vacuolar proton translocating atpases


Summary: Proton-translocating ATPases that are involved in acidification of a variety of intracellular compartments.

Top Publications

  1. Yan Y, Denef N, Schupbach T. The vacuolar proton pump, V-ATPase, is required for notch signaling and endosomal trafficking in Drosophila. Dev Cell. 2009;17:387-402 pubmed publisher
    ..Our results demonstrate that Rbcn-3 affects Notch signaling and trafficking through regulating V-ATPase function, which implies that the acidification of an intracellular compartment in the receiving cells is crucial for signaling. ..
  2. Lafourcade C, Sobo K, Kieffer Jaquinod S, Garin J, van der Goot F. Regulation of the V-ATPase along the endocytic pathway occurs through reversible subunit association and membrane localization. PLoS ONE. 2008;3:e2758 pubmed publisher
    ..Altogether our findings indicate that the activity of the vATPase in the endocytic pathway is regulated both by reversible association/dissociation and the interaction with specific lipid environments. ..
  3. Sun Wada G, Tabata H, Kawamura N, Aoyama M, Wada Y. Direct recruitment of H+-ATPase from lysosomes for phagosomal acidification. J Cell Sci. 2009;122:2504-13 pubmed publisher
    ..These results show that lysosomal V-ATPase is recruited directly to the phagosomes via tubular lysosomes to establish the acidic environment hostile to pathogens. ..
  4. Beyenbach K, Wieczorek H. The V-type H+ ATPase: molecular structure and function, physiological roles and regulation. J Exp Biol. 2006;209:577-89 pubmed
    ..Some diseases can now be attributed to genetic alterations of specific subunits of the V-type H+ ATPase. ..
  5. Cipriano D, Wang Y, Bond S, Hinton A, Jefferies K, Qi J, et al. Structure and regulation of the vacuolar ATPases. Biochim Biophys Acta. 2008;1777:599-604 pubmed publisher
    ..This review focuses on recent advances in our lab in understanding the structure and regulation of the V-ATPases. ..
  6. Sun Wada G, Toyomura T, Murata Y, Yamamoto A, Futai M, Wada Y. The a3 isoform of V-ATPase regulates insulin secretion from pancreatic beta-cells. J Cell Sci. 2006;119:4531-40 pubmed
    ..The secretion of insulin from isolated islets in response to glucose or depolarizing stimulation was impaired. These results suggest that the a3 isoform of V-ATPase has a regulatory function in the exocytosis of insulin secretion. ..
  7. Sun Wada G, Tabata H, Kawamura N, Futai M, Wada Y. Differential expression of a subunit isoforms of the vacuolar-type proton pump ATPase in mouse endocrine tissues. Cell Tissue Res. 2007;329:239-48 pubmed
    ..We have found that the a3 isoform is strongly expressed in all these endocrine tissues. Our results suggest that functions of the a3 isoform are commonly involved in the process of exocytosis in regulated secretion. ..
  8. Jefferies K, Cipriano D, Forgac M. Function, structure and regulation of the vacuolar (H+)-ATPases. Arch Biochem Biophys. 2008;476:33-42 pubmed publisher
    ..V-ATPases are emerging as potential drug targets in treating a number of human diseases including osteoporosis and cancer. ..
  9. Askmyr M, Holmberg J, Flores C, Ehinger M, Hjalt T, Richter J. Low-dose busulphan conditioning and neonatal stem cell transplantation preserves vision and restores hematopoiesis in severe murine osteopetrosis. Exp Hematol. 2009;37:302-8 pubmed publisher
    ..Low-dose busulphan conditioning and neonatal SCT leads to prolonged survival of oc/oc mice, reverses osteopetrosis and prevents blindness even at low engraftment levels. ..

More Information


  1. Peri F, NUSSLEIN VOLHARD C. Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell. 2008;133:916-27 pubmed publisher
    ..As a real-time description of microglial phagocytosis in vivo, this work advances our understanding of microglial-mediated neuronal degeneration, a hallmark of many neuronal diseases. ..
  2. Feng H, Cheng T, Pavlos N, Yip K, Carrello A, Seeber R, et al. Cytoplasmic terminus of vacuolar type proton pump accessory subunit Ac45 is required for proper interaction with V(0) domain subunits and efficient osteoclastic bone resorption. J Biol Chem. 2008;283:13194-204 pubmed publisher
    ..In all, our data suggest that the cytoplasmic terminus of Ac45 contains elements necessary for its proper interaction with V(0) domain and efficient osteoclastic bone resorption. ..
