Assembly and disassembly of the ESCRT-III membrane scission complex

Abstract

The ESCRT (endosomal sorting complex required for transport) pathway promotes the final membrane scission step at the end of cytokinesis, assists viral budding and generates multivesicular bodies (MVBs). These seemingly unrelated processes require a topologically similar membrane deformation and scission event that buds membranes/vesicles out of the cytoplasm. The topology of this budding reaction is 'opposite' to reactions that bud endocytic and secretory vesicles into the cytoplasm. Here we summarize recent findings that help to understand how the ESCRT machinery, in particular the ESCRT-III complex, assembles on its target membranes, executes membrane scission and is disassembled by the AAA-ATPase Vps4.

Fig. 1

The three ESCRT pathways. (A) In the MVB pathway ESCRT-0 initiates the sequential recruitment of ESCRT-I, -II to endosomes. In cytokinesis, Cep55 recruits ESCRT-I and Alix to the midbody. HIV-1 Gag recruits ESCRT-I and Alix to the plasma membrane. All processes require ESCRT-III and Vps4 for membrane remodelling, potentially in different assemblies. (B) ESCRT pathways: The red lines mark direct protein–protein interactions and the arrowheads indicate the direction of the interaction.

Fig. 2

ESCRT-III subunit cycling. Cartoon of an ESCRT-III subunit based on the crystal structure of human CHMP3. Inactive, autoinhibited ESCRT-III subunits can be activated either by Vps25 or Alix. Vps4 resets the active ESCRT-III subunits to the ‘inactive’ state.

Fig. 3

Models of ESCRT mediated membrane scission. (A) The ‘ESCRT-III only’ model (left panel): ESCRT-III triggers membrane budding and scission. Vps4 activity is limited to ESCRT-III recycling. The ‘ESCRT-III Vps4’ (right panel) model presumes an active role for Vps4. Vps4 mediated disassembly of ESCRT-III results in membrane scission. (B) Left panel: The ‘Purse String model’: Vps4 removes one ESCRT-III subunit after another. The shrinking filament constricts and scission the membrane. Right panel: ESCRT-III assembly has deformed the membrane. Binding of Vps4 and rapid ESCRT-III disassembly trigger membrane scission.