Skip to main content
SpringerLink
Log in

Vacuolar ATPase in Physiology and Pathology: Roles in Neurobiology, Infectious Disease, and Cancer

  • Chapter
  • First Online:
Regulation of Ca2+-ATPases,V-ATPases and F-ATPases

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 14))

Abstract

Vacuolar ATPase (V-ATPase) is an ATP-dependent proton pump present in all eukaryotic cells. V-ATPase is a critical regulator of intracellular pH across the endomembrane system and is essential for fundamental cellular functions including endocytosis and exocytosis, protein modification and maturation and loading of secretory vesicles. Here we describe the structure, regulation, and function of V-ATPase in pH regulation and the roles of V-ATPase in neurobiology, infectious disease, and cancer. V-ATPase is composed of two domains: a membrane-peripheral domain, V1, and a membrane-integral domain, Vo. When extracellular glucose concentrations drop the V1Vo complex disassembles to inhibit V-ATPase activity and prevent energy depletion; this ability allows yeast cells to quickly respond to alterations in energy state. Next, we present a body of growing new evidence that highlights the importance of V-ATPase in human health and disease. We discuss mechanisms by which V-ATPase participates in neurotransmission, neurodegeneration, and stroke-associated neuronal cell death. Then, we focus on the involvement of pH and V-ATPase in the pathogenesis of viruses, bacteria, and fungi and the processes necessary to ensure pathogen replication. In the last section, we capitalize upon a repertoire of studies in recent years that indicate that V-ATPase is a critical player in adaptation to cellular stress and that V-ATPase activity directly and indirectly contributes to many of the hallmarks of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Muench SP, Trinick J, Harrison MA (2011) Structural divergence of the rotary ATPases. Q Rev Biophys 44:311–356

    Article  CAS  PubMed  Google Scholar 

  2. Parra KJ, Chan C-Y, Chen J (2014) Saccharomyces cerevisiae vacuolar H + -ATPase regulation by disassembly and reassembly: one structure and multiple signals. Eukaryot Cell 13:706–714

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Marshansky V, Rubinstein JL, Grüber G (2014) Eukaryotic V-ATPase: novel structural findings and functional insights. Biochim Biophys Acta 1837:857–879

    Article  CAS  PubMed  Google Scholar 

  4. Zhao J, Rubinstein JL (2014) The study of vacuolar-type ATPases by single particle electron microscopy. Biochem Cell Biol 92:460–466

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Kane PM (2006) The where, when, and how of organelle acidification by the yeast vacuolar H + -ATPase. Microbiol Mol Biol Rev 70:177–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nakanishi-Matsui M, Sekiya M, Nakamoto RK et al (2010) The mechanism of rotating proton pumping ATPases. Biochim Biophys Acta 1797:1343–1352

    Article  CAS  PubMed  Google Scholar 

  8. Futai M, Nakanishi-Matsui M, Okamoto H et al (2012) Rotational catalysis in proton pumping ATPases: from E. coli F-ATPase to mammalian V-ATPase. Biochim Biophys Acta 1817:1711–1721

    Article  CAS  PubMed  Google Scholar 

  9. Hirata T, Iwamoto-Kihara A, Sun-Wada G-H et al (2003) Subunit rotation of vacuolar-type proton pumping ATPase relative rotation of the G and c subunits. J Biol Chem 278:23714–23719

    Article  CAS  PubMed  Google Scholar 

  10. Nelson N, Perzov N, Cohen A et al (2000) The cellular biology of proton-motive force generation by V-ATPase. J Exp Biol 203:89–95

    CAS  PubMed  Google Scholar 

  11. Kane PM (1995) Disassembly and reassembly of the yeast vacuolar H + -ATPase in vivo. J Biol Chem 270:17025–17032

    CAS  PubMed  Google Scholar 

  12. Feng Y, Forgac M (1992) A novel mechanism for regulation of vacuolar acidification. J Biol Chem 267:19769–19772

    CAS  PubMed  Google Scholar 

  13. Feng Y, Forgac M (1994) Inhibition of vacuolar H(+)-ATPase by disulfide bond formation between cysteine 254 and cysteine 532 in subunit A. J Biol Chem 269:13224–13230

    CAS  PubMed  Google Scholar 

  14. Müller ML, Jensen M, Taiz L (1999) The vacuolar H + -ATPase of lemon fruits is regulated by variable H+/ATP coupling and slip. J Biol Chem 274:10706–10716

    Article  PubMed  Google Scholar 

  15. Müller ML, Taiz L (2002) Regulation of the lemon-fruit V-ATPase by variable stoichiometry and organic acids. J Membr Biol 185:209–220

    Article  PubMed  CAS  Google Scholar 

  16. Toyomura T, Murata Y, Yamamoto A et al (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

    Article  CAS  PubMed  Google Scholar 

  17. Hinton A, Sennoune SR, Bond S et al (2009) 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 284:16400–16408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Alzamora R, Thali RF, Gong F et al (2010) PKA regulates vacuolar H + -ATPase localization and activity via direct phosphorylation of the A subunit in kidney cells. J Biol Chem 285:24676–24685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee M-R, Lee G-H, Lee H-Y et al (2014) BAX inhibitor-1-associated V-ATPase glycosylation enhances collagen degradation in pulmonary fibrosis. Cell Death Dis 5, e1113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mulberg AE, Tulk BM, Forgac M (1991) Modulation of coated vesicle chloride channel activity and acidification by reversible protein kinase A-dependent phosphorylation. J Biol Chem 266:20590–20593

    CAS  PubMed  Google Scholar 

  21. Nishi T, Forgac M (2002) The vacuolar (H+)-ATPases – nature’s most versatile proton pumps. Nat Rev Mol Cell Biol 3:94–103

    Article  CAS  PubMed  Google Scholar 

  22. Nelson N (2003) A journey from mammals to yeast with vacuolar H + -ATPase (V-ATPase). J Bioenerg Biomembr 35:281–289

    Article  CAS  PubMed  Google Scholar 

  23. Arai H, Pink S, Forgac M (1989) Interaction of anions and ATP with the coated vesicle proton pump. Biochemistry (Mosc) 28:3075–3082

    Article  CAS  Google Scholar 

  24. Shao E, Forgac M (2004) Involvement of the nonhomologous region of subunit A of the yeast V-ATPase in coupling and in vivo dissociation. J Biol Chem 279:48663–48670

    Article  CAS  PubMed  Google Scholar 

  25. Manolson MF, Wu B, Proteau D et al (1994) STV1 gene encodes functional homologue of 95-kDa yeast vacuolar H(+)-ATPase subunit Vph1p. J Biol Chem 269:14064–14074

    CAS  PubMed  Google Scholar 

  26. Manolson MF, Proteau D, Preston RA et al (1992) The VPH1 gene encodes a 95-kDa integral membrane polypeptide required for in vivo assembly and activity of the yeast vacuolar H(+)-ATPase. J Biol Chem 267:14294–14303