  3. Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol. 2007;8:917-29 pubmed
    ..The V-ATPases have been implicated in a number of diseases and, coupled with their complex isoform composition, represent attractive and potentially highly specific drug targets. ..
  4. Pallen M, Bailey C, Beatson S. Evolutionary links between FliH/YscL-like proteins from bacterial type III secretion systems and second-stalk components of the FoF1 and vacuolar ATPases. Protein Sci. 2006;15:935-41 pubmed
    ..In particular, we show that the FliH/YscL-like proteins and the E subunits of vacuolar ATPases represent fusions of domains homologous to second-stalk components of the F(o)F(1) ATPase (the b and delta subunits). ..
  5. Hinton A, Sennoune S, Bond S, Fang M, Reuveni M, Sahagian G, et al. Function of a subunit isoforms of the V-ATPase in pH homeostasis and in vitro invasion of MDA-MB231 human breast cancer cells. J Biol Chem. 2009;284:16400-8 pubmed publisher
    ..However, other V-ATPases affecting the pH of the cytosol and intracellular compartments, particularly those containing a3, are also involved in invasion. ..
  6. Liegeois S, Benedetto A, Garnier J, Schwab Y, Labouesse M. The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans. J Cell Biol. 2006;173:949-61 pubmed
    ..These mutations allowed us to establish that the V0 sector mediates secretion of Hedgehog-related proteins. Our data raise the possibility that the V0 sector mediates exosome and morphogen release in mammals. ..
  7. Giorgione J, Clarke M. Heterogeneous modes of uptake for latex beads revealed through live cell imaging of phagocytes expressing a probe for phosphatidylinositol-(3,4,5)-trisphosphate and phosphatidylinositol-(3,4)-bisphosphate. Cell Motil Cytoskeleton. 2008;65:721-33 pubmed publisher
    ..We conclude that caution is needed in extrapolating results from latex bead phagosomes to phagosomes containing physiological substances, especially in early stages of the endocytic pathway. ..
  8. Brown D, Paunescu T, Breton S, Marshansky V. Regulation of the V-ATPase in kidney epithelial cells: dual role in acid-base homeostasis and vesicle trafficking. J Exp Biol. 2009;212:1762-72 pubmed publisher
    ..Recent information about these pH-sensing mechanisms, which include the role of the V-ATPase itself as a pH sensor and the soluble adenylyl cyclase as a bicarbonate sensor, will be addressed in this review. ..
  9. Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens R, Yu L, et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 2006;69:105-13 pubmed
    ..Renin-induced increases in TGF-beta1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin. ..
  10. Bowman E, Bowman B. V-ATPases as drug targets. J Bioenerg Biomembr. 2005;37:431-5 pubmed
    ..Because of the variety of processes and diseases associated with V-ATPases and the possibility of designing selective inhibitors, the V-ATPases are attractive targets for development of therapeutic agents. ..
  11. Kane P. The long physiological reach of the yeast vacuolar H+-ATPase. J Bioenerg Biomembr. 2007;39:415-21 pubmed
  12. Nuckels R, Ng A, Darland T, Gross J. The vacuolar-ATPase complex regulates retinoblast proliferation and survival, photoreceptor morphogenesis, and pigmentation in the zebrafish eye. Invest Ophthalmol Vis Sci. 2009;50:893-905 pubmed publisher
  13. Jansen E, Scheenen W, Hafmans T, Martens G. Accessory subunit Ac45 controls the V-ATPase in the regulated secretory pathway. Biochim Biophys Acta. 2008;1783:2301-10 pubmed publisher
    ..We conclude that in neuroendocrine cells Ac45 guides the V-ATPase through the secretory pathway, thereby regulating the V-ATPase-mediated process of Ca(2+)-dependent peptide secretion. ..
  14. Yadav J, Muend S, Zhang Y, Rao R. A phenomics approach in yeast links proton and calcium pump function in the Golgi. Mol Biol Cell. 2007;18:1480-9 pubmed
    ..We conclude that overlapping phenotypes with Pmr1 reveal Golgi-localized functions of the V-ATPase and emphasize the importance of calcium and proton transport in secretory/prevacuolar traffic. ..
