The MVB Pathway
Membrane transport pathways from both the plasma membrane and Golgi intersect at endosomes. As endosomes mature into multivesicular bodies (MVBs), some transmembrane proteins are incorporated into vesicles that bud into the lumen (see figure, left). Most of these transmembrane proteins are marked as cargo molecules of lumenal MVB vesicles by a single ubiquitin (Ub) or a short chain of 2-3 Ub subunits that are added to their cytosolic domains after translation. When the limiting (outer) membrane of an MVB fuses with the lysosome in animal cells or with the vacuole in yeast, MVB vesicles and their protein contents become vulnerable to degradation.
The ESCRTs
Both the biogenesis of MVB vesicles and the recognition of ubiquitinated transmembrane proteins as MVB vesicle cargoes depend on a set of cytosolic protein complexes known as the endosomal sorting complexes required for transport (ESCRTs). The ESCRTs associate transiently with endosomal membranes ESCRTs-0, -I, and -II each have Ub-binding subunits and function specifically to concentrate ubiquitinated MVB cargoes. In contrast, ESCRT-III does not bind Ub but, instead, appears to polymerize on endosomal membranes, the significance of which is currently a mystery. The dissociation of ESCRTs requires Vps4, an AAA-type ATPase. The model at the right depicts the hypothetical sequence of ESCRT activity based on the concentric circle model proposed in Nickerson et al. (2007).
The least understood aspect of ESCRT function concerns its role in the biogenesis of lumenal vesicles. Abundant data support the concept that ESCRTs function in vesicle formation: disruption of the ESCRT machinery results in 1) a block in MVB vesicle budding, 2) a block in budding of HIV-1 and other enveloped viruses via a process that is topologically equivalent to MVB vesicle formation (click here for review), and 3) a block in cytokinesis, which also depends on membrane dynamics similar to those that occur during MVB biogenesis (click here to read why). However, the budding of exosomal vesicles into the endosome lumen also resembles MVB vesicle formation yet occurs independently of ESCRTs (click here to read this discovery). In the absence of data that directly demonstrates a molecular mechanism for ESCRTs in MVB vesicle budding, a role for ESCRTs in this process remains speculative.