Non-canonical functions of the V-ATPase and their disease implications

The vacuolar H+ ATPase (V-ATPase) is an ATP dependent proton pump localized to the endomembrane system of all eukaryotic cells, where it acidifies intracellular compartments. As such, the V-ATPase maintains optimum organellar pH for their respective functions. Acidification by the V-ATPase is required for basic cellular functions such as pH and ion homeostasis, endocytosis, protein degradation, hormone secretion, neurotransmitter uptake and pathogen entry. Aberration in V-ATPase's proton pumping activity is associated with diseases of the kidney and bone, deafness, diabetes and cancer, with complete abrogation resulting in embryonic lethality.    

​The V-ATPase is a multisubunit, membrane protein complex which works as a rotary molecular motor and years of structural and biochemical investigation has delineated the enzyme's mechanism to a significant extent. Recently, the V-ATPase has emerged as a protein-protein interaction hub with functional involvement in metabolic signaling, autophagy, immune response and embryonic development. These non-canonical functions of the V-ATPase have implications in neurodegenerative diseases and cancer. The V-ATPase is a large and conformationally dynamic motor complex and understanding how this molecular machine accomplishes multiple roles will be the overarching goal of our lab.