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V-ATPase functions in normal and disease processes


Eukaryotic cells have evolved a family of ATP-dependent proton pumps known as the vacuolar (H+)-ATPases (or V-ATPases) to regulate the pH of intracellular compartments, the extracellular space, and the cytoplasm. V-ATPases present within intracellular compartments are important for such normal cellular processes as receptor-mediated endocytosis and intracellular membrane traffic, protein processing and degradation and coupled transport of small molecules and ions. They also facilitate the entry of a number of envelope viruses and bacterial toxins, including influenza virus and anthrax toxin. V-ATPases present in the plasma membranes of cells are also important in normal physiology. They facilitate bone resorption by osteoclasts, acid secretion by intercalated cells of the kidney, pH homeostasis in macrophages and neutrophils, angiogenesis by endothelial cells, and sperm maturation and storage in the male reproductive tract. In the insect midgut, they establish a membrane potential used to drive K+ secretion. Plasma membrane V-ATPases are especially important in human disease, with genetic defects in V-ATPases expressed in osteoclasts and intercalated cells leading to the diseases osteopetrosis and renal tubule acidosis, respectively. 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.

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  1. 1.

    Forgac M (2007) Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nature Rev Mol Cell Biol 8:917–929

    Google Scholar 

  2. 2.

    Wagner CA, Finberg KE, Breton S, Marshansky V, Brown D, Geibel JP (2004) Renal vacuolar H+-ATPase. Physiol Rev 84:1263–1314

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Beyenbach KW, Wieczorek H (2006) The V-type H+ ATPase: molecular structure and function, physiological roles and regulation. J Exp Biol 209:577–589

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Smith AN, Borthwick KJ, Karet FE (2002) Molecular cloning and characterization of novel tissue-specific isoforms of the human vacuolar H+-ATPase C, G and d subunits, and their evaluation in autosomal recessive distal renal tubular acidosis. Gene 297:169–177

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Sun-Wada GH, Yoshimizu T, Imai-Senga Y, Wada Y, Futai M (2003) Diversity of mouse proton-translocating ATPase: presence of multiple isoforms of the C, d and G subunits. Gene 302:147–153

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Manolson MF, Wu B, Proteau D, Taillon BE, Roberts BT, Hoyt MA, Jones EW (1994) stv1 gene encodes functional homologue of 95-kDa yeast vacuolar H+-ATPase subunit vph1p. J Biol Chem 269:14064–14074

    PubMed  CAS  Google Scholar 

  7. 7.

    Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A (2000) Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 25:343–346

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Toyomura T, Murata Y, Yamamoto A, Oka T, Sun-Wada GH, Wada Y, Futai M (2003) From lysosomes to the plasma membrane: localization of vacuolar-type H+-ATPase with the a3 isoform during osteoclast differentiation. J Biol Chem 278:22023–22030

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Smith AN, Skaug J, Choate KA, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, Sanjad SA, Al-Sabban EA, Lifton RP, Scherer SW, Karet FE (2000) Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116 kDa subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nature Genetics 26:71–75

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Maxfield FR, McGraw TE (2004) Endocytic recycling. Nat Rev Mol Cell Biol 5:121–132

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Gu F, Gruenberg J (2000) ARF1 regulates pH-dependent COP functions in the early endocytic pathway. J Biol Chem 275:8154–8160

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Hurtado-Lorenzo A, Skinner M, El Annan J, Futai M, Sun-Wada GH, Bourgoin S, Casanova J, Wildeman A, Bechoua S, Ausiello DA, Brown D, Marshansky V (2006) V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat Cell Biol 8:124–136

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Ghosh P, Dahms NM, Kornfeld S (2003) Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 4:202–212

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Peters C, Bayer MJ, Buhler S, Andersen JS, Mann M, Mayer A (2001) Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion. Nature 409:581–588

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Bonifacino JS, Glick BS (2004) The mechanisms of vesicle budding and fusion. Cell 116:153–166

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Hiesinger PR, Fayyazuddin A, Mehta SQ, Rosenmund T, Schulze KL, Zhai RG, Verstreken P, Cao Y, Zhou Y, Kunz J, Bellen HJ (2005) The v-ATPase V0 subunit a1 is required for a late step in synaptic vesicle exocytosis in Drosophila. Cell 121:607–620

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Liegeois S, Benedetto A, Garnier JM, Schwab Y, Labouesse M (2006) The V0- ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans. J Cell Biol 173:949–961

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Sun-Wada GH, Toyomura T, Murata Y, Yamamoto A, Futai M, Wada Y (2006) The a3 isoform of V-ATPase regulates insulin secretion from pancreatic beta cells. J Cell Sci 119:4531–4540

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Kane PM (2006) The Where, When and How of Organelle Acidification by the Yeast Vacuolar H+-ATPase. Microbiol Molec Biol Rev 70:177–191

    Article  CAS  Google Scholar 

  20. 20.