  15. Kinchen J, Ravichandran K. Phagosome maturation: going through the acid test. Nat Rev Mol Cell Biol. 2008;9:781-95 pubmed publisher
    ..This suggests that a machinery that is distinct from receptor-mediated endocytosis is used in phagosome maturation. ..
  16. Vos W, Vermeer L, Hemminga M. Conformation of a peptide encompassing the proton translocation channel of vacuolar H(+)-ATPase. Biophys J. 2007;92:138-46 pubmed
    ..We discuss this finding in the light of current models for proton translocation. A novel role for a buried charged residue (H729) is proposed. ..
  17. Poea Guyon S, Amar M, Fossier P, Morel N. Alternative splicing controls neuronal expression of v-ATPase subunit a1 and sorting to nerve terminals. J Biol Chem. 2006;281:17164-72 pubmed
    ..Our results indicate that alternative splicing of exon N controls differential sorting of a1 variants to nerve terminals or distal dendrites, whereas exon C regulates their neuronal expression. ..
  18. Wang Y, Cipriano D, Forgac M. Arrangement of subunits in the proteolipid ring of the V-ATPase. J Biol Chem. 2007;282:34058-65 pubmed
    ..These results suggest that functionally assembled V-ATPase complexes contain the proteolipid subunits arranged in a unique order in the ring. ..
  19. Hong Hermesdorf A, Brüx A, Grüber A, Gruber G, Schumacher K. A WNK kinase binds and phosphorylates V-ATPase subunit C. FEBS Lett. 2006;580:932-9 pubmed
    ..Taken together, our results provide evidence that V-ATPases are potential targets of WNK kinases and their associated signaling pathways. ..
  20. Duarte A, de Jong E, Wechselberger R, van Mierlo C, Hemminga M. Segment TM7 from the cytoplasmic hemi-channel from VO-H+-V-ATPase includes a flexible region that has a potential role in proton translocation. Biochim Biophys Acta. 2007;1768:2263-70 pubmed
    ..This movement in TM7 is suggested to cause the opening and closing of the cytoplasmic proton hemi-channel and enables proton translocation. ..
  21. Marshansky V, Futai M. The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function. Curr Opin Cell Biol. 2008;20:415-26 pubmed publisher
    ..Here, we will review these studies with emphasis on novel direct roles of V-ATPase in the regulation of vesicular trafficking events. ..
  22. Dixon N, Pali T, Kee T, Ball S, Harrison M, Findlay J, et al. Interaction of spin-labeled inhibitors of the vacuolar H+-ATPase with the transmembrane Vo-sector. Biophys J. 2008;94:506-14 pubmed
    ..The INDOL6 derivative, which is closest to the parent INDOL0 inhibitor, displays limited subtype specificity for the osteoclast V-ATPase, with an IC(50) in the 10-nanomolar range. ..
  23. Vidarsson H, Westergren R, Heglind M, Blomqvist S, Breton S, Enerback S. The forkhead transcription factor Foxi1 is a master regulator of vacuolar H-ATPase proton pump subunits in the inner ear, kidney and epididymis. PLoS ONE. 2009;4:e4471 pubmed publisher
  24. Sasazawa Y, Futamura Y, Tashiro E, Imoto M. Vacuolar H+-ATPase inhibitors overcome Bcl-xL-mediated chemoresistance through restoration of a caspase-independent apoptotic pathway. Cancer Sci. 2009;100:1460-7 pubmed publisher
    ..V-ATPase inhibition will be a promising therapeutic approach for Bcl-2- or Bcl-xL-overexpressing malignancies. ..
  25. Martínez Muñoz G, Kane P. Vacuolar and plasma membrane proton pumps collaborate to achieve cytosolic pH homeostasis in yeast. J Biol Chem. 2008;283:20309-19 pubmed publisher
  26. Dawson K, Toone W, Jones N, Wilkinson C. Loss of regulators of vacuolar ATPase function and ceramide synthesis results in multidrug sensitivity in Schizosaccharomyces pombe. Eukaryot Cell. 2008;7:926-37 pubmed publisher
    ..The rav1 and lac1 genes are conserved in both higher eukaryotes and various pathogenic fungi. Thus, our data could provide the basis for strategies to sensitize tumor cells or drug-resistant pathogenic fungi to drugs. ..
