The V-ATPase a3 Subunit: Structure, Function and Therapeutic Potential of an Essential Biomolecule in Osteoclastic Bone Resorption

Abstract

This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting its critical role in bone physiology. Despite its essential role in bone remodeling and its involvement in bone diseases, little is known about the way in which this subunit is targeted and regulated within osteoclasts. To this end, this review is broadened to include the three other mammalian paralogues (a1, a2 and a4) and the two yeast orthologs (Vph1p and Stv1p). By examining the literature on all of the paralogues/orthologs of the V-ATPase a subunit, we hope to provide insight into the molecular mechanisms and future research directions specific to a3. This review starts with an overview on bone, highlighting the role of V-ATPases in osteoclastic bone resorption. We then cover V-ATPases in other location/functions, highlighting the roles which the four mammalian a subunit paralogues might play in differential targeting and/or regulation. We review the ways in which the energy of ATP hydrolysis is converted into proton translocation, and go in depth into the diverse role of the a subunit, not only in proton translocation but also in lipid binding, cell signaling and human diseases. Finally, the therapeutic implication of targeting a3 specifically for bone diseases and cancer is discussed, with concluding remarks on future directions.

The V-ATPases in cancer and cell death

“…V-ATPase containing an a3 isoform translocates to the plasma membrane, acidifying the extracellular space to promote bone resorption. Mutations in the T-cell immune regulator 1, ATPase H + transporting V0 subunit A3 (TCIRG1) gene encoding the a3 isoform are highly associated with osteoporosis [ 55 ]. These findings indicate that abnormal V-ATPase trafficking leads to inflammation-related diseases, such as osteoporosis.…”

Identification of a five-gene signature deriving from the vacuolar ATPase (V-ATPase) sub-classifies gliomas and decides prognoses and immune microenvironment alterations

“…A coding gene signature of subunits and chaperones of the V-ATPase was acquired from a previous study [ 14 ], including 14 genes of the V1 subunit (ATP6V1A, ATP6V1B1, ATP6V1B2, ATP6V1C1, ATP6V1C2, ATP6V1C3, ATP6V1D, ATP6V1E1, ATP6V1E2, ATP6V1F, ATP6V1G1, ATP6V1G2, ATP6V1G3 and ATP6V1H), 13 genes of the V0 subunit (ATP6V0A1, ATP6V0A2, TCIRG1, ATP6V0A4, ATP6V0C, ATP6V0B, ATP6V0D1, ATP6V0D2, ATP6V0E1, ATP6V0E2, RNASEK, ATP6AP1 and ATP6AP2) and three chaperone molecules (TMEM199, VMA21 and CCDC115). Transcriptome data of glioma patients were acquired from the Cancer Genome Atlas (TCGA) using the UCSC Xena browser (TCGA-GBMLGG dataset (n = 702), https://xenabrowser.net/datapages/ ) and the Chinese Glioma Genome Atlas (CGGA) database (CGGA-mRNA693 (n = 693), CGGA-mRNA325 (n = 325) and CGGA-mRNA301 (n = 301), http://www.cgga.org.cn/ ) and Gliovis platform (Rembrandt (n = 472) and Gravendeel (n = 284), http://gliovis.bioinfo.cnio.es ) [ 15–25 ].…”

V-ATPase a3 Subunit in Secretory Lysosome Trafficking in Osteoclasts

“…The V 1 sector is a soluble complex with three catalytic A subunits, and the V o sector is a membrane-embedded complex with a proton pathway formed by the a subunit and the c-ring. [13][14][15][16][17][18] Similar to F-ATPase (ATP synthase), V-ATPase couples catalysis and proton transport through subunit rotation, which is called rotational catalysis. [16][17][18] The mechanism has been analyzed in detail using bacterial enzymes, and these studies have been covered elsewhere.…”

“…[19][20][21] Among the subunits composing mammalian V-ATPase, six subunits have cell-and/or organellespecific isoforms, resulting in diversity in isoform composition. [13][14][15][16][17][18] For example, the a subunit in the V o sector has four isoforms (a1, a2, a3, and a4). The a4 isoform is specifically expressed in kidney, while the other three isoforms are ubiquitously expressed, but localized in specific organelles.…”