    Nelson H, Nelson N (1990) Disruption of genes encoding subunits of yeast V-ATPase causes conditional lethality. Proc Natl Acad Sci 87:3503–3507

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Milgrom E, Diab H, Middleton F, Kane PM (2007) Loss of vacuolar proton- translocating ATPase activity in yeast results in chronic oxidative stress. J Biol Chem 282:7125–7136

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Gruenberg J, van der Goot FG (2006) Mechanisms of pathogen entry through the endosomal compartments. Nature Rev Mol Cell Biol 7:495–504

    Article  CAS  Google Scholar 

  23. 23.

    Gruenke JA, Armstrong RT, Newcomb WW, Brown JC, White JM (2002) New insights into the spring-loaded conformational change of influenza virus hemagglutinin. J Virol 76:4456–4466

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Abrami L, Lindsay M, Parton RG, Leppla SH, van der Goot FG (2004) Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway. J Cell Biol 166:645–651

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Goldstein DJ, Finbow ME, Andresson T, McLean P, Smith K, Bubb V, Schlegel R (1991) Bovine papillomavirus E5 oncoprotein binds to the 16 K component of vacuolar H+-ATPases. Nature 352:347–349

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Straight SW, Herman B, McCance DJ (1995) The E5 oncoprotein of human papillomavirus type 16 inhibits acidification of endosomes in human keratinocytes. J Virol 69:3185–3192

    PubMed  CAS  Google Scholar 

  27. 27.

    Schapiro F, Sparkowski J, Adduci A, Suprynowicz F, Schlegel R, Grinstein S (2000) Golgi alkalinization by papillomavirus E5 oncoprotein. J Cell Biol 148:305–315

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Li YP, Chen W, Liang Y, Li E, Stashenko P (1999) Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet 23:447–451

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Pastor-Soler N, Beaulieu V, Litvin TN, Da Silva N, Chen Y, Brown D, Buck J, Levin LR, Breton S (2003) Bicarbonate-regulated adenylyl cyclase (sAC) is a sensor that regulates pH-dependent V-ATPase recycling. J Biol Chem 278:49523–49529

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Nanda A, Brumell JH, Nordstrom T, Kjeldsen L, Sengelov H, Borregaard N, Rotstein OD, Grinstein S (1996) Activation of proton pumping in human neutrophils occurs by exocytosis of vesicles bearing vacuolar-type H+-ATPases. J Biol Chem 271:15963–15970

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Rojas JD, Sennoune SR, Maiti D, Bakunts K, Reuveni M, Sanka SC, Martinez GM, Seftor EA, Meininger CJ, Wu G, Wesson DE, Hendrix MJ, Martinez-Zaguilan R (2006) Vacuolar-type H+-ATPases at the plasma membrane regulate pH and cell migration in microvascular endothelial cells. Am J Physiol Heart Circ Physiol 291:1147–1157

    Article  Google Scholar 

  32. 32.

    Rojas JD, Sennoune SR, Martinez GM, Bakunts K, Meininger CJ, Wu G, Wesson DE, Seftor EA, Hendrix MJ, Martinez-Zaguilan R (2004) Plasmalemmal vacuolar H+-ATPase is decreased in microvascular endothelial cells from a diabetic model. J Cell Physiol 201:190–200

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Sautin YY, Lu M, Gaugler A, Zhang L, Gluck SL (2005) PI-3-kinase mediated effects of glucose on V-ATPase assembly, translocation and acidification of intracellular compartments in renal epithelial cells. Mol Cell Biol 25:575–589

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Trombetta ES, Ebersold M, Garrett W, Pypaert M, Mellman I (2003) Activation of lysosomal function during dendritic cell maturation. Science 299:1400–1403

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Karet FE, Finberg KE, Nelson RD, Nayir A, Mocan H, Sanjad SA, Rodriguez-Soriano J, Santos F, Cremers CW, Di Pietro A, Hoffbrand BI, Winiarski J, Bakkaloglu A, Ozen S, Dusunsel R, Goodyer P, Hulton SA, Wu DK, Skvorak AB, Morton CC, Cunningham MJ, Jha V, Lifton RP (1999) Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet 21:84–90

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Sennoune SR, Bakunts K, Martinez GM, Chua-Tuan JL, Kebir Y, Attaya MN, Martinez-Zaguilan R (2004) Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. Am J Physiol 286:C1443–1452

    Article  CAS  Google Scholar 

  37. 37.

