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      Orm family proteins mediate sphingolipid homeostasis

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          Abstract

          Despite the essential roles of sphingolipids as both structural components of membranes and critical signalling molecules, we have a limited understanding of how cells sense and regulate their levels. Here we reveal the function in sphingolipid metabolism of the ORM/ORMDL genes, a conserved gene family that includes ORMDL3, which has recently been identified as a potential risk factor for childhood asthma. Starting from an unbiased functional genomic approach, we identify Orm proteins as negative regulators of sphingolipid synthesis that form a conserved complex with serine palmitoyltransferase, the first and rate-limiting enzyme in sphingolipid production. We also define a regulatory pathway in which phosphorylation of Orm proteins relieves their inhibitory activity when sphingolipid production is disrupted. Changes in ORM gene expression or mutations to their phosphorylation sites cause dysregulation of sphingolipid metabolism. Our work identifies the Orm proteins as critical mediators of sphingolipid homeostasis and raises the possibility that sphingolipid misregulation contributes to the development of childhood asthma.

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          Most cited references43

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          Phosphate-binding tag, a new tool to visualize phosphorylated proteins.

          We introduce two methods for the visualization of phosphorylated proteins using alkoxide-bridged dinuclear metal (i.e. Zn(2+) or Mn(2+)) complexes as novel phosphate-binding tag (Phos-tag) molecules. Both Zn(2+)- and Mn(2+)-Phos-tag molecules preferentially capture phosphomonoester dianions bound to Ser, Thr, and Tyr residues. One method is based on an ECL system using biotin-pendant Zn(2+)-Phos-tag and horseradish peroxidase-conjugated streptavidin. We demonstrate the electroblotting analyses of protein phosphorylation status by the phosphate-selective ECL signals. Another method is based on the mobility shift of phosphorylated proteins in SDS-PAGE with polyacrylamide-bound Mn(2+)-Phos-tag. Phosphorylated proteins in the gel are visualized as slower migration bands compared with corresponding dephosphorylated proteins. We demonstrate the kinase and phosphatase assays by phosphate affinity electrophoresis (Mn(2+)-Phos-tag SDS-PAGE).
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            Molecular machinery for non-vesicular trafficking of ceramide.

            Synthesis and sorting of lipids are essential for membrane biogenesis; however, the mechanisms underlying the transport of membrane lipids remain little understood. Ceramide is synthesized at the endoplasmic reticulum and translocated to the Golgi compartment for conversion to sphingomyelin. The main pathway of ceramide transport to the Golgi is genetically impaired in a mammalian mutant cell line, LY-A. Here we identify CERT as the factor defective in LY-A cells. CERT, which is identical to a splicing variant of Goodpasture antigen-binding protein, is a cytoplasmic protein with a phosphatidylinositol-4-monophosphate-binding (PtdIns4P) domain and a putative domain for catalysing lipid transfer. In vitro assays show that this lipid-transfer-catalysing domain specifically extracts ceramide from phospholipid bilayers. CERT expressed in LY-A cells has an amino acid substitution that destroys its PtdIns4P-binding activity, thereby impairing its Golgi-targeting function. We conclude that CERT mediates the intracellular trafficking of ceramide in a non-vesicular manner.
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              The alliance of sphingosine-1-phosphate and its receptors in immunity.

              Sphingosine-1-phosphate (S1P) is a biologically active metabolite of plasma-membrane sphingolipids that is essential for immune-cell trafficking. Its concentration is increased in many inflammatory conditions, such as asthma and autoimmunity. Much of the immune function of S1P results from the engagement of a family of G-protein-coupled receptors (S1PR1-S1PR5). Recent findings on the role of S1P in immunosurveillance, the discovery of regulatory mechanisms in S1P-mediated immune-cell trafficking and new advances in understanding the mechanism by which S1P affects immune-cell function indicate that the alliance between S1P and its receptors has a fundamental role in immunity.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                1 January 2010
                25 February 2010
                25 August 2010
                : 463
                : 7284
                : 1048-1053
                Affiliations
                [1 ]Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 1700 4 th Street, San Francisco, California 94158, USA
                [2 ]Howard Hughes Medical Institute, University of California, San Francisco, 1700 4 th Street, San Francisco, California 94158, USA
                [3 ]Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, 1700 4 th Street, San Francisco, California 94158, USA
                [4 ]The California Institute for Quantitative Biomedical Research, University of California, San Francisco, 1700 4 th Street, San Francisco, California 94158, USA
                [5 ]Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
                [6 ]Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany
                [7 ]Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
                Author notes
                Correspondence to: Jonathan S. Weissman, weissman@ 123456cmp.ucsf.edu
                [†]

                Present address: Chemical and Systems Biology, Bio-X Program, Stanford University, Stanford, CA 94305, USA

                [‡]

                Present address: Department of Microbiology and Immunology, Baxter Laboratory in Genetic Pharmacology, Stanford University, 269 Campus Drive, Stanford, California 94305, USA

                Article
                nihpa166293
                10.1038/nature08787
                2877384
                20182505
                af4cd8d5-bf4f-4838-bed9-b24c35d06587

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                History
                Funding
                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: P50 GM073210-06 ||GM
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