1. Cell Biology

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
https://doi.org/10.7554/eLife.82348
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

Data availability

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.

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.

Metrics

  • 2,461
    views
  • 407
    downloads
  • 11
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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

Share this article

https://doi.org/10.7554/eLife.82348

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Ezrin defines TSC complex activation at endosomal compartments through EGFR–AKT signaling

    Giuliana Giamundo, Daniela Intartaglia ... Ivan Conte
    Research Article

    Endosomes have emerged as major signaling hubs where different internalized ligand–receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane–actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.

    1. Cell Biology

    Pharmacologic activation of integrated stress response kinases inhibits pathologic mitochondrial fragmentation

    Kelsey R Baron, Samantha Oviedo ... R Luke Wiseman
    Research Article

    Excessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI – is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that pharmacologic activation of the ISR reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions, including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.

    1. Cell Biology

    Beta Cells: Opportunity makes a hub or a leader

    Marjan Slak Rupnik
    Insight

    Functional subpopulations of β-cells emerge to control pulsative insulin secretion in the pancreatic islets of mice through calcium oscillations.