Proton Pump

The vacuolar (H+)-ATPases (V-ATPases) are ATP-driven proton pumps present in a variety of cellular membranes. Within intracellular membranes, V-ATPases function in membrane trafficking processes such as receptor-mediated endocytosis and intracellular trafficking of lysosomal enzymes. Acidification of endocytic compartments by the V-ATPases signals the release of internalized ligands (such as low density liporotein) from their receptors and allows these receptors to recycle to the cell surface. The released ligands are targeted to the lysosome, where the low pH facilitates their degradation by cathepsins. Acidification of endosomes is also involved in the vesicle budding that moves ligands along the endocytic pathway. Lysosomal enzymes bound to mannose-6-phosphate receptors in the trans Golgi network similarly transit endocytic compartments, where the low pH causes their dissociation from the receptors and their subsequent targeting to lysosomes. Thus, V-ATPase-dependent acidification plays an important signaling role in the cell. The V-ATPase is composed of fourteen subunits organized into two domains: the cytosolic V1 domain and the integral V0 domain. V1 is composed of subunits A-H and is responsible for ATP hydrolysis. 
Regulated assembly represents an important mode of regulating V-ATPase activity in cells. The reversible dissociation of the V1 and V0 domains occurs in response to glucose depletion in both yeast and mammalian cells and in response to molting in insect cells, likely as a means to conserve cellular stores of ATP. Assembly of V1 and V0 occurs during maturation of dendritic cells to aid in antigen processing and in response to EGF (epidermal growth factor). Assembly in yeast is promoted by activation of PKA (protein kinase A), interaction with aldolase and the heterotrimeric complex RAVE (Regulator of the ATPase of Vacuolar and Endosomal memranes), whereas dissociation requires catalytic activity and intact microtubules. Assembly in mammalian cells is promoted by activation of PI3K and, in dendritic cells, activation of mTORC1 (mechanistic target of rapamycin complex 1). V-ATPase-dependent acidification is now established as a central regulator of many cellular and organismal processes, including membrane traffic, protein degradation, pH homeostasis and bone resorption.


1.Cotter K,et al. Trends Biochem Sci. 2015;40(10):611–622.