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 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. It is, however, 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.
Highlights
It has been appreciated for decades that a primary function of the H þ -ATPase is to create an electrochemical proton gradient across eukaryotic cell membranes, which energizes fundamental cellular processes
After dissociation of mammalian target of rapamycin complex 1 (mTORC1), AMP kinase (AMPK) is recruited to the V-ATPase-Ragulator-Axin-LKB1 complex, where it is phosphorylated and activated by LKB1, which promotes the conversion of cellular processes from anabolic to catabolic [164] (Fig. 10)
The Forgac group [44], on the other hand, looked mainly at acute (15 min) glucose starvation and focused on lysosomal assembly. One explanation for these discrepancies could be that the process is dynamic, and while acute glucose starvation leads to assembly on the lysosomal membrane, longer glucose starvation results in overall disassembly of V-ATPase, especially those present at the plasma membrane, to conserve energy
Summary
It has been appreciated for decades that a primary function of the H þ -ATPase (or V-ATPase) is to create an electrochemical proton gradient across eukaryotic cell membranes, which energizes fundamental cellular processes. While the four common isoforms of the transmembrane “a” subunit are known as a1–4, a total of 11 splice variants were identified in our database search, raising the need for further work to dissect the cellular roles of this important VO sector component [18] This is overshadowed, by the remarkable discovery that 17 “a” subunit genes are present in Paramecium, providing a rich tapestry of potential V-ATPase assemblies to direct intracellular targeting and function [19]. While most membrane proteins appear as globular structures usually between 5–12 nm in diameter, VATPase-rich membranes contain characteristic elongated particles $20-nm long that frequently appear to be composed of two (or sometimes more) globular particles fused together, often resulting in a dumbbell like appearance (Fig. 3C) Such particles are commonly seen in V-ATPase-rich intercalated cells in the kidney, amphibian epidermis and bladder, turtle bladder, osteoclasts, and narrow cells in the epididymis [31]. Transmembrane proton transport by the V-ATPase can be regulated in several different ways to modify pH in extracellular compartments or within intracellular vesicles
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