    CAS  PubMed  Google Scholar 

  27. Kawasaki-Nishi S, Nishi T, Forgac M (2001) Yeast V-ATPase complexes containing different isoforms of the 100-kDa a-subunit differ in coupling efficiency and in vivo dissociation. J Biol Chem 276:17941–17948

    Article  CAS  PubMed  Google Scholar 

  28. Shao E, Nishi T, Kawasaki-Nishi S, Forgac M (2003) Mutational analysis of the non-homologous region of subunit A of the yeast V-ATPase. J Biol Chem 278:12985–12991

    Article  CAS  PubMed  Google Scholar 

  29. Owegi MA, Pappas DL, Finch MW et al (2006) Identification of a domain in the Vo subunit d that is critical for coupling of the yeast vacuolar proton-translocating ATPase. J Biol Chem 281:30001–30014

    Article  CAS  PubMed  Google Scholar 

  30. Curtis KK, Kane PM (2002) Novel vacuolar H + -ATPase complexes resulting from overproduction of Vma5p and Vma13p. J Biol Chem 277:2716–2724

    Article  CAS  Google Scholar 

  31. Tojo A, Guzman NJ, Garg LC et al (1994) Nitric oxide inhibits bafilomycin-sensitive H(+)-ATPase activity in rat cortical collecting duct. Am J Physiol 267:F509–F515

    CAS  PubMed  Google Scholar 

  32. Dschida WJA, Bowman BJ (1995) The vacuolar ATPase: sulfite stabilization and the mechanism of nitrate inactivation. J Biol Chem 270:1557–1563

    Article  CAS  PubMed  Google Scholar 

  33. Oluwatosin YE, Kane PM (1997) Mutations in the CYS4 gene provide evidence for regulation of the yeast vacuolar H + -ATPase by oxidation and reduction in vivo. J Biol Chem 272:28149–28157

    Article  CAS  PubMed  Google Scholar 

  34. Grüber G, Radermacher M, Ruiz T et al (2000) Three-dimensional structure and subunit topology of the V1 ATPase from Manduca sexta midgut. Biochemistry (Mosc) 39:8609–8616

    Article  CAS  Google Scholar 

  35. Sumner J-P, Dow JAT, Earley FGP et al (1995) Regulation of plasma membrane V-ATPase activity by dissociation of peripheral subunits. J Biol Chem 270:5649–5653

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. Nakamura S (2004) Glucose activates H + -ATPase in kidney epithelial cells. Am J Physiol Cell Physiol 287:C97–C105

    Article  CAS  PubMed  Google Scholar 

  38. Lafourcade C, Sobo K, Kieffer-Jaquinod S, Garin J, van der Goot FG (2008) Regulation of the V-ATPase along the endocytic pathway occurs through reversible subunit association and membrane localization. PLoS One 3(7), e2758

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Parra KJ, Kane PM (1998) Reversible association between the V1 and V0 domains of yeast vacuolar H + -ATPase is an unconventional glucose-induced effect. Mol Cell Biol 18:7064–7074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dechant R, Binda M, Lee SS et al (2010) Cytosolic pH is a second messenger for glucose and regulates the PKA pathway through V-ATPase. EMBO J 29:2515–2526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bond S, Forgac M (2008) The Ras/cAMP/protein kinase A pathway regulates glucose-dependent assembly of the vacuolar (H+)-ATPase in yeast. J Biol Chem 283:36513–36521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kane PM (2012) Targeting reversible disassembly as a mechanism of controlling V-ATPase activity. Curr Protein Pept Sci 13:117–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Smardon AM, Tarsio M, Kane PM (2002) The RAVE complex is essential for stable assembly of the yeast V-ATPase. J Biol Chem 277:13831–13839

    Article  CAS  PubMed  Google Scholar 

  44. Smardon AM, Kane PM (2007) RAVE is essential for the efficient assembly of the c subunit with the vacuolar H + -ATPase. J Biol Chem 282:26185–26194

    Article  CAS  PubMed  Google Scholar 

  45. Smardon AM, Diab HI, Tarsio M et al (2014) The RAVE complex is an isoform-specific V-ATPase assembly factor in yeast. Mol Biol Cell 25:356–367

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Seol JH, Shevchenko A, Shevchenko A, Deshaies RJ (2001) Skp1 forms multiple protein complexes, including RAVE, a regulator of V-ATPase assembly. Nat Cell Biol 3:384–391

    Article  CAS  PubMed  Google Scholar 

  47. Sethi N, Yan Y, Quek D et al (2010) Rabconnectin-3 is a functional regulator of mammalian notch signaling. J Biol Chem 285:34757–34764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lu M, Holliday LS, Zhang L et al (2001) Interaction between aldolase and vacuolar H + -ATPase evidence for direct coupling of glycolysis to the ATP-hydrolyzing proton pump. J Biol Chem 276:30407–30413

    Article  CAS  PubMed  Google Scholar 

  49. Su Y, Zhou A, Al-Lamki RS, Karet FE (2003) The a-subunit of the V-type H + -ATPase interacts with phosphofructokinase-1 in humans. J Biol Chem 278:20013–20018

    Article  CAS  PubMed  Google Scholar 

  50. Sautin YY, Lu M, Gaugler A et al (2005) Phosphatidylinositol 3-kinase-mediated effects of glucose on vacuolar H + -ATPase assembly, translocation, and acidification of intracellular compartments in renal epithelial cells. Mol Cell Biol 25:575–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lu M, Ammar D, Ives H et al (2007) Physical interaction between aldolase and vacuolar H + -ATPase is essential for the assembly and activity of the proton pump. J Biol Chem 282:24495–24503

    Article  CAS  PubMed  Google Scholar 

  52. Lu M, Sautin YY, Holliday LS, Gluck SL (2004) The glycolytic enzyme aldolase mediates assembly, expression, and activity of vacuolar H + -ATPase. J Biol Chem 279:8732–8739

    Article  CAS  PubMed  Google Scholar 

  53. Chan C-Y, Parra KJ (2014) Yeast phosphofructokinase-1 subunit Pfk2p is necessary for pH homeostasis and glucose-dependent vacuolar ATPase reassembly. J Biol Chem 289:19448–19457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Su Y, Blake-Palmer KG, Sorrell S et al (2008) Human H + ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1. Am J Physiol Renal Physiol 295:F950–F958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tiburcy F, Beyenbach KW, Wieczorek H (2013) Protein kinase A-dependent and -independent activation of the V-ATPase in Malpighian tubules of Aedes aegypti. J Exp Biol 216:881–891

    Article  CAS  PubMed  Google Scholar 

  56. Alzamora R, Al-Bataineh MM, Liu W et al (2013) AMP-activated protein kinase regulates the vacuolar H + -ATPase via direct phosphorylation of the A subunit (ATP6V1A) in the kidney. Am J Physiol Renal Physiol 305:F943–F956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Al-bataineh Mohammad M, Gong F, Marciszyn AL, Myerburg MM, Pastor-Soler NM (2014) Regulation of proximal tubule vacuolar H + -ATPase by PKA and AMP-activated protein kinase. Am J Physiol Renal Physiol 306:F981–F995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dechant R, Saad S, Ibáñez AJ, Peter M (2014) Cytosolic pH regulates cell growth through distinct GTPases, Arf1 and Gtr1, to promote Ras/PKA and TORC1 activity. Mol Cell 55:409–421

