Abstract
Author SummaryEndocytosis is a complex and efficient process that cells utilize to take up nutrients and communicate with other cells. Eukaryotes have diverse endocytic pathways with two common features, mechanical and chemical. Proper mechanical forces are necessary to deform the plasma membrane and, eventually, pinch off the cargo-laden endocytic vesicles; and tightly regulated endocytic protein assembly and disassembly reactions drive the progression of endocytosis. Many experiments have yielded a lot of detailed information on the sub-processes of endocytosis, but how these sub-processes fit together into a coherent process in vivo is still not clear. To address this question, we constructed the first integrated theoretical model of endocytic vesicle formation, building on detailed knowledge from experiments in yeast. The key notion is that the mechanical force generation during endocytosis is both slave to, and master over, the accompanying endocytic reaction pathway, which is mediated by local membrane curvature. Our model can quantitatively recapitulate the endocytic events leading to vesicle scission in budding yeast and can explain key aspects of mammalian endocytosis. The phenotypes predicted from variations within the feedback components of our model reproduce observed mutant phenotypes, and we predict additional unique and testable endocytic phenotypes in yeast and mammalian cells. We further demonstrate that the functional significance of such mechanochemical feedback is to ensure the robustness of endocytic vesicle scission.
Highlights
During clathrin-mediated endocytosis, cells regulate plasma membrane molecular composition and internalize essential nutrients
Many endocytic proteins, including clathrin, adaptor proteins, and cytoskeletal proteins, are highly conserved from yeast to mammals. In both yeast and mammalian cells, dynamics of the key endocytic proteins are coordinated in space and time, and internalization and vesicle scission are accompanied by a transient burst of actin assembly [1,2]
Proper mechanical forces are necessary to deform the plasma membrane and, eventually, pinch off the cargo-laden endocytic vesicles; and tightly regulated endocytic protein assembly and disassembly reactions drive the progression of endocytosis
Summary
During clathrin-mediated endocytosis, cells regulate plasma membrane molecular composition and internalize essential nutrients. This process involves coordination of biochemical activities with membrane shape changes [1,2]. Among the most obvious differences, clathrin-mediated endocytosis in mammalian cells involves formation of spherical clathrin-coated vesicle buds and recruitment of the GTPase dynamin to the vesicle neck, while endocytic structures in yeast are tubular invaginations lacking dynamin [15,17]. Many endocytic proteins, including clathrin, adaptor proteins, and cytoskeletal proteins, are highly conserved from yeast to mammals In both yeast and mammalian cells, dynamics of the key endocytic proteins are coordinated in space and time, and internalization and vesicle scission are accompanied by a transient burst of actin assembly [1,2]. Despite intensive study in many laboratories, the mechanisms underlying coordination of protein recruitment, lipid modification, and membrane shape changes are not well understood in any organism
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