Mechano-sensitivity of multi-component caveolae

Caveolae are small spherical invaginations of the cell membrane with well established mechano-sensing and mechano-regulation functions. The release of caveolae components upon tension elevation is key to their mechao-signalling function. We present a thermodynamic model of caveolae stability under tension based on the phase separation of membrane-associated proteins into invaginated, multi-component membrane domains enriched in the curvature-generating membrane protein caveolin, and stabilised by the curvature-dependent binding of cytosolic proteins: members of the Cavin family which can form a rigid coat over caveolin domains, and the ATPase EHD2 which can form ring-like oligomers at the caveolae neck. This model shows that purely membrane domains show gradual release of their components upon tension elevation. Invaginations stabilised by a Cavin coat can sustain higher tensions with potentially sharp Cavin unbinding at a threshold tension but still release their membrane components smoothly upon tension increase. On the other hand, caveolae stabilised by an EHD2 ring exhibit increased mechano-protection and allow for a sharp release of membrane components. Therefore, the multi-component nature of caveolae self-organisation bestows these membrane domains with a switch-like response to tension variations which leads to the abrupt release of caveolae content beyond a well defined membrane tension threshold. Significance statement Caveolae are small invaginated domains of Caveolin proteins at the plasma membrane, stabilised by coat of Cavin proteins and a ring of EHD2 proteins at their neck. They contribute to cellular mechano-sensing by disassembling under elevated membrane tension, thereby releasing components that can regulate signalling events. Using a thermodynamic model of protein self-assembly, we show that caveolin domains disassemble smoothly under tension. While the Cavin coat affords mechanical protection without altering this gradual release, the EHD2 ring induces a switch-like release near a threshold tension, enabling acute mechano-sensing.