The Mechanochemistry of Endocytosis

Abstract

Endocytic vesicle formation is a complex process that couples sequential protein recruitment and lipid modifications with dramatic shape transformations of the plasma membrane. Although individual molecular players have been studied intensively, how they all fit into a coherent picture of endocytosis remains unclear. That is, how the proper temporal and spatial coordination of endocytic events is achieved and what drives vesicle scission are not known. Drawing upon detailed knowledge from experiments in yeast, we develop the first integrated mechanochemical model that quantitatively recapitulates the temporal and spatial progression of endocytic events leading to vesicle scission. The central idea is that membrane curvature is coupled to the accompanying biochemical reactions. This coupling ensures that the process is robust and culminates in an interfacial force that pinches off the vesicle. Calculated phase diagrams reproduce endocytic mutant phenotypes observed in experiments and predict unique testable endocytic phenotypes in yeast and mammalian cells. The combination of experiments and theory in this work suggest a unified mechanism for endocytic vesicle formation across eukaryotes. Endocytosis 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.