Lipid accumulation promotes scission of caveolae

Abstract

19Caveolae, bulb-shaped invaginations of the plasma membrane (PM), show distinct behaviors 20 of scission and fusion at the cell surface. Although it is known that caveolae are enriched in 21 cholesterol and sphingolipids, exactly how lipid composition influences caveolae surface 22 stability has not yet been elucidated. Accordingly, we inserted specific lipids into the PM of 23 cells via membrane fusion and studied acute effects on caveolae dynamics. We demonstrate 24 that cholesterol and glycosphingolipids specifically accumulate in caveolae, which decreases 25 their neck diameter and drives their scission from the cell surface. The lipid-induced scission 26 was counteracted by the ATPase EHD2. We propose that lipid accumulation in caveolae 27 generates an intrinsically unstable domain prone to scission if not balanced by the restraining 28 force of EHD2 at the neck. Our work advances the understanding of how lipids contribute to 29 caveolae dynamics, providing a mechanistic link between caveolae and their ability to sense 30 the PM lipid composition. 31 SUMMARY 32 Caveolae serve as mechanoprotectors and membrane buffers but their specific role in sensing 33 plasma membrane lipid composition remains unclear. Hubert et al. show that cholesterol and 34 glycosphingolipids accumulate in caveolae and drive subsequent scission from the cell 35 surface. These results provide new insight into how lipids contribute to budding and scission 36 of membrane domains in cells.37