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Originally published In Press as doi:10.1074/jbc.M205211200 on June 24, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35642-35649, September 20, 2002
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Upstream of Growth and Differentiation Factor 1 (uog1), a Mammalian Homolog of the Yeast Longevity Assurance Gene 1 (LAG1), Regulates N-Stearoyl-sphinganine (C18-(Dihydro)ceramide) Synthesis in a Fumonisin B1-independent Manner in Mammalian Cells*

Krishnan VenkataramanDagger , Christian RiebelingDagger §, Jacques BodennecDagger , Howard Riezman||, Jeremy C. Allegood**, M. Cameron Sullards**, Alfred H. Merrill Jr.**, and Anthony H. FutermanDagger Dagger Dagger

From the Dagger  Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel, || Biozentrum, University of Basel, CH-4056 Basel, Switzerland, and ** School of Biology, Georgia Institute of Technology, Atlanta, Georgia 30332-0230

The longevity assurance gene (LAG1) and its homolog (LAC1) are required for acyl-CoA-dependent synthesis of ceramides containing very long acyl chain (e.g. C26) fatty acids in yeast, and a homolog of LAG1, ASC1, confers resistance in plants to fumonisin B1, an inhibitor of ceramide synthesis. To understand further the mechanism of regulation of ceramide synthesis, we now characterize a mammalian homolog of LAG1, upstream of growth and differentiation factor-1 (uog1). cDNA clones of uog1 were obtained from expression sequence-tagged clones and sub-cloned into a mammalian expression vector. Transient transfection of human embryonic kidney 293T cells with uog1 followed by metabolic labeling with [4,5-3H]sphinganine or L-3-[3H]serine demonstrated that uog1 conferred fumonisin B1 resistance with respect to the ability of the cells to continue to produce ceramide. Surprisingly, this ceramide was channeled into neutral glycosphingolipids but not into gangliosides. Electrospray tandem mass spectrometry confirmed the elevation in sphingolipids and revealed that the ceramides and neutral glycosphingolipids of uog1-transfected cells contain primarily stearic acid (C18), that this enrichment was further increased by FB1, and that the amount of stearic acid in sphingomyelin was also increased. UOG1 was localized to the endoplasmic reticulum, demonstrating that the fatty acid selectivity and the fumonisin B1 resistance are not due to a subcellular localization different from that found previously for ceramide synthase activity. Furthermore, in vitro assays of uog1-transfected cells demonstrated elevated ceramide synthase activity when stearoyl-CoA but not palmitoyl-CoA was used as substrate. We propose a role for UOG1 in regulating C18-ceramide (N-stearoyl-sphinganine) synthesis, and we note that not only is this the first case of ceramide formation in mammalian cells with such a high degree of fatty acid specificity, but also that the N-stearoyl-sphinganine produced by UOG1 most significantly impacts neutral glycosphingolipid synthesis.

* This work was supported in part by the Minerva Foundation, Munich, Germany (to A. H. F.) and by National Institutes of Health Grant GM46368 (to A. H. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a Research Training Network Fellowship HPRN-CT-2000-00077 from the European Union.

Supported by a Koschland Scholar award.

Dagger Dagger To whom correspondence should be addressed: Dept. of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-8-9342704; Fax: 972-8-9344112; E-mail: tony.futerman@weizmann.ac.il.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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