The role of membrane-shaping BAR domain proteins in caveolar invagination: from mechanistic insights to pathophysiological consequences

The formation of caveolae, bulb-shaped plasma membrane invaginations, requires the coordinated action of distinct lipid-interacting and -shaping proteins. The interdependence of caveolar structure and function has evoked substantial scientific interest given the association of human diseases with caveolar dysfunction. Model systems deficient of core components of caveolae, caveolins or cavins, did not allow for an explicit attribution of observed functional defects to the requirement of caveolar invagination as they lack both invaginated caveolae and caveolin proteins. Knockdown studies in cultured cells and recent knockout studies in mice identified an additional family of membrane-shaping proteins crucial for caveolar formation, syndapins (PACSINs) — BAR domain superfamily proteins characterized by crescent-shaped membrane binding interfaces recognizing and inducing distinct curved membrane topologies. Importantly, syndapin loss-of-function resulted exclusively in impairment of caveolar invagination without a reduction in caveolin or cavin at the plasma membrane, thereby allowing the specific role of the caveolar invagination to be unveiled. Muscle cells of syndapin III KO mice showed severe reductions of caveolae reminiscent of human caveolinopathies and were more vulnerable to membrane damage upon changes in membrane tensions. Consistent with the lack of syndapin III-dependent invaginated caveolae providing mechanoprotection by releasing membrane reservoirs through caveolar flattening, physical exercise of syndapin III KO mice resulted in pathological defects reminiscent of the clinical symptoms of human myopathies associated with caveolin 3 mutation suggesting that the ability of muscular caveolae to respond to mechanical forces is a key physiological process.