Adsorptive and receptor-mediated endocytosis via clathrin-coated vesicles provides the major and best-characterized portal for uptake of multiple molecules and particles into cells. Via clathrin-dependent endocytosis, cells receive nutrients, regulate receptors and other plasma membrane constituents, take up antigens, and remove senescent, excess, and potentially harmful substances from the extracellular fluid.

Because of their typical bristle-like coats, the pits, buds, and vesicles formed during clathrin-dependent endocytosis can easily be differentiated under the electron microscope (panels A and C). The coat consists mainly of clathrin and adaptor proteins. The individual cytosolic clathrin molecules are triskelions, which assemble and recruit to the cytoplasmic face of the plasma membrane in concerted interactions with adaptor proteins and the lipid bilayer, which results in the formation of a mainly hexagonal lattice. Through rapid disassembly and reassembly of the clathrin triskelions, the membrane deforms into pits and deeply invaginated buds coated by a clathrin basketwork of polygons in which pentagons and heptagons are juxtaposed to hexagons. The basket seems to function as a stabilizing coat for the molecular machineries necessary to concentrate plasma membrane proteins into the endocytic pits and vesicles. Adaptors, such as the AP-2 adaptor protein complex, facilitate selection of the cargo for uptake into the vesicles and connect the clathrin coat with the transmembrane receptors. Detachment of the buds from the plasma membrane involves the action of dynamins, a class of scission-molecules essential for the pinching-off of the buds to create vesicles. Shortly after a vesicle is formed, the clathrin coat disassembles and detaches from the membrane, and the coat-free endocytic vesicle is capable of fusing with other endosomes. By correlating fluorescence microscopy of key proteins and electron tomography, protein-mediated consecutive events during endocytosis, such as membrane bending, membrane constriction, scission, and vesicle formation, could be studied in detail in budding yeast.

In panels D and E, human immunodeficiency virus (HIV) particles (arrowheads) bound to the surface of a macrophage are shown. They are seen attached to the plasma membrane (PM), contained in large endocytic vacuoles or surface invaginations (arrows in panel E). Viruses use different endocytic pathways; in addition to internalization by clathrin-coated vesicles, viruses can be taken up into cells via caveolae (cf. Fig. 63), lipid-raft-mediated endocytosis routes, macropinocytosis, and presumably other mechanisms as well. HIV1 enters cells by direct fusion with the plasma membrane and by fusion with the membrane of macropinosomes. The large vacuoles in panel E containing HIV particles possibly correspond to macropinosomes formed by deep plasma membrane invaginations and closure of membrane ruffles.

SG: secretory granule

Different endocytic portals and pathways are known in mammalian cells (see diagram), roughly classified as clathrin-dependent (1, cf. Fig. 58) and clathrin-independent ones. The latter include endocytosis by budding of “smooth” vesicles lacking a distinct morphologically visible coat (2, cf. Fig. 64A), uptake via pits containing lipid rafts (3), traffic via caveolae (4, cf. Fig. 63) and caveolar carriers (C), phagocytosis (5, cf. Fig. 64B) and uptake via macropinocytosis (6) leading to the formation of large endocytic vacuoles, termed macropinosomes (MP, cf. Fig. 58). The routes traveled by endocytosed molecules involve complex endosomal compartments with mosaics of specialized structural and functional domains. Endosomes belong to the most dynamic cellular compartments and transform in response to endocytosis-connected signals. Early endosomes, classified in early sorting endosomes (SE) and recycling endosomes (RE), represent first stations from where proteins and lipids are sorted to different routes. These can be either routes to late endosomes (LE) and lysosomes (LY) for degradation, or recycling pathways to the plasma membrane (PM), or routes to other destinations involving trans Golgi networks (TGN), and the Golgi apparatus (GA). The endoplasmic reticulum (ER) is reached by retrograde pathways across the Golgi apparatus and pre-Golgi intermediates (pGI), or via more direct routes, as is known for caveolae-derived endosomes.

Different endocytic portals and pathways are known in mammalian cells (see diagram), roughly classified as clathrin-dependent (1, cf. Fig. 58) and clathrin-independent. The latter include endocytosis by budding of “smooth” vesicles lacking a distinct morphologically visible coat (2, cf. Fig. 64), uptake via pits containing lipid rafts (3), traffic via caveolae (4, cf. Fig. 63) and caveosomes (C), phagocytosis (5, cf. Fig. 63), and uptake via macropinocytosis (6) leading to the formation of large endocytic vacuoles, termed macropinosomes (MP, cf. Fig. 58). The routes traveled by endocytosed molecules involve complex endosomal compartments with mosaics of specialized structural and functional domains. Endosomes belong to the most dynamic cellular compartments and transform in response to endocytosis-connected signals. Early endosomes, classified as early sorting endosomes (SE) and recycling endosomes (RE), represent first stations from where proteins and lipids are sorted to different routes. These can be either routes to late endosomes (LE) and lysosomes (LY) for degradation, or recycling pathways to the plasma membrane (PM), or routes to other destinations involving trans Golgi networks (TGN) and the Golgi apparatus (GA). The endoplasmic reticulum (ER) is reached by retrograde pathways across the Golgi apparatus and pre-Golgi intermediates (pGI), or via more direct routes, as is known for caveolae-derived endosomes.

In HepG2 hepatoma cells, internalized WGA is taken up into the Golgi apparatus by a complex multistep process (cf. also Fig. 60), which starts with an accumulation of early vesicular endosomes at the trans Golgi side (panel D). The Golgi apparatus is small and inconspicuous in the control cells. It expands during endocytosis, and an endocytic TGN starts to form. Initial endocytic networks labeled with internalized WGA (TGN) are visible in panel D (cf. also Fig. 60).