    Article  CAS  PubMed  Google Scholar 

  59. Marshansky V (2007) The V-ATPase a2-subunit as a putative endosomal pH-sensor. Biochem Soc Trans 35:1092–1099

    Article  CAS  PubMed  Google Scholar 

  60. Diakov TT, Kane PM (2010) Regulation of vacuolar proton-translocating ATPase activity and assembly by extracellular pH. J Biol Chem 285:23771–23778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Padilla-López S, Pearce DA (2006) Saccharomyces cerevisiae lacking Btn1p modulate vacuolar ATPase activity to regulate pH imbalance in the vacuole. J Biol Chem 281:10273–10280

    Article  PubMed  CAS  Google Scholar 

  62. Hackstadt T (2000) Redirection of host vesicle trafficking pathways by intracellular parasites. Traffic 1:93–99

    Article  CAS  PubMed  Google Scholar 

  63. Méresse S, Steele-Mortimer O, Moreno E et al (1999) Controlling the maturation of pathogen-containing vacuoles: a matter of life and death. Nat Cell Biol 1:E183–E188

    Article  PubMed  Google Scholar 

  64. Suzuki T, Yamaya M, Sekizawa K et al (2001) Bafilomycin A1 inhibits rhinovirus infection in human airway epithelium: effects on endosome and ICAM-1. Am J Physiol Lung Cell Mol Physiol 280:L1115–L1127

    CAS  PubMed  Google Scholar 

  65. Tsukano H, Kura F, Inoue S et al (1999) Yersinia pseudotuberculosis blocks the phagosomal acidification of B10.A mouse macrophages through the inhibition of vacuolar H + -ATPase activity. Microb Pathog 27:253–263

    Article  CAS  PubMed  Google Scholar 

  66. Wong D, Bach H, Sun J et al (2011) Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H + –ATPase to inhibit phagosome acidification. Proc Natl Acad Sci 108:19371–19376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aridor M, Hannan LA (2002) Traffic Jams II: an update of diseases of intracellular transport. Traffic 3:781–790

    Article  CAS  PubMed  Google Scholar 

  68. Olkkonen VM, Ikonen E (2000) Genetic defects of intracellular-membrane transport. N Engl J Med 343:1095–1104

    Article  CAS  PubMed  Google Scholar 

  69. Shacka JJ, Klocke BJ, Roth KA (2006) Autophagy, bafilomycin and cell death: the “A-B-Cs” of plecomacrolide-induced neuroprotection. Autophagy 2:228–230

    Article  CAS  PubMed  Google Scholar 

  70. Syntichaki P, Samara C, Tavernarakis N (2005) The vacuolar H + -ATPase mediates intracellular acidification required for neurodegeneration in C. elegans. Curr Biol 15:1249–1254

    Article  CAS  PubMed  Google Scholar 

  71. Michel V, Licon-Munoz Y, Trujillo K et al (2013) Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion. Int J Cancer 132:E1–E10

    Article  CAS  PubMed  Google Scholar 

  72. Mindell JA (2012) Lysosomal acidification mechanisms. Annu Rev Physiol 74:69–86. doi:10.1146/annurev-physiol-012110-142317

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Gaxiola RA, Palmgren MG, Schumacher K (2007) Plant proton pumps. FEBS Lett 581:2204–2214

    Article  CAS  PubMed  Google Scholar 

  75. Toei M, Saum R, Forgac M (2010) Regulation and isoform function of the V-ATPases. Biochemistry (Mosc) 49:4715–4723

    Article  CAS  Google Scholar 

  76. Marshansky V, Futai M (2008) The V-type H + -ATPase in vesicular trafficking: targeting, regulation and function. Curr Opin Cell Biol 20:415–426

    Article  CAS  PubMed  Google Scholar 

  77. Sun-Wada G-H, Murata Y, Yamamoto A et al (2000) Acidic endomembrane organelles are required for mouse postimplantation development. Dev Biol 228:315–325

    Article  CAS  PubMed  Google Scholar 

  78. Oka T, Toyomura T, Honjo K et al (2001) Four subunit a isoforms of Caenorhabditis elegans vacuolar H + -ATPase cell-specific expression during development. J Biol Chem 276:33079–33085

    Article  CAS  PubMed  Google Scholar 

  79. Hurtado-Lorenzo A, Skinner M, El Annan J et al (2006) V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat Cell Biol 8:124–136

    Article  CAS  PubMed  Google Scholar 

  80. Kozik P, Hodson NA, Sahlender DA et al (2013) A human genome-wide screen for regulators of clathrin-coated vesicle formation reveals an unexpected role for the V-ATPase. Nat Cell Biol 15:50–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sun-Wada G-H, Tabata H, Kawamura N et al (2009) Direct recruitment of H + -ATPase from lysosomes for phagosomal acidification. J Cell Sci 122:2504–2513

    Article  CAS  PubMed  Google Scholar 

  82. Von Schwarzenberg K, Lajtos T, Simon L et al (2014) V-ATPase inhibition overcomes trastuzumab resistance in breast cancer. Mol Oncol 8:9–19

    Article  CAS  Google Scholar 

  83. Scherer O, Steinmetz H, Kaether C et al (2014) Targeting V-ATPase in primary human monocytes by archazolid potently represses the classical secretion of cytokines due to accumulation at the endoplasmic reticulum. Biochem Pharmacol 91:490–500

    Article  CAS  PubMed  Google Scholar 

  84. Kubisch R, Fröhlich T, Arnold GJ et al (2014) V-ATPase inhibition by archazolid leads to lysosomal dysfunction resulting in impaired cathepsin B activation in vivo. Int J Cancer 134:2478–2488

    Article  CAS  PubMed  Google Scholar 

  85. Baravalle G, Schober D, Huber M et al (2005) Transferrin recycling and dextran transport to lysosomes is differentially affected by bafilomycin, nocodazole, and low temperature. Cell Tissue Res 320:99–113

    Article  CAS  PubMed  Google Scholar 

  86. Bayer N, Schober D, Prchla E et al (1998) Effect of bafilomycin A1 and nocodazole on endocytic transport in HeLa Cells: implications for viral uncoating and infection. J Virol 72:9645–9655

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Cruciat C-M, Ohkawara B, Acebron SP et al (2010) Requirement of prorenin receptor and vacuolar H + -ATPase-mediated acidification for Wnt signaling. Science 327:459–463

    Article  CAS  PubMed  Google Scholar 

  88. Kim W, Kim M, Jho E (2013) Wnt/β-catenin signalling: from plasma membrane to nucleus. Biochem J 450:9–21

    Article  CAS  PubMed  Google Scholar 

  89. Tuttle AM, Hoffman TL, Schilling TF (2014) Rabconnectin-3a regulates vesicle endocytosis and canonical Wnt signaling in zebrafish neural crest migration. PLoS Biol 12, e1001852

