Intracellular sphingosine releases calcium from lysosomes

  1. Doris Höglinger
  2. Per Haberkant
  3. Auxiliadora Aguilera-Romero
  4. Howard Riezman
  5. Forbes D Porter
  6. Frances M Platt
  7. Antony Galione
  8. Carsten Schultz  Is a corresponding author
  1. European Molecular Biology Laboratory, Germany
  2. University of Geneva, Switzerland
  3. National Institutes of Health, United States
  4. University of Oxford, United Kingdom

Abstract

To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in endosomes/lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.

Article and author information

Author details

  1. Doris Höglinger

    Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Per Haberkant

    Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Auxiliadora Aguilera-Romero

    Department of Biochemistry, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Howard Riezman

    Department of Biochemistry, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Forbes D Porter

    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Frances M Platt

    Department of Pharmacology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Antony Galione

    Department of Pharmacology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Carsten Schultz

    Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany
    For correspondence
    schultz@embl.de
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University School of Medicine, United States

Version history

  1. Received: August 4, 2015
  2. Accepted: November 27, 2015
  3. Accepted Manuscript published: November 27, 2015 (version 1)
  4. Version of Record published: January 27, 2016 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Doris Höglinger
  2. Per Haberkant
  3. Auxiliadora Aguilera-Romero
  4. Howard Riezman
  5. Forbes D Porter
  6. Frances M Platt
  7. Antony Galione
  8. Carsten Schultz
(2015)
Intracellular sphingosine releases calcium from lysosomes
eLife 4:e10616.
https://doi.org/10.7554/eLife.10616

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https://doi.org/10.7554/eLife.10616

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