Resolving the two-body problem: A postulated role for the V0 sector of the V0V1-ATPase in exosome biogenesis and multivesicular body fate

Because the discovery of the multivesicular body (MVB) as the origin of secreted vesicles or exosomes, the question arose and still looms-what distinguishes an MVB destined for fusion with the plasma membrane (EXO-MVB) facilitating exosome release from an MVB involved in transport of content to the lysosome (LYSO-MVB). Do they have independent origins? Hence, the two-body problem. We hypothesize that a key to this conundrum is the membrane spanning V0 sector of the proton pump, V0V1-ATPase. The V0V1-ATPase participates in the acidification of intracellular compartments, although V0 can function separately from V1 and different V0 isoforms are endowed with membrane binding capabilities that allow the V0V1-ATPase to selectively localize to different endocytic compartments including early and late endosomes and lysosomes. We propose that V0, in collaboration with cholesterol and phosphoinositides, plays a central role in the early endosome as a nucleation center to direct the de novo assembly of an EXO-MVB scaffold. The EXO-MVB scaffold may play multiple roles-operating as an assembly platform, participating in membrane fission as well as providing downstream navigational queues necessary for exosome secretion. Thus, V0 may represent an influential nexus, a starting point, in exosome biogenesis.