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Maranda B, Brown D, Bourgoin S et al (2001) Intra-endosomal pH-sensitive recruitment of the Arf-nucleotide exchange factor ARNO and Arf6 from cytoplasm to proximal tubule endosomes. J Biol Chem 276:18540–18550

    Article  CAS  PubMed  Google Scholar 

  91. Donaldson JG (2003) Multiple roles for Arf6: sorting, structuring, and signaling at the plasma membrane. J Biol Chem 278:41573–41576

    Article  CAS  PubMed  Google Scholar 

  92. Shmuel M, Santy LC, Frank S (2006) ARNO through its coiled-coil domain regulates endocytosis at the apical surface of polarized epithelial cells. J Biol Chem 281:13300–13308

    Article  CAS  PubMed  Google Scholar 

  93. Monier S, Chardin P, Robineau S, Goud B (1998) Overexpression of the ARF1 exchange factor ARNO inhibits the early secretory pathway and causes the disassembly of the Golgi complex. J Cell Sci 111(Pt 22):3427–3436

    CAS  PubMed  Google Scholar 

  94. Hosokawa H, Dip PV, Merkulova M et al (2013) The N termini of a-subunit isoforms are involved in signaling between vacuolar H + -ATPase (V-ATPase) and cytohesin-2. J Biol Chem 288:5896–5913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ernstrom GG, Weimer R, Pawar DRL et al (2012) V-ATPase V1 sector is required for corpse clearance and neurotransmission in Caenorhabditis elegans. Genetics 191:461–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yan Y, Denef N, Schüpbach T (2009) The vacuolar proton pump (V-ATPase) is required for Notch signaling and endosomal trafficking in Drosophila. Dev Cell 17:387–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Brown D, Paunescu TG, Breton S, Marshansky V (2009) Regulation of the V-ATPase in kidney epithelial cells: dual role in acid–base homeostasis and vesicle trafficking. J Exp Biol 212:1762–1772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. O’Callaghan KM, Ayllon V, O’Keeffe J et al (2010) Heme-binding protein HRG-1 is induced by insulin-like growth factor I and associates with the vacuolar H + -ATPase to control endosomal pH and receptor trafficking. J Biol Chem 285:381–391

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  100. Peri F, Nüsslein-Volhard C (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133:916–927

    Article  CAS  PubMed  Google Scholar 

  101. Peters C, Bayer MJ, Bühler S et al (2001) Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion. Nature 409:581–588

    Article  CAS  PubMed  Google Scholar 

  102. Strasser B, Iwaszkiewicz J, Michielin O, Mayer A (2011) The V-ATPase proteolipid cylinder promotes the lipid-mixing stage of SNARE-dependent fusion of yeast vacuoles. EMBO J 30:4126–4141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Poëa-Guyon S, Ammar MR, Erard M et al (2013) The V-ATPase membrane domain is a sensor of granular pH that controls the exocytotic machinery. J Cell Biol 203:283–298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Chung C, Mader CC, Schmitz J et al (2011) The vacuolar-ATPase (V-ATPase) modulates matrix metalloproteinase (MMP) isoforms in human pancreatic cancer. Lab Invest J Tech Methods Pathol 91:732–743

    Article  CAS  Google Scholar 

  105. Xu X, Liu B, Zou P et al (2014) Silencing of LASS2/TMSG1 enhances invasion and metastasis capacity of prostate cancer cell. J Cell Biochem 115:731–743

    Article  CAS  PubMed  Google Scholar 

  106. Sun-Wada GH, Wada Y (2015) Role of vacuolar-type proton ATPase in signal transduction. Biochem Biophys Acat 10:1166–1172

    Google Scholar 

  107. Sun-Wada G-H, Toyomura T, Murata Y et al (2006) The a3 isoform of V-ATPase regulates insulin secretion from pancreatic β-cells. J Cell Sci 119:4531–4540

    Article  CAS  PubMed  Google Scholar 

  108. Tapper H, Sundler R (1995) Bafilomycin A1 inhibits lysosomal, phagosomal, and plasma membrane H(+)-ATPase and induces lysosomal enzyme secretion in macrophages. J Cell Physiol 163:137–144

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. Van Weert AW, Dunn KW, Geuze HJ et al (1995) Transport from late endosomes to lysosomes, but not sorting of integral membrane proteins in endosomes, depends on the vacuolar proton pump. J Cell Biol 130:821–834

    Article  PubMed  Google Scholar 

  111. Pereda AE (2014) Electrical synapses and their functional interactions with chemical synapses. Nat Rev Neurosci 15:250–263

    Google Scholar 

  112. Takamori S, Holt M, Stenius K et al (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846

    Article  CAS  PubMed  Google Scholar 

  113. Wilhelm BG, Mandad S, Truckenbrodt S et al (2014) Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344:1023–1028

    Article  CAS  PubMed  Google Scholar 

  114. El Mestikawy S, Wallén-Mackenzie Å, Fortin GM et al (2011) From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci 12:204–216

    Article  PubMed  CAS  Google Scholar 

  115. Maycox PR, Deckwerth T, Hell JW, Jahn R (1988) Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes J Biol Chem 263:15423–15428

    CAS  PubMed  Google Scholar 

  116. Einhorn Z, Trapani JG, Liu Q, Nicolson T (2012) Rabconnectin3α promotes stable activity of the H+ pump on synaptic vesicles in hair cells. J Neurosci 32:11144–11156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rizo J, Südhof TC (2002) Snares and munc18 in synaptic vesicle fusion. Nat Rev Neurosci 3:641–653

    Article  CAS  PubMed  Google Scholar 

  118. Hiesinger PR, Fayyazuddin A, Mehta SQ et al (2005) The v-ATPase V0 subunit a1 is required for a late step in synaptic vesicle exocytosis in Drosophila. Cell 121:607–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Di Giovanni J, Boudkkazi S, Mochida S et al (2010) V-ATPase membrane sector associates with synaptobrevin to modulate neurotransmitter release. Neuron 67:268–279

    Article  PubMed  CAS  Google Scholar 

  120. Morel N (2003) Neurotransmitter release: the dark side of the vacuolar-H + ATPase. Biol Cell Auspices Eur Cell Biol Organ 95:453–457

    CAS  Google Scholar 

  121. El Far O, Seagar M (2011) SNARE, V-ATPase and neurotransmission. Méd Sci 27:28–31

    Google Scholar 

  122. Vavassori S, Mayer A (2014) A new life for an old pump: V-ATPase and neurotransmitter release. J Cell Biol 205:7–9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Morel N, Dunant Y, Israël M (2001) Neurotransmitter release through the V0 sector of V-ATPase. J Neurochem 79:485–488

