Caveolin-1 protects endothelial cells from extensive expansion of transcellular tunnel by stiffening the plasma membrane-Reference-Cited by-同舟云学术

Caveolin-1 protects endothelial cells from extensive expansion of transcellular tunnel by stiffening the plasma membrane

Published:2023-11-24 Issue: Volume: Page:
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Author:

Morel Camille¹,Lemerle Eline²,Tsai Feng-Ching³,Obadia Thomas⁴⁵,Srivastava Nishit⁶,Marechal Maud¹,Salles Audrey⁷,Albert Marvin⁸,Stefani Caroline⁹,Benito Yvonne¹⁰,Vandenesch François¹¹,Lamaze Christophe¹²,Vassilopoulos Stéphane²,Piel Matthieu⁶,Bassereau Patricia³,Gonzalez-Rodriguez David¹³,Leduc Cécile¹⁴^ORCID,Lemichez Emmanuel¹^ORCID

Affiliation:

1. Institut Pasteur, Université Paris Cité, CNRS UMR6047, INSERM U1306, Unité des Toxines Bactériennes, Département de Microbiologie, F-75015 Paris, France

2. Sorbonne Université, INSERM UMR U974, Institut de Myologie, Centre de Recherche en Myologie, F-75013 Paris, France

3. Institut Curie, PSL Research University, CNRS UMR168, Laboratoire Physico-Chimie Curie, F-75005 Paris, France

4. Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, F-75015 Paris, France

5. Institut Pasteur, Université Paris Cité, G5 Infectious Diseases Epidemiology and Analytics, F-75015, Paris, France

6. Institut Curie and Institut Pierre Gilles de Gennes, PSL Research University, Sorbonne University, CNRS UMR144, F-75005 Paris, France

7. Institut Pasteur, Université de Paris Cité, Unit of Technology and Service Photonic BioImaging (UTechS PBI), C2RT, F-75015 Paris, France

8. Institut Pasteur, Université Paris Cité, Image Analysis Hub, F-75015 Paris, France

9. Benaroya Research Institute at Virginia Mason, Department of Immunology, Seattle, USA

10. Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, Lyon, France

11. CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS UMR5308, ENS de Lyon, Lyon, France

12. Institut Curie, PSL Research University, INSERM U1143, CNRS UMR3666, Membrane Mechanics and Dynamics of Intracellular Signaling Laboratory, F-75005 Paris, France

13. Université de Lorraine, LCP-A2MC, F-57000 Metz, France

14. Université Paris Cité, Institut Jacques Monod, CNRS UMR7592, F-75013 Paris, France

Abstract

Large transcellular pores elicited by bacterial mono-ADP-ribosyltransferase (mART) exotoxins inhibiting the small RhoA GTPase compromise the endothelial barrier. Recent advances in biophysical modeling point towards membrane tension and bending rigidity as the minimal set of mechanical parameters determining the nucleation and maximal size of transendothelial cell macroaperture (TEM) tunnels induced by bacterial RhoA-targeting mART exotoxins. We report that cellular depletion of caveolin-1, the membrane-embedded building block of caveolae, and depletion of cavin-1, the master regulator of caveolae invaginations, increase the number of TEM per cell. The enhanced nucleation of TEM correlates with a reduction of cell height, due to the increase of cell spreading and decrease of cell volume, which, together with the disruption of RhoA-driven F-actin meshwork, favor membrane apposition for TEM nucleation. Strikingly, caveolin-1 specifically controls the opening speed of TEMs leading to their dramatic 5.4-fold larger widening. Consistent with the increase of TEM density and width in siCAV1 cells, we record a higher lethality in caveolin-1-deficient mice subjected to a catalytically active mART exotoxin targeting RhoA during staphylococcal bloodstream infection. Combined theoretical modeling with independent biophysical measurements of plasma membrane bending rigidity point toward a specific contribution of caveolin-1 to membrane stiffening in addition to the role of cavin-1/caveolin-1-dependent caveolae in the control of membrane tension homeostasis.

Publisher

eLife Sciences Publications, Ltd