UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling

  1. Stéphanie Torrino  Is a corresponding author
  2. Victor Tiroille
  3. Bastien Dolfi
  4. Maeva Dufies
  5. Charlotte Hinault
  6. Laurent Bonesso
  7. Sonia Dagnino
  8. Jennifer Uhler
  9. Marie Irondelle
  10. Anne-sophie Gay
  11. Lucile Fleuriot
  12. Delphine Debayle
  13. Sandra Lacas-Gervais
  14. Mireille Cormont
  15. Thomas Bertero
  16. Frederic Bost
  17. Jerome Gilleron
  18. Stephan Clavel  Is a corresponding author
  1. IPMC, France
  2. C3M, France
  3. Centre Scientifique de Monaco, Monaco
  4. CHU, France
  5. Imperial College London, United Kingdom
  6. University of Gothenburg, Sweden
  7. UFR Sciences, Université Côte d'Azur, France

Abstract

To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that UBTD1 (Ubiquitin domain-containing protein 1) plays a crucial role in both the EGFR (Epidermal Growth Factor Receptor) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through ASAH1 (N-Acylsphingosine Amidohydrolase 1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of SQSTM1/p62 (Sequestosome 1) by RNF26 and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGFR-driven human cell proliferation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided.

Article and author information

Author details

  1. Stéphanie Torrino

    CNRS, IPMC, VALBONNE, France
    For correspondence
    stephanie.torrino@unice.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8280-5907
  2. Victor Tiroille

    INSERM, C3M, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Bastien Dolfi

    INSERM, C3M, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Maeva Dufies

    Biomedical Department, Centre Scientifique de Monaco, Monaco, Monaco
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1732-0388
  5. Charlotte Hinault

    INSERM, C3M, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Laurent Bonesso

    Biochemistry Laboratory, CHU, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Sonia Dagnino

    MRC-PHE Centre for Environment & Health, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6846-7190
  8. Jennifer Uhler

    Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  9. Marie Irondelle

    INSERM, C3M, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Anne-sophie Gay

    CNRS, IPMC, VALBONNE, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Lucile Fleuriot

    CNRS, IPMC, VALBONNE, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Delphine Debayle

    CNRS, IPMC, VALBONNE, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2807-9198
  13. Sandra Lacas-Gervais

    CCMA, UFR Sciences, Université Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Mireille Cormont

    INSERM, C3M, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Thomas Bertero

    CNRS, IPMC, VALBONNE, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Frederic Bost

    INSERM, C3M, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4509-4701
  17. Jerome Gilleron

    INSERM, C3M, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  18. Stephan Clavel

    INSERM, C3M, Nice, France
    For correspondence
    Stephan.CLAVEL@univ-cotedazur.fr
    Competing interests
    The authors declare that no competing interests exist.

Funding

Agence Nationale de la Recherche (ANR-15-IDEX-01)

  • Stephan Clavel

Agence Nationale de la Recherche (ANR18-CE14-0035-01-GILLERON)

  • Jerome Gilleron

Fondation de France

  • Stéphanie Torrino

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

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Publication history

  1. Received: March 12, 2021
  2. Accepted: April 20, 2021
  3. Accepted Manuscript published: April 22, 2021 (version 1)
  4. Version of Record published: May 13, 2021 (version 2)

Copyright

© 2021, Torrino 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. Stéphanie Torrino
  2. Victor Tiroille
  3. Bastien Dolfi
  4. Maeva Dufies
  5. Charlotte Hinault
  6. Laurent Bonesso
  7. Sonia Dagnino
  8. Jennifer Uhler
  9. Marie Irondelle
  10. Anne-sophie Gay
  11. Lucile Fleuriot
  12. Delphine Debayle
  13. Sandra Lacas-Gervais
  14. Mireille Cormont
  15. Thomas Bertero
  16. Frederic Bost
  17. Jerome Gilleron
  18. Stephan Clavel
(2021)
UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling
eLife 10:e68348.
https://doi.org/10.7554/eLife.68348
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