    Google Scholar 

  124. Südhof TC (2013) A molecular machine for neurotransmitter release: synaptotagmin and beyond. Nat Med 19:1227–1231

    Article  PubMed  CAS  Google Scholar 

  125. Hirasawa H, Yamada M, Kaneko A (2012) Acidification of the synaptic cleft of cone photoreceptor terminal controls the amount of transmitter release, thereby forming the receptive field surround in the vertebrate retina. J Physiol Sci 62:359–375

    Article  PubMed  Google Scholar 

  126. Jouhou H, Yamamoto K, Homma A et al (2007) Depolarization of isolated horizontal cells of fish acidifies their immediate surrounding by activating V-ATPase. J Physiol 585:401–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wang T-M, Holzhausen LC, Kramer RH (2014) Imaging an optogenetic pH sensor reveals that protons mediate lateral inhibition in the retina. Nat Neurosci 17:262–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ikemoto A, Bole DG, Ueda T (2003) Glycolysis and glutamate accumulation into synaptic vesicles role of glyceraldehyde phosphate dehydrogenase and 3-phosphoglycerate kinase. J Biol Chem 278:5929–5940

    Article  CAS  PubMed  Google Scholar 

  129. Yamada KA, Rensing N, Izumi Y et al (2004) Repetitive hypoglycemia in young rats impairs hippocampal long-term potentiation. Pediatr Res 55:372–379

    Article  CAS  PubMed  Google Scholar 

  130. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nat Med 10:10–17

    Article  CAS  Google Scholar 

  131. Nixon RA (2006) Autophagy in neurodegenerative disease: friend, foe or turncoat? Trends Neurosci 29:528–535

    Article  CAS  PubMed  Google Scholar 

  132. Lee J-H, Yu WH, Kumar A et al (2010) Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141:1146–1158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Cataldo AM, Peterhoff CM, Schmidt SD et al (2004) Presenilin mutations in familial Alzheimer disease and transgenic mouse models accelerate neuronal lysosomal pathology. J Neuropathol Exp Neurol 63:821–830

    Article  CAS  PubMed  Google Scholar 

  134. Metcalf DJ, García-Arencibia M, Hochfeld WE, Rubinsztein DC (2012) Autophagy and misfolded proteins in neurodegeneration. Exp Neurol 238:22–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983–997

    Article  CAS  PubMed  Google Scholar 

  136. Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13:805–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mehrpour M, Esclatine A, Beau I, Codogno P (2010) Overview of macroautophagy regulation in mammalian cells. Cell Res 20:748–762

    Article  PubMed  Google Scholar 

  138. Nixon RA, Wegiel J, Kumar A et al (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64:113–122

    Article  PubMed  Google Scholar 

  139. Anglade P, Vyas S, Javoy-Agid F et al (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31

    CAS  PubMed  Google Scholar 

  140. Sapp E, Schwarz C, Chase K et al (1997) Huntingtin localization in brains of normal and Huntington’s disease patients. Ann Neurol 42:604–612

    Article  CAS  PubMed  Google Scholar 

  141. Williamson WR, Wang D, Haberman AS, Hiesinger PR (2010) A dual function of V0-ATPase a1 provides an endolysosomal degradation mechanism in Drosophila melanogaster photoreceptors. J Cell Biol 189:885–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Williamson WR, Hiesinger PR (2010) On the role of v-ATPase V0a1-dependent degradation in Alzheimer disease. Commun Integr Biol 3:604–607

    Article  PubMed  PubMed Central  Google Scholar 

  143. Pamenter ME, Ryu J, Hua ST et al (2012) DIDS prevents ischemic membrane degradation in cultured hippocampal neurons by inhibiting matrix metalloproteinase release. PLoS One 7, e43995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lo EH (2008) A new penumbra: transitioning from injury into repair after stroke. Nat Med 14:497–500

    Article  CAS  PubMed  Google Scholar 

  145. Sieczkarski SB, Brown HA, Whittaker GR (2003) Role of protein kinase C βII in influenza virus entry via late endosomes. J Virol 77:460–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Pinto LH, Lamb RA (2006) The M2 proton channels of influenza A and B viruses. J Biol Chem 281:8997–9000

    Article  CAS  PubMed  Google Scholar 

  147. Adamson AL, Chohan K, Swenson J, LaJeunesse D (2011) A Drosophila model for genetic analysis of influenza viral/host interactions. Genetics 189:495–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kohio HP, Adamson AL (2013) Glycolytic control of vacuolar-type ATPase activity: a mechanism to regulate influenza viral infection. Virology 444:301–309

    Article  CAS  PubMed  Google Scholar 

  149. Hoekstra D, Klappe K (1993) Fluorescence assays to monitor fusion of enveloped viruses. In: Duzgunees N (ed) Methods enzymology. Academic, Waltham, MA, pp 261–276

    Google Scholar 

  150. Marjuki H, Gornitzky A, Marathe BM et al (2011) Influenza A virus-induced early activation of ERK and PI3K mediates V-ATPase-dependent intracellular pH change required for fusion. Cell Microbiol 13:587–601

    Article  CAS  PubMed  Google Scholar 

  151. Umata T, Moriyama Y, Futai M, Mekada E (1990) The cytotoxic action of diphtheria toxin and its degradation in intact Vero cells are inhibited by bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase. J Biol Chem 265:21940–21945

    CAS  PubMed  Google Scholar 

  152. Müller KH, Spoden GA, Scheffer KD et al (2014) Inhibition by cellular vacuolar ATPase impairs human papillomavirus uncoating and infection. Antimicrob Agents Chemother 58:2905–2911

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Vidricaire G, Imbeault M, Tremblay MJ (2004) Endocytic host cell machinery plays a dominant role in intracellular trafficking of incoming human immunodeficiency virus type 1 in human placental trophoblasts. J Virol 78:11904–11915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  155. Hunt SR, Hernandez R, Brown DT (2011) Role of the vacuolar-ATPase in Sindbis virus infection. J Virol 85:1257–1266

    Article  CAS  PubMed  Google Scholar 

  156. Miller ME, Adhikary S, Kolokoltsov AA, Davey RA (2012) Ebolavirus requires acid sphingomyelinase activity and plasma membrane sphingomyelin for infection. J Virol 86:7473–7483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Yip CW, Hon CC, Zeng F, Leung FCC (2012) Cell culture-adapted IBDV uses endocytosis for entry in DF-1 chicken embryonic fibroblasts. Virus Res 165:9–16

    Article  CAS  PubMed  Google Scholar 

  158. Chen H-W, Cheng JX, Liu M-T et al (2013) Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses. Antiviral Res 99:371–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Silva-Ayala D, López T, Gutiérrez M et al (2013) Genome-wide RNAi screen reveals a role for the ESCRT complex in rotavirus cell entry. Proc Natl Acad Sci U S A 110:10270–10275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Arias CF, Silva-Ayala D, López S (2015) Rotavirus entry: a deep journey into the cell with several exits. J Virol 89:890–893

    Article  PubMed  CAS  Google Scholar 

  161. Abrami L, Reig N, van der Goot FG (2005) Anthrax toxin: the long and winding road that leads to the kill. Trends Microbiol 13:72–78

