Diffusing caveolin-1 scaffolds regulate mechanosignalling

Caveolae are invaginated plasma membrane nanodomains traditionally associated with membrane trafficking and signalling. These multifunctional organelles are also essential mechanosensors mediating the cell response to mechanical stress. We investigated the role of caveolae mechanics in regulating various signalling pathways. Single-molecule imaging and super-resolution microscopy revealed that mechanical stress rapidly triggers caveolae disassembly and the release of caveolin-1 scaffolds, which then exhibit enhanced diffusion at the plasma membrane. This promoted direct interaction between the caveolin-1 scaffolding domain and the tyrosine kinase JAK1, leading to the inhibition of its catalytic activity. A similar process was observed for eNOS, PTEN and PTP1B. The control of signalling by diffusing Cav1 scaffolds was further validated by a theoretical model based on caveolae thermodynamics. These findings establish a mechanotransduction paradigm in which signalling information is decoded remotely from the initial mechanosensing caveola, through dynamic and reversible assembly of tension-controlled complexes between signalling effectors and caveolin-1 scaffolds.