Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway

  1. Tolulope Sokoya
  2. Jan Parolek
  3. Mads Møller Foged
  4. Dmytro I Danylchuk
  5. Manuel Bozan
  6. Bingshati Sarkar
  7. Angelika Hilderink
  8. Michael Philippi
  9. Lorenzo D Botto
  10. Paulien A Terhal
  11. Outi Mäkitie
  12. Jacob Piehler
  13. Yeongho Kim
  14. Christopher G Burd
  15. Andrey S Klymchenko
  16. Kenji Maeda
  17. Joost CM Holthuis  Is a corresponding author
  1. Osnabrück University, Germany
  2. Danish Cancer Society, Denmark
  3. Université de Strasbourg, UMR 7021, CNRS, France
  4. University of Utah, United States
  5. Utrecht University, Netherlands
  6. University of Helsinki, Finland
  7. Yale University, United States

Abstract

Sphingomyelin is a dominant sphingolipid in mammalian cells. Its production in the trans-Golgi traps cholesterol synthesized in the ER to promote formation of a sphingomyelin/sterol gradient along the secretory pathway. This gradient marks a fundamental transition in physical membrane properties that help specify organelle identify and function. We previously identified mutations in sphingomyelin synthase SMS2 that cause osteoporosis and skeletal dysplasia. Here we show that SMS2 variants linked to the most severe bone phenotypes retain full enzymatic activity but fail to leave the ER owing to a defective autonomous ER export signal. Cells harboring pathogenic SMS2 variants accumulate sphingomyelin in the ER and display a disrupted transbilayer sphingomyelin asymmetry. These aberrant sphingomyelin distributions also occur in patient-derived fibroblasts and are accompanied by imbalances in cholesterol organization, glycerophospholipid profiles and lipid order in the secretory pathway. We postulate that pathogenic SMS2 variants undermine the capacity of osteogenic cells to uphold nonrandom lipid distributions that are critical for their bone forming activity.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file. Source Data files have been provided for Figures 2-4, 7-9 and Appendix 1 - figure 3.

Article and author information

Author details

  1. Tolulope Sokoya

    Department of Biology and Center of Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Jan Parolek

    Department of Biology and Center of Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Mads Møller Foged

    Center for Autophagy, Recycling and Disease, Danish Cancer Society, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  4. Dmytro I Danylchuk

    Laboratoire de Bioimagerie et Pathologies, Université de Strasbourg, UMR 7021, CNRS, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Manuel Bozan

    Department of Biology and Center of Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8426-369X
  6. Bingshati Sarkar

    Department of Biology and Center of Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Angelika Hilderink

    Department of Biology and Center of Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Michael Philippi

    Department of Biology and Center of Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Lorenzo D Botto

    Department of Pediatrics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Paulien A Terhal

    Department of Genetics, Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Outi Mäkitie

    Children's Hospital, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4547-001X
  12. Jacob Piehler

    Department of Biology and Center of Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2143-2270
  13. Yeongho Kim

    Department of Cell Biology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1477-925X
  14. Christopher G Burd

    Department of Cell Biology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1831-8706
  15. Andrey S Klymchenko

    Laboratoire de Bioimagerie et Pathologies, Université de Strasbourg, UMR 7021, CNRS, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Kenji Maeda

    Center for Autophagy, Recycling and Disease, Danish Cancer Society, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  17. Joost CM Holthuis

    Department of Biology and Center of Cellular Nanoanalytics, Osnabrück University, Osnabrück, Germany
    For correspondence
    jholthuis@uni-osnabrueck.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8912-1586

Funding

Deutsche Forschungsgemeinschaft (SFB944-P14)

  • Joost CM Holthuis

Deutsche Forschungsgemeinschaft (HO3539/1-1)

  • Joost CM Holthuis

Deutsche Forschungsgemeinschaft (SFB944-P8)

  • Jacob Piehler

National Institutes of Health (R35 GM144096)

  • Christopher G Burd

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Arun Radhakrishnan, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: April 6, 2022
  2. Accepted: September 13, 2022
  3. Accepted Manuscript published: September 14, 2022 (version 1)

Copyright

© 2022, Sokoya et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Tolulope Sokoya
  2. Jan Parolek
  3. Mads Møller Foged
  4. Dmytro I Danylchuk
  5. Manuel Bozan
  6. Bingshati Sarkar
  7. Angelika Hilderink
  8. Michael Philippi
  9. Lorenzo D Botto
  10. Paulien A Terhal
  11. Outi Mäkitie
  12. Jacob Piehler
  13. Yeongho Kim
  14. Christopher G Burd
  15. Andrey S Klymchenko
  16. Kenji Maeda
  17. Joost CM Holthuis
(2022)
Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
eLife 11:e79278.
https://doi.org/10.7554/eLife.79278

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