  27. Huss M, Wieczorek H. Inhibitors of V-ATPases: old and new players. J Exp Biol. 2009;212:341-6 pubmed publisher
  28. Imamura H, Funamoto S, Yoshida M, Yokoyama K. Reconstitution in vitro of V1 complex of Thermus thermophilus V-ATPase revealed that ATP binding to the A subunit is crucial for V1 formation. J Biol Chem. 2006;281:38582-91 pubmed
    ..Kinetics of binding of a fluorescent ADP analog, N-methylanthraniloyl ADP (mant-ADP), to the monomeric A subunit also supported the rapid nucleotide binding to the A subunit. ..
  29. Sun Wada G, Tabata H, Kawamura N. Selective assembly of V-ATPase subunit isoforms in mouse kidney. J Bioenerg Biomembr. 2005;37:415-8 pubmed
  30. Bulwin G, Heinemann T, Bugge V, Winter M, Lohan A, Schlawinsky M, et al. TIRC7 inhibits T cell proliferation by modulation of CTLA-4 expression. J Immunol. 2006;177:6833-41 pubmed
    ..Splenocytes obtained from CTLA-4-deficient mice are not responsive to TIRC7 Ab targeting. Thus, TIRC7 acts as an upstream regulatory molecule of CTLA-4 expression. ..
  31. Kawasaki Nishi S, Yamaguchi A, Forgac M, Nishi T. Tissue specific expression of the splice variants of the mouse vacuolar proton-translocating ATPase a4 subunit. Biochem Biophys Res Commun. 2007;364:1032-6 pubmed
    ..During development, a4-I was expressed beginning with the early embryonic stage, but a4-II mRNA was detected from day 17. These results suggest that each a4 variant has both a tissue and developmental stage specific function. ..
  32. Lee S, Rho J, Jeong D, Sul J, Kim T, Kim N, et al. v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat Med. 2006;12:1403-9 pubmed
  33. Hinton A, Bond S, Forgac M. V-ATPase functions in normal and disease processes. Pflugers Arch. 2009;457:589-98 pubmed
    ..Plasma membrane V-ATPases have also been implicated in tumor cell invasion. V-ATPases are thus emerging as potential targets in the treatment of diseases such as osteoporosis and cancer. ..
  34. Xu J, Cheng T, Feng H, Pavlos N, Zheng M. Structure and function of V-ATPases in osteoclasts: potential therapeutic targets for the treatment of osteolysis. Histol Histopathol. 2007;22:443-54 pubmed publisher
    ..This review summarizes recent research developments in V-ATPases with particular emphasis on osteoclast biology. ..
  35. Kane P. The where, when, and how of organelle acidification by the yeast vacuolar H+-ATPase. Microbiol Mol Biol Rev. 2006;70:177-91 pubmed
    ..cerevisiae and also examines the relationship between biosynthesis and transport of V-ATPase and compartment-specific regulation of acidification. ..
  36. Nakanishi Matsui M, Futai M. Stochastic proton pumping ATPases: from single molecules to diverse physiological roles. IUBMB Life. 2006;58:318-22 pubmed
    ..Emphasis is placed on the stochastic rotational catalysis of F-ATPase and isoforms of V-ATPase. ..
  37. Schinke T, Schilling A, Baranowsky A, Seitz S, Marshall R, Linn T, et al. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med. 2009;15:674-81 pubmed publisher
    ..Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification. ..
  38. Louagie E, Taylor N, Flamez D, Roebroek A, Bright N, Meulemans S, et al. Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate. Proc Natl Acad Sci U S A. 2008;105:12319-24 pubmed publisher
    ..Together, these data establish an important role for furin in regulated secretion, particularly in intragranular acidification most likely due to impaired processing of Ac45. ..
  39. Du J, Kean L, Allan A, Southall T, Davies S, McInerny C, et al. The SzA mutations of the B subunit of the Drosophila vacuolar H+ ATPase identify conserved residues essential for function in fly and yeast. J Cell Sci. 2006;119:2542-51 pubmed
    ..These classical Drosophila mutants thus identify residues that are essential for function in organisms with wide phylogenetic separation. ..
  40. Tabata H, Kawamura N, Sun Wada G, Wada Y. Vacuolar-type H(+)-ATPase with the a3 isoform is the proton pump on premature melanosomes. Cell Tissue Res. 2008;332:447-60 pubmed publisher
    ..These observations suggest that the V-ATPase keeps the lumen of premature melanosomes acidic, whereas melanosomal acidification is less significant in mature melanosomes. ..
