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bioRxiv · 10.1101/2022.09.27.509635

Caveolae govern plasma membrane mechanics to protect cells against EDIN B-induced transcellular tunnel formation and lethality from S. aureus septicaemia

Morel, C.·Lemerle, E.·Tsai, F.-C.·Obadia, T.·Srivastava, N.·Marechal, M.·Salles, A.·Albert, M.·Stefani, C.·Lamaze, C.·Vassilopoulos, S.·Piel, M.·Bassereau, P.·Gonzalez-Rodriguez, D.·Leduc, C.·Lemichez, E.
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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 TEMs per cell. The enhanced occurrence of TEM nucleation events 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.

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Morel, C., Lemerle, E., Tsai, F.-C., Obadia, T., Srivastava, N., Marechal, M., Salles, A., Albert, M., Stefani, C., Lamaze, C., Vassilopoulos, S., Piel, M., Bassereau, P., Gonzalez-Rodriguez, D., Leduc, C., Lemichez, E.. 2022-09-28. Caveolae govern plasma membrane mechanics to protect cells against EDIN B-induced transcellular tunnel formation and lethality from S. aureus septicaemia. https://doi.org/10.1101/2022.09.27.509635

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