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

The spontaneous opening of large transendothelial cell macroaperture (TEM) tunnels can accompany leukocyte diapedesis and is triggered by bacterial exoenzymes that inhibit RhoA-driven cytoskeleton contractility. Modelling the dynamics of TEM via a theoretical framework used for soft matter physics allowed us to depict the essential driving forces at play on the membrane to enlarge TEMs. In this study, we conducted multidisciplinary experiments to characterize the role respectively played by cavin-1-structured caveolae and non-caveolar caveolin-1 in plasma membrane mechanics and identify their functional effects on TEM size. The results pointed towards a contributing role for non-caveolar caveolin-1 in the membrane bending rigidity, a mechanical parameter we quantified in a model system of tubes pulled from plasma membrane spheres. Depletion of cavin-1-structured caveolae showed no effect on membrane rigidity, whereas caveolae controlled cell height favouring TEM nucleation. Hence, caveolae confer protection against exoenzyme EDIN-B in mice with staphylococcal septicaemia. ### Competing Interest Statement The authors have declared no competing interest.