Recent experimental efforts have greatly advanced our understanding of clathrin- and actin- dependent endocytosis. Endocytic vesicle formation typically takes ~ 1–2 minutes, and is highly robust in vivo
]. Despite differences in details, general themes are emerging for different endocytic vesicle formation pathways, both across and within species.
Endocytic vesicle formation involves a sequence of dramatic membrane shape changes. From a mechanical standpoint, endocytic vesicle formation can be divided into two stages. First, the cargo-laden membrane at the endocytic site is intruded to form a tubular or spherical vesicle. Second, the vesicle is pinched off into the interior cytoplasm. The large energy penalty for bending the cell plasma membrane (~ 100's kB
T) makes it resist deforming to high curvatures [3
]. Therefore, substantial forces must be generated to power endocytic vesicle formation. Many proteins and lipids have been identified as part of the endocytic machinery [1
], some of which conspire to generate the forces that deform the membrane and pinch off the vesicle. Thus, finding the link between force generation and biochemical reactions on endocytic membranes is key to understanding the mechanism of endocytic vesicle formation.
Endocytic proteins often bind to each other via specific motifs [6
], and many bind directly to the membrane [7
]. However, in the noisy cellular environment, specific protein-protein and/or protein-lipid interactions alone are not sufficient to achieve rapid and robust endocytic internalization. For this reason, self-accelerating feedback mechanisms—which are widely utilized in many cellular processes—must facilitate endocytic vesicle formation. Specifically, biochemical pathways generate forces that remodel the membrane, and membrane shape changes in turn regulate biochemical pathways, forming a closed mechanochemical feedback loop. Testing this hypothesis in vivo
is difficult because the process takes but a few seconds. A theoretical model, however, can establish whether such feedback loops can account for the observed robust dynamics.
We first summarize recent experimental evidence for a mechanochemical feedback loop during endocytic vesicle formation. Clathrin- and actin-dependent endocytosis will be used as an example to address how the mechanochemical model can account for the sequential dynamics of the endocytic machinery. Finally, we will discuss the implications of the model for other membrane trafficking processes.