The H⁺-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

Abstract

A primary function of the H+-ATPase (or V-ATPase) is to create an electrochemical proton gradient across eukaryotic cell membranes, which energizes fundamental cellular processes. Its activity notably allows for the acidification of intracellular vesicles and organelles, which is necessary for many essential cell biological events to occur. In addition, many specialized cell types in various organ systems such as the kidney, bone, male reproductive tract, inner ear, olfactory mucosa, and more, use plasma membrane V-ATPases to perform specific activities that depend on extracellular acidification. However, it is increasingly apparent that V-ATPases are central players in many normal and pathophysiological processes that directly influence human health in many different, and sometimes unexpected ways. These include cancer, neurodegenerative diseases, diabetes, and sensory perception, as well as energy and nutrient sensing functions within cells. This review first covers the well-established role of the V-ATPase as a transmembrane proton pump in the plasma membrane and intracellular vesicles, and outlines factors contributing to its physiological regulation in different cell types. This is followed by a discussion of the more recently emerging unconventional roles for the V-ATPase, such as its role as a protein interaction hub involved in cell signaling, and the (patho)physiological implications of these interactions. Finally, the central importance of endosomal acidification and V-ATPase activity on viral infection will be discussed in the context of the current COVID-19 pandemic.

From Pinocytosis to Methuosis—Fluid Consumption as a Risk Factor for Cell Death

“…Its dysfunction may play critical roles in various diseases including diabetes, cancer, neurodegeneration, osteopetrosis, skin disorders, or renal tubular acidosis and other pathologies. Furthermore, it is also essential for viral entry into cells (for reviews on v-ATPase, see Nishi and Forgac, 2002 ; Platt et al, 2012 ; Maxson and Grinstein, 2014 ; Rappaport et al, 2016 ; Kissing et al, 2018 ; Futai et al, 2019 ; Collins and Forgac, 2020 ; Song Q. et al, 2020 ; Vasanthakumar and Rubinstein, 2020 ; Chadwick et al, 2021a , b ; Eaton et al, 2021 ).…”

“…Beyond that, targeting specific ion transport mechanisms or their regulators will help to combat cellular entry of pathogens such as viruses or bacteria. For example, inhibition of PIKfyve, TPCs, NHEs, or the v-ATPase could help prevent cellular infection by Ebola virus, SARS-CoV-2, and other viruses ( Mercer and Helenius, 2009 ; Sakurai et al, 2015 ; Kang et al, 2020 ; Mercer et al, 2020 ; Petersen et al, 2020 ; Spix et al, 2020 ; Eaton et al, 2021 ).…”

RAVE and Rabconnectin-3 Complexes as Signal Dependent Regulators of Organelle Acidification

“…V-ATPase dependent endosomal acidification is essential for cellular homeostasis and developmental processes ( Eaton et al, 2021 ). Two important developmental processes which depend on V-ATPase activity are Wnt and Notch signaling ( Yan et al, 2009 ; Cruciat et al, 2010 ).…”

Purification of active human vacuolar H+-ATPase in native lipid-containing nanodiscs

“…The internal pH of subcellular compartments, critical to their identity and function, is maintained by a large multisubunit ATP hydrolysis–driven proton pump referred to as vacuolar H + -ATPase (V-ATPase). V-ATPase activity is essential for diverse cellular processes including pH and ion homeostasis, endocytosis and exocytosis, protein degradation, zymogen activation, insulin secretion, neurotransmitter release, and pro-growth and developmental signaling pathways including Wnt, Notch, and mTOR ( 1 , 2 ). The V-ATPase can also be found on the plasma membrane of dedicated acid-secreting cells such as osteoclasts and renal α-intercalated cells where the enzyme is required for bone demineralization and urinary acidification, respectively ( 3 , 4 ).…”

“…For example, isoform a 3 is enriched in the plasma membrane of osteoclasts where enzyme function is required for bone resorption ( 6 , 45 ). In renal α-intercalated cells, isoform a 4 is enriched in the apical membrane where it acidifies the urine, which is critical to maintenance of systemic pH homeostasis ( 2 , 5 ). It should be noted that while some tissues or cell types contain an enriched a subunit isoform population required for specialized function, such subpopulations coexist with V-ATPases containing different a isoforms found on other compartments in the same cell ( 63 , 64 ).…”