Vacuolar H+-ATPases (V-ATPases) are large multisubunit proton pumps that are required for housekeeping acidification of membrane-bound compartments in eukaryotic cells. Mammalian V-ATPases are composed of 13 different subunits. Their housekeeping functions include acidifying endosomes, lysosomes, phagosomes, compartments for uncoupling receptors and ligands, autophagosomes, and elements of the Golgi apparatus. Specialized cells, including osteoclasts, intercalated cells in the kidney and pancreatic beta cells, contain both the housekeeping V-ATPases and an additional subset of V-ATPases, which plays a cell type specific role. The specialized V-ATPases are typically marked by the inclusion of cell type specific isoforms of one or more of the subunits. Three human diseases caused by mutations of isoforms of subunits have been identified. Cancer cells utilize V-ATPases in unusual ways; characterization of V-ATPases may lead to new therapeutic modalities for the treatment of cancer. Two accessory proteins to the V-ATPase have been identified that regulate the proton pump. One is the (pro)renin receptor and data is emerging that indicates that V-ATPase may be intimately linked to renin/angiotensin signaling both systemically and locally. In summary, V-ATPases play vital housekeeping roles in eukaryotic cells. Specialized versions of the pump are required by specific organ systems and are involved in diseases. 1. The Importance of “Housekeeping” Acidification in Eukaryotic Cells Eukaryotic cells use the localized concentration of protons in vesicles, powered by ATP hydrolysis by the vacuolar H+-ATPase (V-ATPase), for essential purposes [1]. Acidic proteases in the lysosome are converted by changes in pH to active forms that can degrade other proteins as in the case of acid cysteine proteinases of the cathepsin family [2]. The low pH also triggers changes in the conformation of proteins that make them more susceptible to proteolytic degradation. In a more selective sense, many proteins are processed by proteolytic enzymes from a pro form, and this is often linked to cycling of the proteins through acidic compartments on their way to their final destination (Figure 1) [3]. In compartments for uncoupling receptors and ligands (CURL compartments) receptors make use of V-ATPase-dependent acidification to release their ligand in order to allow recycling of the receptor to the plasma membrane and reuse [1]. Figure 1: Roles of V-ATPases in cell physiology. V-ATPases have vital roles in the Golgi apparatus. Mutations in the a2-subunit, which is found in the Golgi,
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