MVB vesicle formation: ESCRT-dependent, ESCRT-independent and everything in between

Abstract

Multivesicular bodies (MVBs) are endosomes that have internalized portions of the limiting membrane into the compartment, thereby forming intralumenal vesicles. This vesicle formation is unusual in that it is directed away from the cytoplasm, which requires a unique mechanism unlike any mechanism described for other vesicle formation events. The best contenders for the machinery that drives MVB vesicle formation are the ESCRT protein complexes. However, increasing evidence suggests that lipids may play a key role in this membrane-deformation process. This review attempts to combine the seemingly contradictory findings into a MVB vesicle formation model that is based on a lipid-driven and ESCRT-regulated mechanism.

Figure 1

Models for ESCRT-dependent and independent mechanisms of ILV formation. The deformation of the membrane is mainly driven by the formation of a membrane domain with a unique lipid composition and is supported by the pH gradient across the endosomal membrane. (A) ESCRT-0 sorts ubiquitinated cargo proteins into the lipid domain. The neck of the forming vesicle is first stabilized by ESCRT-I and ESCRT-II. The neck is further narrowed by the formation of ESCRT-III. The recruitment of the Vps4 complex to ESCRT-III initiates the scission of the vesicle neck and the disassembly of the ESCRT-III complex. (B) Protozoan parasites lack ESCRT-I and ESCRT-II and thus exhibit a simplified MVB vesicle formation that may not include sorting of ubiquitinated cargoes. (C) Melanosomes and exosomes exhibit ESCRT-independent ILV formation that is dependent on self-organizing lipid and cargo domains.