The ESCRT machinery

Abstract

The endosomal sorting complexes required for transport (ESCRT) assemble into a multisubunit machinery that performs a topologically unique membrane bending and scission reaction away from the cytoplasm. This evolutionarily highly conserved process is required for the multivesicular body (MVB) pathway, cytokinesis and HIV budding. The modular setup of the machinery with five distinct ESCRT complexes (ESCRT-0, -I, -II, -III and the Vps4 complex) that have a clear division of tasks — from interaction with ubiquitinated membrane proteins to membrane deformation and abscission — allows them to be flexibly integrated into these three very different biological processes (Figure 1).

Figure 1

ESCRT-dependent processes. ESCRT complexes catalyze a topologically distinct membrane-remodelling event: budding and scission of membranes away from the cytosol. During multivesicular body (MVB) sorting the ESCRT machinery generates intraluminal vesicles (diameter of ∼25 nmeast and ∼50 nm in human cells) of MVBs to deliver ubiquitinated membrane proteins into lysosomes for degradation. During cytokinesis ESCRT complexes catalyze the final membrane abscission at the midbody. Additionally, the ESCRT machinery is required for the release of certain enveloped viruses (i.e. human immunodeficiency virus, HIV) from the surface of infected cells.

Figure 2

Model for cargo clustering and sequential assembly of the ESCRT complexes. ESCRT-0 (brown) initiates the MVB pathway. ESCRT-0 binds to PI3P and clusters ubiquitinated membrane proteins via multiple ubiquitin-binding domains. ESCRT-I (green) is recruited by ESCRT-0 (Vps27) and also binds to ubiquitinated cargo. ESCRT-II (blue) interacts via the Glue domain of Vps36 with ESCRT-I, PI3P and cargo. The ESCRT-II subunit Vps25 serves as a nucleation point for stepwise assembly of the filamentous ESCRT-III complex (yellow–orange), which sequesters cargo and drives inward budding of the vesicle.

Figure 3

Membrane scission and ESCRT-III disassembly by Vps4. The ESCRT-III subunits Vps24 and Vps2 terminate assembly of the ESCRT-III filament (orange) on the endosome surface. Vps2 together with Did2, Ist1 and Vps60 build a recruitment complex for the AAA-ATPase Vps4 and its cofactor Vta1. Once assembled, the Vps4 complex (pink) catalyzes disassembly of the ESCRT-III filament in an ATP-driven reaction. ESCRT-III disassembly terminates each round of the MVB pathway, which results in the generation of a cargo-laden 25 nm MVB vesicle (50 nm in human cells).