  41. Lebreton S, Jaunbergs J, Roth M, Ferguson D, De Brabander J. Evaluating the potential of vacuolar ATPase inhibitors as anticancer agents and multigram synthesis of the potent salicylihalamide analog saliphenylhalamide. Bioorg Med Chem Lett. 2008;18:5879-83 pubmed publisher
    ..To further validate the potential of V-ATPase inhibitors as leads for cancer chemotherapy, we developed a multigram synthesis of the potent salicylihalamide analog saliphenylhalamide. ..
  42. Wada Y, Sun Wada G, Tabata H, Kawamura N. Vacuolar-type proton ATPase as regulator of membrane dynamics in multicellular organisms. J Bioenerg Biomembr. 2008;40:53-7 pubmed publisher
    ..In this article, we focus and overview the non-classical, beyond proton-pumping function of the vacuolar-type ATPase in exo/endocytic systems. ..
  43. Smardon A, Kane P. RAVE is essential for the efficient assembly of the C subunit with the vacuolar H(+)-ATPase. J Biol Chem. 2007;282:26185-94 pubmed
    ..Our data support a model where RAVE, through its interaction with subunit C, is facilitating V(1) peripheral stalk subunit interactions with V(0) during V-ATPase assembly. ..
  44. Recchi C, Chavrier P. V-ATPase: a potential pH sensor. Nat Cell Biol. 2006;8:107-9 pubmed
  45. Compton M, Graham L, Stevens T. Vma9p (subunit e) is an integral membrane V0 subunit of the yeast V-ATPase. J Biol Chem. 2006;281:15312-9 pubmed
    ..These results demonstrate that Vma9p is an integral membrane subunit of the yeast V-ATPase V0 subcomplex and suggest a model for the arrangement of polypeptides within the V0 subcomplex. ..
  46. Saroussi S, Nelson N. Vacuolar H(+)-ATPase-an enzyme for all seasons. Pflugers Arch. 2009;457:581-7 pubmed publisher
    ..Knowledge of its involvement in several diseases, including cancer, has helped to establish the importance of V-ATPase for the preservation of life. ..
  47. Oliver J. Receptor-mediated actions of renin and prorenin. Kidney Int. 2006;69:13-5 pubmed
    ..Hence, like other proteases such as thrombin, renin and prorenin are capable of receptor-mediated cellular signaling. ..
  48. Liegeois S, Benedetto A, Michaux G, Belliard G, Labouesse M. Genes required for osmoregulation and apical secretion in Caenorhabditis elegans. Genetics. 2007;175:709-24 pubmed
    ..Finally, we show that RDY-1/VHA-5 distribution changes prior to molting in parallel with that of actin microfilaments and propose a model for molting whereby actin provides a spatial cue for secretion. ..
  49. Hurtado Lorenzo A, Skinner M, El Annan J, Futai M, Sun Wada G, Bourgoin S, et al. V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat Cell Biol. 2006;8:124-36 pubmed
  50. Duarte A, van Mierlo C, Hemminga M. Molecular dynamics study of the solvation of an alpha-helical transmembrane peptide by DMSO. J Phys Chem B. 2008;112:8664-71 pubmed publisher
    ..The dual solvation properties of DMSO cause it to be a good membrane-mimicking solvent for transmembrane peptides that do not unfold due to the presence of DMSO. ..
  51. You H, Jin J, Shu H, Yu B, De Milito A, Lozupone F, et al. Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells. Cancer Lett. 2009;280:110-9 pubmed publisher
    ..These results support the role of tumor acidity in resistance to chemotherapy and provide a rationale for the use of tumor pH modifier agents as coadjuvants in novel anticancer therapies. ..
  52. Yokoyama K, Imamura H. Rotation, structure, and classification of prokaryotic V-ATPase. J Bioenerg Biomembr. 2005;37:405-10 pubmed
    ..Last, we discuss classification of the V-ATPase family. We propose that the term prokaryotic V-ATPases should be used rather than the term archaeal-type ATPase (A-ATPase). ..
  53. Utku N, Heinemann T, Winter M, Bulwin C, Schlawinsky M, Fraser P, et al. Antibody targeting of TIRC7 results in significant therapeutic effects on collagen-induced arthritis in mice. Clin Exp Immunol. 2006;144:142-51 pubmed
    ..The results demonstrate the therapeutic potential of TIRC7 targeting with mAb in diseases associated with exaggerated T and B cell responses. ..