Molecular mechanisms of the membrane sculpting ESCRT pathway

Abstract

The endosomal sorting complexes required for transport (ESCRT) drive multivesicular body (MVB) biogenesis and cytokinetic abscission. Originally identified through genetics and cell biology, more recent work has begun to elucidate the molecular mechanisms of ESCRT-mediated membrane remodeling, with special focus on the ESCRT-III complex. In particular, several light and electron microscopic studies provide high-resolution imaging of ESCRT-III rings and spirals that purportedly drive MVB morphogenesis and abscission. These studies highlight unifying principles to ESCRT-III function, in particular: (1) the ordered assembly of the ESCRT-III monomers into a heteropolymer, (2) ESCRT-III as a dynamic complex, and (3) the role of the AAA ATPase Vps4 as a contributing factor in membrane scission. Mechanistic comparisons of ESCRT-III function in MVB morphogenesis and cytokinesis suggest common mechanisms in membrane remodeling.

Figure 1.

ESCRT-mediated membrane remodeling in cellular physiology and pathophysiology. (A) Schematic of ESCRT-III helices driving MVB cargo sorting, HIV budding, and cell division. (B) Helical model of a Snf7 subunit from Saccharomyces cervisiae (top). ESCRT-III subunits undergo conformational changes from a closed (middle) to open state (bottom).

Figure 2.

High-resolution imaging of ESCRT-III assemblies. (A) Electron micrograph of circular array protein scaffolds on membrane tubules in COS-7 cells expressing Snf7-1/CHMP4A and VPS4B(E235Q)-GFP. (Image from Hanson et al. 2008; adapted, with permission, from The Rockefeller University Press © 2008.) (B) Electron micrograph of reconstituted yeast Snf7 spirals assembled on lipid monolayers. (C) A helical polymer of reconstituted yeast Snf7, Vps24, and Vps2, imaged by electron microscopy. (Panels B and C are from Henne et al. 2012; adapted, with permission, from Cell Press © 2012.) (D) Electron tomography of high-pressure frozen cells, which show 17-nm filaments spiraling along the constriction zone. (This image is from Guizetti et al. 2011; adapted, with permission, from the author.) Scale bars, 100 nm, unless stated otherwise.

Figure 3.

Helical and dome models for ESCRT-III-mediated membrane remodeling and vesicle scission.

Figure 4.

Three models for ESCRT-III-mediated abscission.