    Gocheva V, Joyce JA (2007) Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle 6:60–64

    PubMed  CAS  Google Scholar 

  38. 38.

    Gatenby A, Gillies R (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891–899

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Volk C, Albert T, Kempski OS (1998) A proton-translocating H+-ATPase is involved in C6 glial pH regulation. Biochim Biophys Acta 1372:28–36

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    McSheehy PMJ, Troy H, Kelland LR, Judson IR, Leach MO, Griffiths JR (2003) Increased tumour extracellular pH induced by Bafilomycin A1 inhibits tumour growth and mitosis in vivo and alters 5-fluorouracil pharmacokinetics. Eur J Cancer 39:532–540

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Aiko K, Tsujisawa T, Koseki T, Hashimoto S, Morimoto Y, Amagasa T, Nishihara T (2002) Involvement of cytochrome c and caspases in apoptotic cell death of human submandibular gland ductal cells induced by concanamycin A. Cell Signal 14:717–722

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    De Milito A, Iessi E, Logozzi M, Lozupone F, Spada M, Marino ML, Federici C, Perdicchio M, Matarrese P, Lugini L, Nilsson A, Fais S (2007) Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res 67:5408–5417

    PubMed  Article  Google Scholar 

  43. 43.

    Gottlieb RA, Giesing HA, Zhu JY, Engler RL, Babior BM (1995) Cell acidification in apoptosis: GCSF delays programmed cell death in neutrophils by up-regulating vacuolar H+-ATPase. Proc Natl Acad Sci 92:5965–5968

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Xu J, Feng HT, Wang C, Yip KH, Pravlos N, Papadimitriou JM, Wood D, Zheng MH (2003) Effect s of bafilomycin A1: an inhibitor of vacuolar H+-ATPAses on endocytosis and apoptosis in RAW cells and RAW cell-derived osteoclasts. J Cell Biochem 88:1256–1264

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Murakami T, Shibuya I, Ise T, Chen Z, Akiyama S, Nakagawa M, Izumi H, Nakamura T, Natsuo K, Yamada Y, Kohno K (2001) Elevated expression of vacuolar proton pump genes and cellular pH in cisplatin resistance. Int J Cancer 93:869–874

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Torigoe T, Izumi H, Ishiguchi H, Uramoto H, Murakami T, Ise T, Yoshida Y, Tanabe M, Nomoto M, Itoh H, Kohno K (2002) Enhanced expression of the human vacuolar H+-ATPase c subunit gene (ATP6L) in response to anticancer agents. J Biol Chem 277:36534–36543

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Sennoune S, Luo D, Martinez-Zaguilan R (2004) Plasmalemmal vacuolar-type H+-ATPase in cancer biology. Cell Biochem, Biophys 40:185–206

    Article  CAS  Google Scholar 

  48. 48.

    Lu X, Yu H, Liu SH, Brodsky FM, Peterlin BM (1998) Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization of CD4. Immunity 8:657–656

    Article  Google Scholar 

  49. 49.

    Geyer M, Yu H, Mandic R, Linnemann T, Zheng YH, Fackler OT, Peterlin BM (2002) Subunit H of the V-ATPase binds to the medium chain of adaptor protein complex 2 and connects Nef to the endocytic machinery. J Biol Chem 277:28521–2859

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Niikura K, Takano M, Sawada M (2004) A novel inhibitor of vacuolar ATPase, FR167356, which can discriminate between osteoclast vacuolar ATPase and lysosomal vacuolar ATPase. Brit J Pharm 142:558–566

    Article  CAS  Google Scholar 

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This work was supported by NIH Grant GM34478 (to M.F.). A.H. and S.B. were supported by NIH Training Grant DK 07542. The authors thank Daniel Cipriano, Kevin Jefferies, Jie Qi and Yanru Wang for helpful discussions.

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Correspondence to Michael Forgac.

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Ayana Hinton and Sarah Bond contributed equally to this work.

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Hinton, A., Bond, S. & Forgac, M. V-ATPase functions in normal and disease processes. Pflugers Arch - Eur J Physiol 457, 589–598 (2009).

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  • pH regulation
  • Transport
  • Protons
  • Endocytosis
  • Ion transport
  • Renal function