    Article  CAS  PubMed  Google Scholar 

  162. Flannagan RS, Jaumouillé V, Grinstein S (2012) The cell biology of phagocytosis. Annu Rev Pathol Mech Dis 7:61–98

    Article  CAS  Google Scholar 

  163. Drecktrah D, Knodler LA, Howe D, Steele-Mortimer O (2007) Salmonella trafficking is defined by continuous dynamic interactions with the endolysosomal system. Traffic Cph Den 8:212–225

    Article  CAS  Google Scholar 

  164. Arpaia N, Godec J, Lau L et al (2011) TLR signaling is required for virulence of an intracellular pathogen. Cell 144:675–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Santic M, Asare R, Skrobonja I et al (2008) Acquisition of the vacuolar ATPase proton pum ad phagosome acidification are essential for escape of Francisella tularensis into the macrophage cytosol. Infect Immun 76:2671–2677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Birmingham CL, Canadien V, Kaniuk NA et al (2008) Listeriolysin O allows Listeria monocytogenes replication in macrophage vacuoles. Nature 451:350–354

    Article  CAS  PubMed  Google Scholar 

  167. Portnoy DA, Chakraborty T, Goebel W, Cossart P (1992) Molecular determinants of Listeria monocytogenes pathogenesis. Infect Immun 60:1263–1267

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Tweten RK (2005) Cholesterol-dependent cytolysins, a family of versatile pore-forming toxins. Infect Immun 73:6199–6209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Petchampai N, Sunyakumthorn P, Guillotte ML et al (2014) Molecular and functional characterization of vacuolar-ATPase from the American dog tick Dermacentor variabilis. Insect Mol Biol 23:42–51

    Article  CAS  PubMed  Google Scholar 

  170. Mansilla Pareja ME, Colombo MI (2013) Autophagic clearance of bacterial pathogens: molecular recognition of intracellular microorganisms. Front Cell Infect Microbiol 3:54

    Article  PubMed Central  Google Scholar 

  171. Jung CW, Shih L-Y, Xiao Z et al (2014) Efficacy and safety of ruxolitinib in Asian patients with myelofibrosis. Leuk Lymphoma 1–8

    Google Scholar 

  172. Schwartz JT, Allen L-AH (2006) Role of urease in megasome formation and Helicobacter pylori survival in macrophages. J Leukoc Biol 79:1214–1225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Xu L, Shen X, Bryan A et al (2010) Inhibition of host vacuolar H + -ATPase activity by a Legionella pneumophila effector. PLoS Pathog 6:1000822

    Article  CAS  Google Scholar 

  174. Nordenfelt P, Grinstein S, Björck L, Tapper H (2012) V-ATPase-mediated phagosomal acidification is impaired by Streptococcus pyogenes through Mga-regulated surface proteins. Microbes Infect 14:1319–1329

    Article  CAS  PubMed  Google Scholar 

  175. Tsukano H, Kura F, Inoues et al (1999) Yessernia pseudotuberculosis blocks the phagosomal acidification of B10A mouse macrophages through inhibition of vacuolar H (+) -ATPase acivity. Microb Pathog 4:253–263

    Google Scholar 

  176. Wong D, Bach H, Sun J et al (2011) Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar H+-ATPase to inhibit phagosome acidifcation. Proc Natl Acad Sci USA 48:19371–19376

    Article  Google Scholar 

  177. Moran C, Grussemeyer CA, Spalding JR et al (2009) Candida albicans and non-albicans bloodstream infections in adult and pediatric patients: comparison of mortality and costs. Pediatr Infect Dis J 28:433–435

    Article  PubMed  PubMed Central  Google Scholar 

  178. Brissaud O, Guichoux J, Harambat J et al (2012) Invasive fungal disease in PICU: epidemiology and risk factors. Ann Intensive Care 2:6

    Article  PubMed  PubMed Central  Google Scholar 

  179. Perlin DS (1998) Ion pumps as targets for therapeutic intervention: old and new paradigms. Electron J Biotechnol 1:55–64

    Article  Google Scholar 

  180. Olsen I (2014) Attenuation of Candida albicans virulence with focus on disruption of its vacuole functions. J Oral Microbiol 6, PMC3974176

    Google Scholar 

  181. Davis DA (2009) How human pathogenic fungi sense and adapt to pH: the link to virulence. Curr Opin Microbiol 12:365–370

    Article  CAS  PubMed  Google Scholar 

  182. Sudbery P, Gow N, Berman J (2004) The distinct morphogenic states of Candida albicans. Trends Microbiol 12:317–324

    Article  CAS  PubMed  Google Scholar 

  183. Kabir MA, Hussain MA, Ahmad Z (2012) Candida albicans: a model organism for studying fungal pathogens. ISRN Microbiol 2012:Article ID 538694

    Google Scholar 

  184. Zhang Y-Q, Gamarra S, Garcia-Effron G et al (2010) Requirement for ergosterol in V-ATPase function underlies antifungal activity of azole drugs. PLoS Pathog 6(6):1000939

    Article  CAS  Google Scholar 

  185. Patenaude C, Zhang Y, Cormack B et al (2013) Essential role for vacuolar acidification in Candida albicans virulence. J Biol Chem 288:26256–26264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Rane HS, Bernardo SM, Raines SM et al (2013) Candida albicans VMA3 is necessary for V-ATPase assembly and function and contributes to secretion and filamentation. Eukaryot Cell 12:1369–1382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Erickson T, Liu L, Gueyikian A et al (2001) Multiple virulence factors of Cryptococcus neoformans are dependent on VPH1. Mol Microbiol 42:1121–1131

    Article  CAS  PubMed  Google Scholar 

  188. Hayek SR, Lee SA, Parra KJ (2014) Advances in targeting the vacuolar proton-translocating ATPase (V-ATPase) for anti-fungal therapy. Front Pharmacol 5:4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Strasser JE, Newman SL, Ciraolo GM et al (1999) Regulation of the macrophage vacuolar ATPase and phagosome-lysosome fusion by Histoplasma capsulatum. J Immunol 162:6148–6154

    CAS  PubMed  Google Scholar 

  190. Hilty J, Smulian AG, Newman SL (2008) The Histoplasma capsulatum vacuolar ATPase is required for iron homeostasis, intracellular replication in macrophages, and virulence in a murine model of histoplasmosis. Mol Microbiol 70:127–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Parra KJ (2012) Vacuolar ATPase: a model proton pump for antifungal drug discovery. In: Tegos A, Mylonakis E (eds) Antimicrobial drug discovery: emerging strategies. CABI, Wallingford, CT, pp 89–100

    Chapter  Google Scholar 

  192. Zhang Y-Q, Rao R (2010) Beyond ergosterol: linking pH to antifungal mechanisms. Virulence 1:551–554

    Article  PubMed  Google Scholar 

  193. Martínez-Muñoz GA, Kane P (2008) Vacuolar and plasma membrane proton pumps collaborate to achieve cytosolic pH homeostasis in yeast. J Biol Chem 283:20309–20319

