Caveolae are an abundant and characteristic surface feature of many vertebrate cells. The uniform shape of caveolae is characterized by a bulb with consistent curvature connected to the plasma membrane (PM) by a neck region with opposing curvature. Caveolae act in mechanoprotection by flattening in response to increased membrane tension, and their disassembly influences the lipid organization of the PM. Here, we review evidence for caveolae as a specialized lipid domain and speculate on mechanisms that link changes in caveolar shape and/or protein composition to alterations in specific lipid species. We propose that high membrane curvature in specific regions of caveolae can enrich specific lipid species, with consequent changes in their localization upon caveolar flattening. In addition, we suggest how changes in the association of lipid-binding caveolar proteins upon flattening of caveolae could allow release of specific lipids into the bulk PM. We speculate that the caveolae-lipid system has evolved to function as a general stress-sensing and stress-protective membrane domain.

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