Cell biology of the ESCRT machinery

Abstract

The ESCRT (endosomal sorting complex required for transport) machinery comprises a set of protein complexes that regulate sorting and trafficking into multivesicular bodies en route to the lysosome. The physical mechanism responsible for generating lumenal vesicles in this pathway is unknown. Here we review recent studies suggesting that components of the ESCRT-III complex drive lumenal vesicle formation and consider possible mechanisms for this reaction.

Figure 1

Schematic diagram showing multivesicular body biogenesis and topologically related events. The three distinct cellular processes shown - formation of intralumenal vesicles within the MVB, viral budding from the cell surface, and cell abscission at the end of cytokinesis -- share a common membrane topology and depend on at least some aspect of ESCRT pathway function.

Figure 2

The cycle of ESCRT-III polymer assembly and disassembly. The first four helices of an ESCRT-III protein form a helical bundle responsible for membrane binding and polymerization. These properties are masked by a C-terminal autoinhibitory domain in a “closed” conformation in the cytoplasm. Displacement of this autoinhibitory domain allows ESCRT-III proteins to assume an “open” conformation and assemble into polymers on the membrane. VPS4 hydrolyzes ATP to disassemble these polymers and return the proteins to their "closed" state.

Figure 3

Models of ESCRT-III driven vesicle formation. (A) "Purse-string" model based on [10]. A single ESCRT-III filament with asymmetric ends is used to delineate and later constrict the neck of an evolving vesicle. VPS4 is proposed to disassemble the filament from one end to constrict the string. (B) "Spiral constriction" model based on [65]. A growing ESCRT-III spiral surrounds and eventually constricts a cargo containing membrane domain, forcing cargo at the center into an evolving vesicle. (C) "Moving neck" model based on [64]. ESCRT-III filaments start at the center of a developing vesicle, bending the membrane as they grow. Disassembly of the filament tail allows the spiral to remain in only the neck of the evolving vesicle.