The ESCRT Machinery: Remodeling, Repairing, and Sealing Membranes

Abstract

The ESCRT machinery is an evolutionarily conserved membrane remodeling complex that is used by the cell to perform reverse membrane scission in essential processes like protein degradation, cell division, and release of enveloped retroviruses. ESCRT-III, together with the AAA ATPase VPS4, harbors the main remodeling and scission function of the ESCRT machinery, whereas early-acting ESCRTs mainly contribute to protein sorting and ESCRT-III recruitment through association with upstream targeting factors. Here, we review recent advances in our understanding of the molecular mechanisms that underlie membrane constriction and scission by ESCRT-III and describe the involvement of this machinery in the sealing and repairing of damaged cellular membranes, a key function to preserve cellular viability and organellar function.

Keywords: ESCRT; lysosome; membrane repair; membrane scission; membrane sealing; nuclear envelope; reverse topology.

Figure 1

Model for membrane constriction and fission driven by ESCRT-III filament assembly and disassembly. The figure illustrates the sequential recruitment of ESCRT-III components, polymerization, and replacement of different filament subunits driven by Vps4, resulting in constriction and final scission of the membrane (adapted from [59]).

Figure 2

ESCRT-mediated sealing of the nuclear envelope during mitotic exit. In late anaphase, the inner nuclear membrane protein LEM2 recruits and activates CHMP7 to holes in the reforming nuclear envelope, which drives ESCRT-III polymerization. Premature ESCRT-III recruitment to the nuclear membrane is prevented by CC2D1B, which dissociates prior to ESCRT recruitment. Spastin recruitment by ESCRT-III triggers severing of mitotic spindle microtubules, while VPS4 remodeling of ESCRT-III filaments promotes membrane constriction and sealing of the nuclear envelope.

Figure 3

Membrane repair processes mediated by ESCRT. Left panel: plasma membrane repair. Entry of calcium through the damaged membrane triggers rapid ESCRT recruitment, mediated by PDCD6 and ALIX. ESCRTs are thought to promote membrane budding and shedding of small domains containing the site of damage; middle panel: nuclear envelope (NE) repair. Upon NE rupture, cytosolic BAF coats the exposed chromatin and interacts with LEM2, facilitating the recruitment of nuclear membrane and the interaction with CHMP7. CHMP7 subsequently promotes the nucleation and polymerization of ESCRT-III, which together with VPS4 constricts the rupture and promotes sealing; right panel: lysosome repair. After damage, calcium efflux from the lysosome promotes ESCRT-I and -III recruitment through PDCD6, ALIX, and probably other factors like GAL3 and LRRK2, which phosphorylate the small GTPase Rab8A. It is thought that the membrane-remodeling performed by ESCRT-III filament spirals acts to shed damaged membranes into the lumen of the lysosome for recycling.