proteins correlates with their function, orosomucoid (Orm) fam- ways in which the individual mutant phosphorylation, which seems to the SPOTS ily proteins (encoded by Orm and genes function. As the Orm family alter the higher-order assembly of complex Ormdl genes) are implicated in the are ER proteins, the authors used the SPOTS complex. Phosphomutant dynamically development of childhood asthma. the profiles of mutants from a study Orm1 and Orm2 were able to interact coordinates For example, single nucleotide of ER biology, and identified a link with each other and with serine polymorphisms that are associated between Orm genes and Lcb1 and palmitoyltransferase, but blocked the localization with increased expression of Ormdl Lcb2. The overexpression of Orm1 the normal regulation of SPOTS and activity of genes confer a heightened risk of the or Orm2 produced profiles that cor- oligomerization and disrupted sphingolipid disease. Now, a global approach to related with decreased Lcb1 and Lcb2 sphingolipid homeostasis. In the pres- metabolism characterizing Orm gene function expression, whereas the profile from ence of myriocin, the suborganellar identifies Orm proteins as homeo- the deletion of Orm2 was inverted localization of labelled Orm2 was enzymes static regulators of sphingolipid by comparison. This suggests that also altered. biosynthesis, thus implicating Orm proteins negatively regulate The authors suggest that the sphingolipid metabolism in the sphingolipid biosynthesis, which SPOTS complex dynamically coordi- pathogenesis of asthma. was confirmed by global lipidomic nates the localization and activity of Sphingolipids are a large family of analysis: deletion of Orm1 and Orm2 sphingolipid metabolism enzymes in lipids with complex signalling func- causes higher flux throughout the response to cellular demand. Now the tions. Their synthesis begins in the sphingolipid biosynthetic pathway. focus turns to whether misregulation endoplasmic reticulum (ER), where But how might Orm proteins of this axis can directly cause asthma. the rate-limiting step is catalysed inhibit sphingolipid biosynthesis? Emma Leah, Online Editor, by serine palmitoyltransferase. This A novel protein complex, the serine Lipidomics Gateway enzyme is encoded in yeast by Lcb1 palmitoyltransferase, Orm1 and and Lcb2, and joins the sphingolipid Orm2, Tsc3 and Sac1 (SPOTS) com- Original research paper Breslow, D. et al. precursors fatty acids and L-serine. plex, was identified using binding Orm family proteins mediate sphingolipid homeostasis. Nature, 463, 1048–1053 (2010) Breslow et al. investigated Orm assays. Whereas Tsc3 is an activator Further reading Hannun, Y. A. & Obeid, L. M. function in the yeast Saccharomyces of serine palmitoyltransferase, Sac1 Principles of bioactive lipid signalling: lessons cerevisiae, using a genetic analysis is a phosphoinositide phosphatase from sphingolipids. Nature Rev. Mol. Cell Biol. 9, 139–150 (2008) that compares the phenotypic profiles involved in ER and Golgi trafficking.