Caveolae couple mechanical stress to integrin recycling and activation

  1. Fidel-Nicolás Lolo
  2. Dácil María Pavón
  3. Araceli Grande
  4. Alberto Elósegui Artola
  5. Valeria Inés Segatori
  6. Sara Sánchez
  7. Xavier Trepat
  8. Pere Roca-Cusachs
  9. Miguel Ángel del Pozo  Is a corresponding author
  1. Centro Nacional de Investigaciones Cardiovasculares, Spain
  2. Allergy Therapeutics S.L., Spain
  3. The Francis Crick Institute, United Kingdom
  4. Quilmes National University, Argentina
  5. Institute for Bioengineering of Catalonia, Spain

Abstract

Cells are subjected to multiple mechanical inputs throughout their lives. Their ability to detect these environmental cues is called mechanosensing, a process in which integrins play an important role. During cellular mechanosensing, plasma membrane (PM) tension is adjusted to mechanical stress through the buffering action of caveolae; however, little is known about the role of caveolae in early integrin mechanosensing regulation. Here, we show that Cav1KO fibroblasts increase adhesion to FN-coated beads when pulled with magnetic tweezers, as compared to wild type fibroblasts. This phenotype is Rho-independent and mainly derived from increased active b1-integrin content on the surface of Cav1KO fibroblasts. FRAP analysis and endocytosis/recycling assays revealed that active b1-integrin is mostly endocytosed through the CLIC/GEEC pathway and is more rapidly recycled to the PM in Cav1KO fibroblasts, in a Rab4 and PM tension-dependent manner. Moreover, the threshold for PM tension-driven b1-integrin activation is lower in Cav1KO MEFs than in wild type MEFs, through a mechanism dependent on talin activity. Our findings suggest that caveolae couple mechanical stress to integrin cycling and activation, thereby regulating the early steps of the cellular mechanosensing response.

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Raw data of all figures is included as excel files

Article and author information

Author details

  1. Fidel-Nicolás Lolo

    Cell and developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1635-4770
  2. Dácil María Pavón

    Allergy Therapeutics S.L., Alcalá de Henares, Spain
    Competing interests
    Dácil María Pavón, is affiliated with Allergy Therapeutics S.L. The author has no financial interests to declare.
  3. Araceli Grande

    Structural Biology Programme, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2619-5013
  4. Alberto Elósegui Artola

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    No competing interests declared.
  5. Valeria Inés Segatori

    Quilmes National University, Buenos Aires, Argentina
    Competing interests
    No competing interests declared.
  6. Sara Sánchez

    Cell and developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    No competing interests declared.
  7. Xavier Trepat

    Institute for Bioengineering of Catalonia, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7621-5214
  8. Pere Roca-Cusachs

    Institute for Bioengineering of Catalonia, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6947-961X
  9. Miguel Ángel del Pozo

    Cell and developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    For correspondence
    madelpozo@cnic.es
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9077-391X

Funding

European Union Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie grant 641639)

  • Miguel Ángel del Pozo

Spanish Ministry of Science and Innovation (PID2020-118658RB-I00,SAF2014-51876-R,SAF2017-83130-R,PDC2021-121572-100,CSD2009-0016)

  • Miguel Ángel del Pozo

Worldwide Cancer Research Foundation (#15 -0404)

  • Miguel Ángel del Pozo

Asociación Española Contra el Cáncer Foundation (PROYE20089DELP)

  • Miguel Ángel del Pozo

Spanish Ministry of Science and Innovation (BFU2016-81912-REDC)

  • Miguel Ángel del Pozo

Fundació la Marató de TV3 (674/C/2013)

  • Pere Roca-Cusachs
  • Miguel Ángel del Pozo

Fundació la Marató de TV3 (201936-30-31)

  • Pere Roca-Cusachs
  • Miguel Ángel del Pozo

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

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University, United States

Publication history

  1. Preprint posted: April 29, 2022 (view preprint)
  2. Received: August 2, 2022
  3. Accepted: October 19, 2022
  4. Accepted Manuscript published: October 20, 2022 (version 1)
  5. Accepted Manuscript updated: October 21, 2022 (version 2)

Copyright

© 2022, Lolo 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. Fidel-Nicolás Lolo
  2. Dácil María Pavón
  3. Araceli Grande
  4. Alberto Elósegui Artola
  5. Valeria Inés Segatori
  6. Sara Sánchez
  7. Xavier Trepat
  8. Pere Roca-Cusachs
  9. Miguel Ángel del Pozo
(2022)
Caveolae couple mechanical stress to integrin recycling and activation
eLife 11:e82348.
https://doi.org/10.7554/eLife.82348
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