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Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis

Author

Listed:
  • Tian Xie

    (Southern University of Science and Technology)

  • Peng Liu

    (Southern University of Science and Technology)

  • Xinyue Wu

    (Southern University of Science and Technology)

  • Feitong Dong

    (Southern University of Science and Technology)

  • Zike Zhang

    (Southern University of Science and Technology)

  • Jian Yue

    (Southern University of Science and Technology)

  • Usha Mahawar

    (Virginia Commonwealth University School of Medicine)

  • Faheem Farooq

    (Virginia Commonwealth University School of Medicine)

  • Hisham Vohra

    (Virginia Commonwealth University School of Medicine)

  • Qi Fang

    (Southern University of Science and Technology)

  • Wenchen Liu

    (Southern University of Science and Technology)

  • Binks W. Wattenberg

    (Virginia Commonwealth University School of Medicine)

  • Xin Gong

    (Southern University of Science and Technology)

Abstract

The ORM/ORMDL family proteins function as regulatory subunits of the serine palmitoyltransferase (SPT) complex, which is the initiating and rate-limiting enzyme in sphingolipid biosynthesis. This complex is tightly regulated by cellular sphingolipid levels, but the sphingolipid sensing mechanism is unknown. Here we show that purified human SPT-ORMDL complexes are inhibited by the central sphingolipid metabolite ceramide. We have solved the cryo-EM structure of the SPT-ORMDL3 complex in a ceramide-bound state. Structure-guided mutational analyses reveal the essential function of this ceramide binding site for the suppression of SPT activity. Structural studies indicate that ceramide can induce and lock the N-terminus of ORMDL3 into an inhibitory conformation. Furthermore, we demonstrate that childhood amyotrophic lateral sclerosis (ALS) variants in the SPTLC1 subunit cause impaired ceramide sensing in the SPT-ORMDL3 mutants. Our work elucidates the molecular basis of ceramide sensing by the SPT-ORMDL complex for establishing sphingolipid homeostasis and indicates an important role of impaired ceramide sensing in disease development.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39274-y
    DOI: 10.1038/s41467-023-39274-y
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    References listed on IDEAS

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    1. 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.
    2. Miriam F. Moffatt & Michael Kabesch & Liming Liang & Anna L. Dixon & David Strachan & Simon Heath & Martin Depner & Andrea von Berg & Albrecht Bufe & Ernst Rietschel & Andrea Heinzmann & Burkard Simma, 2007. "Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma," Nature, Nature, vol. 448(7152), pages 470-473, July.
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    1. 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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