Endocytosis unplugged: multiple ways to enter the cell

Abstract

Endocytosis occurs at the cell surface and involves internalization of the plasma membrane (PM) along with its constituent membrane proteins and lipids. Endocytosis is involved in sampling of the extracellular milieu and also serves to regulate various processes initiated at the cell surface. These include nutrient uptake, signaling from cell-surface receptors, and many other processes essential for cell and tissue functioning in metazoans. It is also central to the maintenance of PM lipid and protein homeostasis. There are multiple means of internalization that operate concurrently, at the cell surface. With advancement in high-resolution visualization techniques, it is now possible to track multiple endocytic cargo at the same time, revealing a remarkable diversity of endocytic processes in a single cell. A combination of live cell imaging and efficient genetic manipulations has also aided in understanding the functional hierarchy of molecular players in these mechanisms of internalization. Here we provide an account of various endocytic routes, their mechanisms of operation and occurrence across phyla.

Figure 1

Macroscale endocytic processes. (A) A simplified schematic representing molecular and membrane events occurring during macroscale endocytic processes. During phagocytic cup formation (left panel), sequential engagement of Fc-receptor initiates a zipper-like arrangement in opposition with bacterial surface. The process is orchestrated by stepwise involvement of GTPases and involves actin polymerization. Membrane remodeling during phagocytosis is accompanied with membrane addition to PM, in an AP1-dependent vesicular process. In trigger-type particle entry (right panel), the process involves injection of soluble effectors into cell, which, among other events, can activate Rho GTase effectors, and hence culminating in actin polymerization at the site of bacterial entry. Variations that exhibit intermediate forms, also exist, but have not been included here. (B) EGF-induced macropinocytosis–a most extensively studied example of macropinocytosis. Binding of EGF to EGF receptor triggers the intracellular signaling cascade and activation of downstream proteins, as indicated, eventually leading to actin-rich membrane ruffle formation. Collapse of ruffle on membrane is followed with macropinosome formation.

Figure 2

Microscale endocytic processes. Microscale endocytic processes can be broadly classified according to the requirement for dynamin for pinching. (A) Pathways that are dependent on dynamin activity for vesicle formation, (B) Pathways that are independent of dynamin function. Most examples in (B) are less-explored in terms of their molecular mechanisms, and their specificity for particular cargo is less well defined. For example, CD59 is endocytosed by both the ARF6-associated pathway and the flotillin-mediated endocytic route. The routes illustrated here represent pathways that have been shown to be distinct from one another.