Vacuolar ATPase in Physiology and Pathology: Roles in Neurobiology, Infectious Disease, and Cancer

Vacuolar ATPase (V-ATPase) is an ATP-dependent proton pump present in all eukaryotic cells. V-ATPase is a critical regulator of intracellular pH across the endomembrane system and is essential for fundamental cellular functions including endocytosis and exocytosis, protein modification and maturation and loading of secretory vesicles. Here we describe the structure, regulation, and function of V-ATPase in pH regulation and the roles of V-ATPase in neurobiology, infectious disease, and cancer. V-ATPase is composed of two domains: a membrane-peripheral domain, V1, and a membrane-integral domain, Vo. When extracellular glucose concentrations drop the V1Vo complex disassembles to inhibit V-ATPase activity and prevent energy depletion; this ability allows yeast cells to quickly respond to alterations in energy state. Next, we present a body of growing new evidence that highlights the importance of V-ATPase in human health and disease. We discuss mechanisms by which V-ATPase participates in neurotransmission, neurodegeneration, and stroke-associated neuronal cell death. Then, we focus on the involvement of pH and V-ATPase in the pathogenesis of viruses, bacteria, and fungi and the processes necessary to ensure pathogen replication. In the last section, we capitalize upon a repertoire of studies in recent years that indicate that V-ATPase is a critical player in adaptation to cellular stress and that V-ATPase activity directly and indirectly contributes to many of the hallmarks of cancer.