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Tarsio M, Zheng H, Smardon AM et al (2011) Consequences of loss of Vph1 protein-containing vacuolar ATPases (V-ATPases) for overall cellular pH homeostasis. J Biol Chem 286:28089–28096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  196. Graham RM, Thompson JW, Webster KA (2014) Inhibition of the vacuolar ATPase induces Bnip3-dependent death of cancer cells and a reduction in tumor burden and metastasis. Oncotarget 5:1162–1173

    Article  PubMed  Google Scholar 

  197. Schempp CM, von Schwarzenberg K, Schreiner L et al (2014) V-ATPase inhibition regulates anoikis resistance and metastasis of cancer cells. Mol Cancer Ther 13:926–937

    Article  CAS  PubMed  Google Scholar 

  198. Von Schwarzenberg K, Wiedmann RM, Oak P et al (2013) Mode of cell death induction by pharmacological vacuolar H + -ATPase (V-ATPase) inhibition. J Biol Chem 288:1385–1396

    Article  CAS  Google Scholar 

  199. McHenry P, Wang W-LW, Devitt E et al (2010) Iejimalides A and B inhibit lysosomal vacuolar H + -ATPase (V-ATPase) activity and induce S-phase arrest and apoptosis in MCF-7 cells. J Cell Biochem 109:634–642

    CAS  PubMed  Google Scholar 

  200. Sasazawa Y, Futamura Y, Tashiro E, Imoto M (2009) Vacuolar H + -ATPase inhibitors overcome Bcl-xL-mediated chemoresistance through restoration of a caspase-independent apoptotic pathway. Cancer Sci 100:1460–1467

    Article  CAS  PubMed  Google Scholar 

  201. De Milito AD, Iessi E, Logozzi M et al (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

    Article  PubMed  CAS  Google Scholar 

  202. Jewell JL, Kim YC, Russell RC et al (2015) Metabolism: differential regulation of mTORC1 by leucine and glutamine. Science 347:194–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Horova V, Hradilova N, Jelinkova I et al (2013) Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase-8 and modulates the trafficking of TRAIL receptosomes. FEBS J 280:3436–3450

    Article  CAS  PubMed  Google Scholar 

  204. Sennoune SR, Arutunyan A, del Rosario C et al (2014) V-ATPase regulates communication between microvasular endothelial cells and metastatic cells. Cell Mol Biol 60:19–25

    CAS  PubMed  Google Scholar 

  205. Kobia F, Duchi S, Deflorian G, Vaccari T (2014) Pharmacologic inhibition of vacuolar H+ ATPase reduces physiologic and oncogenic Notch signaling. Mol Oncol 8:207–220

    Article  CAS  PubMed  Google Scholar 

  206. Shen W, Zou X, Chen M et al (2013) Effect of pantoprazole on human gastric adenocarcinoma SGC7901 cells through regulation of phospho-LRP6 expression in Wnt/β-catenin signaling. Oncol Rep 30:851–855

    CAS  PubMed  Google Scholar 

  207. Han J, Sridevi P, Ramirez M et al (2013) β-Catenin-dependent lysosomal targeting of internalized tumor necrosis factor-α suppresses caspase-8 activation in apoptosis-resistant colon cancer cells. Mol Biol Cell 24:465–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Rath S, Liebl J, Fürst R et al (2014) Regulation of endothelial signaling and migration by v-ATPase. Angiogenesis 17:587–601

    Article  CAS  PubMed  Google Scholar 

  209. Rojas JD, Sennoune SR, Maiti D et al (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:H1147–H1157

    Article  CAS  PubMed  Google Scholar 

  210. Katara GK, Jaiswal MK, Kulshrestha A et al (2014) Tumor-associated vacuolar ATPase subunit promotes tumorigenic characteristics in macrophages. Oncogene 33:5649–5654

    Article  CAS  PubMed  Google Scholar 

  211. Xu Y, Parmar A, Roux E et al (2012) Epidermal growth factor-induced vacuolar (H+)-ATPase assembly a role in signaling via mTORC1 activation. J Biol Chem 287:26409–26422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Liu P (2013) Effect of pantoprazole on human gastric adenocarcinoma SGC7901 cells through regulation of phospho-LRP6 expression in Wnt/β-catenin signaling. Oncol Rep 2524

    Google Scholar 

  213. Sennoune SR, Bakunts K, Martínez GM et al (2004) Vacuolar H + -ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity. Am J Physiol Cell Physiol 286:C1443–C1452

    Article  CAS  PubMed  Google Scholar 

  214. Lu Q, Lu S, Huang L et al (2013) The expression of V-ATPase is associated with drug resistance and pathology of non-small-cell lung cancer. Diagn Pathol 8:145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Dechant R, Peter M (2011) The N-terminal domain of the V-ATPase subunit “a” is regulated by pH in vitro and in vivo. Channels 5:4–8

    Article  CAS  PubMed  Google Scholar 

  216. Long X, Crow MT, Sollott SJ et al (1998) Enhanced expression of p53 and apoptosis induced by blockade of the vacuolar proton ATPase in cardiomyocytes. J Clin Invest 101:1453–1461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Torigoe T, Izumi H, Ishiguchi H et al (2002) Enhanced expression of the human vacuolar H + -ATPase c subunit gene (ATP6L) in response to anticancer agents. J Biol Chem 277:36534–36543

    Article  CAS  PubMed  Google Scholar 

  218. Straud S, Zubovych I, De Brabander JK, Roth MG (2010) Inhibition of iron uptake is responsible for differential sensitivity to V-ATPase inhibitors in several cancer cell lines. PLoS One 5, e11629

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Lee G-H, Kim D-S, Kim H-T et al (2011) Enhanced lysosomal activity is involved in bax inhibitor-1-induced regulation of the endoplasmic reticulum (ER) stress response and cell death against ER stress involvement of vacuolar H + -ATPASE (V-ATPASE). J Biol Chem 286:24743–24753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Lim J-H, Park J-W, Kim M-S et al (2006) Bafilomycin induces the p21-mediated growth inhibition of cancer cells under hypoxic conditions by expressing hypoxia-inducible factor-1α. Mol Pharmacol 70:1856–1865

    Article  CAS  PubMed  Google Scholar 

  221. Zhdanov AV, Dmitriev RI, Golubeva AV et al (2013) Chronic hypoxia leads to a glycolytic phenotype and suppressed HIF-2 signaling in PC12 cells. Biochim Biophys Acta 1830:3553–3569

    Article  CAS  PubMed  Google Scholar 

  222. Li SC, Diakov TT, Rizzo JM, Kane PM (2012) Vacuolar H + -ATPase works in parallel with the HOG pathway to adapt Saccharomyces cerevisiae cells to osmotic stress. Eukaryot Cell 11:282–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Dietz KJ, Tavakoli N, Kluge C et al (2001) Significance of the V‐type ATPase for the adaptation to stressful growth conditions and its regulation on the molecular and biochemical level. J Exp Bot 52:1969–1980

