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Orm family proteins mediate sphingolipid homeostasis

Author

Listed:
  • David K. Breslow

    (Department of Cellular and Molecular Pharmacology,
    Howard Hughes Medical Institute,
    Graduate Program in Chemistry and Chemical Biology,
    The California Institute for Quantitative Biomedical Research, University of California, San Francisco, 1700 4th Street, San Francisco, California 94158, USA)

  • Sean R. Collins

    (Department of Cellular and Molecular Pharmacology,
    Howard Hughes Medical Institute,
    The California Institute for Quantitative Biomedical Research, University of California, San Francisco, 1700 4th Street, San Francisco, California 94158, USA
    Present addresses: Chemical and Systems Biology, Bio-X Program, Stanford University, Stanford, California 94305, USA (S.R.C.); Department of Microbiology and Immunology, Baxter Laboratory in Genetic Pharmacology, Stanford University, 269 Campus Drive, Stanford, California 94305, USA (B.B.).)

  • Bernd Bodenmiller

    (Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
    Present addresses: Chemical and Systems Biology, Bio-X Program, Stanford University, Stanford, California 94305, USA (S.R.C.); Department of Microbiology and Immunology, Baxter Laboratory in Genetic Pharmacology, Stanford University, 269 Campus Drive, Stanford, California 94305, USA (B.B.).)

  • Ruedi Aebersold

    (Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland
    Institute for Systems Biology, Seattle, Washington 98103, USA
    Faculty of Science, University of Zurich)

  • Kai Simons

    (Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany)

  • Andrej Shevchenko

    (Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany)

  • Christer S. Ejsing

    (Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany
    University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark)

  • Jonathan S. Weissman

    (Department of Cellular and Molecular Pharmacology,
    Howard Hughes Medical Institute,
    The California Institute for Quantitative Biomedical Research, University of California, San Francisco, 1700 4th Street, San Francisco, California 94158, USA)

Abstract

Despite the essential roles of sphingolipids both as 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 genes (known as ORMDL genes in humans)—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 in Saccharomyces cerevisiae, 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.

Suggested Citation

  • David K. Breslow & Sean R. Collins & Bernd Bodenmiller & Ruedi Aebersold & Kai Simons & Andrej Shevchenko & Christer S. Ejsing & Jonathan S. Weissman, 2010. "Orm family proteins mediate sphingolipid homeostasis," Nature, Nature, vol. 463(7284), pages 1048-1053, February.
  • Handle: RePEc:nat:nature:v:463:y:2010:i:7284:d:10.1038_nature08787
    DOI: 10.1038/nature08787
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    Cited by:

    1. Tian Xie & Peng Liu & Xinyue Wu & Feitong Dong & Zike Zhang & Jian Yue & Usha Mahawar & Faheem Farooq & Hisham Vohra & Qi Fang & Wenchen Liu & Binks W. Wattenberg & Xin Gong, 2023. "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Jan-Hannes Schäfer & Carolin Körner & Bianca M. Esch & Sergej Limar & Kristian Parey & Stefan Walter & Dovile Januliene & Arne Moeller & Florian Fröhlich, 2023. "Structure of the ceramide-bound SPOTS complex," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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