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.
Highlights
This review focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit
It is clear that the a3 isoform plays a crucial role in bone resorption by osteoclasts; the a3 isoform is a potential drug target for osteoporosis treatment, in which the excessive bone loss associated with this disease could be controlled by inhibiting a3-containing V-ATPases [50,98,99]
An advantage of targeting the V-ATPase a3 subunit to prevent osteolytic diseases is that osteoclast differentiation and fusion is unaffected by the absence of a3, as evidenced by the fact that, to date, all a3 mutations have resulted in osteoclast-rich osteopetrosis [96,131,132,133] (Figure 3, Table 2)
Summary
V-ATPases are ATP-driven proton pumps found in the endomembrane of the intracellular compartments in all of the eukaryotic cells and the plasma membrane of several specialized cells [27]. V-ATPases are responsible for acidifying and maintaining the pH of intracellular organelles, including the Golgi apparatus, endosome, lysosome and secretory vesicles [28,29]. The released ligands are subsequently targeted to the lysosomes, where the low pH maintained by V-ATPases facilitates their degradation [31,32] This process is important for the continued uptake of ligands such as low-density lipoprotein (LDL), a main carrier of plasma membrane cholesterol [33]. In addition to the conventional functions of V-ATPases in intracellular signalling and membrane trafficking by generating pH gradients, recent findings suggest novel emerging roles of V-ATPases in the modulation of the function of receptors and their regulatory complexes through direct protein–protein interactions. The importance and novel emerging roles of V-ATPases in many signalling pathways and diseases, including cancers, makes them promising targets for drug development
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