Vesicle formation within endosomes: An ESCRT marks the spot

Abstract

Vesicle-mediated cargo transport within the endomembrane system requires precise coordination between adaptor molecules, which recognize sorting signals on substrates, and factors that promote changes in membrane architecture. At endosomal compartments, a set of protein complexes collectively known as the ESCRT machinery sequesters transmembrane cargoes that harbor a ubiquitin modification and packages them into vesicles that bud into the endosome lumen. Several models have been postulated to describe this process. However, consensus in the field remains elusive. Here, we discuss recent findings regarding the structure and function of the ESCRT machinery, highlighting specific roles for ESCRT-0 and ESCRT-III in regulating cargo selection and vesicle formation.

Keywords: intralumenal vesicle; membrane curvature; membrane scission; membrane trafficking; multivesicular endosome; phosphatidylinositol 3-phosphate; ubiquitin.

Figure 1.

A model highlighting the multiple functions of the ESCRT machinery during cargo sorting and vesicle biogenesis. Step 1: The membrane bound ESCRT-0 complex captures ubiquitin-modified transmembrane cargoes and subsequently recruits ESCRT-I onto the endosomal membrane. A combination of protein-lipid and protein-protein interactions leads to ESCRT-II accumulation on the membrane, establishing an ESCRT footprint that is ~80–130 nm in diameter. Step 2: The ESCRT-0 complex is released from the membrane, potentially due to conformational changes following ESCRT-I binding, and both ESCRT-I and ESCRT-II prevent the lateral diffusion of cargoes. Additionally, ESCRT-I and ESCRT-II may initiate membrane bending. Step 3: ESCRT-II nucleates filaments of ESCRT-III that associate tightly with membrane. In particular, the association of ESCRT-II with Vps20 generates a curvature-sensitive complex that may further bend the membrane to generate a highly curved vesicle bud neck. Polymerized ESCRT-III filaments ultimately drive the vesicle scission process through additional membrane remodeling events, which may include lipid demixing.