1. Cell Biology
Download icon

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
Research Article
  • Cited 1
  • Views 745
  • Annotations
Cite this article as: eLife 2021;10:e68348 doi: 10.7554/eLife.68348

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.

Metrics

  • 745
    Page views
  • 159
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Physics of Living Systems
    Clotilde Cadart et al.
    Research Article

    The way proliferating animal cells coordinate the growth of their mass, volume, and other relevant size parameters is a long-standing question in biology. Studies focusing on cell mass have identified patterns of mass growth as a function of time and cell cycle phase, but little is known about volume growth. To address this question, we improved our fluorescence exclusion method of volume measurement (FXm) and obtained 1700 single-cell volume growth trajectories of HeLa cells. We find that, during most of the cell cycle, volume growth is close to exponential and proceeds at a higher rate in S-G2 than in G1. Comparing the data with a mathematical model, we establish that the cell-to-cell variability in volume growth arises from constant-amplitude fluctuations in volume steps rather than fluctuations of the underlying specific growth rate. We hypothesize that such ‘additive noise’ could emerge from the processes that regulate volume adaptation to biophysical cues, such as tension or osmotic pressure.

    1. Cell Biology
    2. Structural Biology and Molecular Biophysics
    Elizabeth J Lawrence et al.
    Research Article Updated

    Sjögren’s syndrome nuclear autoantigen-1 (SSNA1/NA14) is a microtubule-associated protein with important functions in cilia, dividing cells, and developing neurons. However, the direct effects of SSNA1 on microtubules are not known. We employed in vitro reconstitution with purified proteins and TIRF microscopy to investigate the activity of human SSNA1 on dynamic microtubule ends and lattices. Our results show that SSNA1 modulates all parameters of microtubule dynamic instability—slowing down the rates of growth, shrinkage, and catastrophe, and promoting rescue. We find that SSNA1 forms stretches along growing microtubule ends and binds cooperatively to the microtubule lattice. Furthermore, SSNA1 is enriched on microtubule damage sites, occurring both naturally, as well as induced by the microtubule severing enzyme spastin. Finally, SSNA1 binding protects microtubules against spastin’s severing activity. Taken together, our results demonstrate that SSNA1 is both a potent microtubule-stabilizing protein and a novel sensor of microtubule damage; activities that likely underlie SSNA1’s functions on microtubule structures in cells.