On the existence of endocytosis driven by membrane phase separations.

Large endocytic responses can occur rapidly in diverse cell types without dynamins, clathrin, or actin remodeling. Our experiments suggest that membrane phase separations are crucial with more ordered plasma membrane domains being internalized. Not only do these endocytic processes rely on coalescence of membrane domains, they are promoted by participation of membrane proteins in such domains, one important regulatory influence being palmitoylation. Membrane actin cytoskeleton in general resists membrane phase transitions, and its remodeling may play many roles. Besides membrane 'caging' and 'pinching' roles, typically ascribed to clathrin and dynamins, cytoskeleton remodeling may modify local membrane tension and buckling, as well as the presence and location of actin- and tension-free membrane patches. Endocytosis that depends on membrane phase separations becomes activated in metabolic stress and in response to Ca and PI3 kinase signaling. Internalized membrane traffics normally, and the secretory pathway eventually resupplies membrane to the plasmalemma or directs internalized membrane to other locations, including the extracellular space as exosomes. We describe here that endocytosis driven by membrane phase transitions is regulated by the same signaling mechanisms that regulate macropinocytosis, and it may play diverse roles in cells from nutrient assimilation to membrane recycling, cell migration, and the initiation of quiescent or hibernating cell states. Membrane ordering and phase separations have been shown to promote endocytosis in diverse cell types, including fibroblasts, myocytes, glial cells, and immune cells. We propose that clathrin/dynamin-independent endocytosis represents a continuum of related mechanisms with variable but universal dependence on membrane ordering and actin remodeling. This article is part of a Special Issue entitled: Molecular biophysics of membranes and membrane proteins.