    Article  CAS  PubMed  Google Scholar 

  224. Lin M, Li SC, Kane PM, Höfken T (2012) Regulation of vacuolar H + -ATPase activity by the Cdc42 effector Ste20 in Saccharomyces cerevisiae. Eukaryot Cell 11:442–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Seidel T, Scholl S, Krebs M et al (2012) Regulation of the V-type ATPase by redox modulation. Biochem J 448:243–251

    Article  CAS  PubMed  Google Scholar 

  226. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  CAS  PubMed  Google Scholar 

  227. Sennoune SR, Martinez-Zaguilan R (2012) Vacuolar H + -ATPase signaling pathway in cancer. Curr Protein Pept Sci 13:152–163

    Article  CAS  PubMed  Google Scholar 

  228. Martinez-Outschoorn U, Sotgia F, Lisanti MP (2014) Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function. Semin Oncol 41:195–216

    Article  CAS  PubMed  Google Scholar 

  229. Salem AF, Whitaker-Menezes D, Howell A et al (2012) Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance. Cell Cycle Georget, TX 11:4174–4180

    Article  CAS  Google Scholar 

  230. Martinez-Outschoorn UE, Whitaker-Menezes D, Valsecchi M et al (2013) Reverse Warburg effect in a patient with aggressive B-cell lymphoma: is lactic acidosis a paraneoplastic syndrome? Semin Oncol 40:403–418

    Article  PubMed  Google Scholar 

  231. Montcourrier P, Mangeat PH, Valembois C et al (1994) Characterization of very acidic phagosomes in breast cancer cells and their association with invasion. J Cell Sci 107:2381–2391

    PubMed  Google Scholar 

  232. Montcourrier P, Silver I, Farnoud R et al (1997) Breast cancer cells have a high capacity to acidify extracellular milieu by a dual mechanism. Clin Exp Metastasis 15:382–392

    Article  CAS  PubMed  Google Scholar 

  233. Capecci J, Forgac M (2013) The function of vacuolar ATPase (V-ATPase) a subunit isoforms in invasiveness of MCF10a and MCF10CA1a human breast cancer cells. J Biol Chem 288:32731–32741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Cotter K, Capecci J, Sennoune S et al (2015) Activity of plasma membrane V-ATPases is critical for the invasion of MDA-MB231 breast cancer cells. J Biol Chem 290:3680–3692

    Article  CAS  PubMed  Google Scholar 

  235. Lu X, Qin W, Li J et al (2005) The growth and metastasis of human hepatocellular carcinoma xenografts are inhibited by small interfering RNA targeting to the subunit ATP6L of proton pump. Cancer Res 65:6843–6849

    Article  CAS  PubMed  Google Scholar 

  236. Nishisho T, Hata K, Nakanishi M, Morita Y, Sun-Wada G-H, Wada Y, Yasui N, Yoneda T (2011) The a3 isoform vacuolar type H+-ATPase promotes distant metastasis in the mouse B16 melanoma cells. Mol Cancer Res 9:845–855. doi:10.1158/1541-7786.MCR-10-0449

    Article  CAS  PubMed  Google Scholar 

  237. Hendrix A, Sormunen R, Westbroek W et al (2013) Vacuolar H+ ATPase expression and activity is required for Rab27B-dependent invasive growth and metastasis of breast cancer. Int J Cancer 133:843–854

    Article  CAS  PubMed  Google Scholar 

  238. Feng S, Cai M, Liu P et al (2014) Atp6v1c1 may regulate filament actin arrangement in breast cancer cells. PLoS One 9, e84833

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. Wiedmann RM, von Schwarzenberg K, Palamidessi A et al (2012) The V-ATPase-inhibitor archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1. Cancer Res 72:5976–5987

    Article  CAS  PubMed  Google Scholar 

  240. Mahoney BP, Raghunand N, Baggett B, Gillies RJ (2003) Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem Pharmacol 66:1207–1218

    Article  CAS  PubMed  Google Scholar 

  241. Simon SM, Schindler M (1994) Cell biological mechanisms of multidrug resistance in tumors. Proc Natl Acad Sci U S A 91:3497–3504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Martínez-Zaguilán R, Raghunand N, Lynch RM et al (1999) pH and drug resistance. I. Functional expression of plasmalemmal V-type H + -ATPase in drug-resistant human breast carcinoma cell lines. Biochem Pharmacol 57:1037–1046

    Article  PubMed  Google Scholar 

  243. Lebreton S, Jaunbergs J, Roth MG et al (2008) Evaluating the potential of vacuolar ATPase inhibitors as anticancer agents and multigram synthesis of the potent salicylihalamide analog saliphenylhalamide. Bioorg Med Chem Lett 18:5879–5883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Murakami T, Toda S, Fujimoto M et al (2001) Constitutive activation of Wnt/β-catenin signaling pathway in migration-active melanoma cells: role of LEF-1 in melanoma with increased metastatic potential. Biochem Biophys Res Commun 288:8–15

    Article  CAS  PubMed  Google Scholar 

  245. You H, Jin J, Shu H et al (2009) Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells. Cancer Lett 280:110–119

    Article  CAS  PubMed  Google Scholar 

  246. Fan S, Niu Y, Tan N et al (2013) LASS2 enhances chemosensitivity of breast cancer by counteracting acidic tumor microenvironment through inhibiting activity of V-ATPase proton pump. Oncogene 32:1682–1690

    Article  CAS  PubMed  Google Scholar 

  247. Patal KJ, Lee C, Tan Q et al (2013) Use of proton pump inhibitor pantoprazole to modify distribution and activity of doxorubcin a potential strategy to improve the therapy of solid tumors. Clin Cancer Res 19:6766–6776

    Article  CAS  Google Scholar 

  248. Suzuki K, Doki K, Homma M et al (2009) Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high dose methotrexate therapy. Br J Clin Pharmacol 67:44–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. De Milito A, Canese R, Marino ML et al (2010) pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity. Int J Cancer 127:207–219

    Article  PubMed  CAS  Google Scholar 

  250. Zhang S, Wang Y, Li SJ (2014) Lansoprazole induces apoptosis of breast cancer cells through inhibition of intracellular proton extrusion. Biochem Biophys Res Commun 448:424–429

    Article  CAS  PubMed  Google Scholar 

  251. De Milito A, Marino ML, Fais S (2012) A rationale for the use of proton pump inhibitors as antineoplastic agents. Curr Pharm Des 18:1395–1406

    Article  PubMed  Google Scholar 

  252. Huang S, Chen M, Ding X et al (2013) Proton pump inhibitor selectively suppresses proliferation and restores the chemosensitivity of gastric cancer cells by inhibiting STAT3 signaling pathway. Int Immunopharmacol 17:585–592

    Article  CAS  PubMed  Google Scholar 

  253. Kastelein F, Spaander MCW, Steyerberg EW et al (2013) Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett’s esophagus. Clin Gastroenterol Hepatol 11:382–388

    Article  CAS  PubMed  Google Scholar 

  254. Kastelein F, Spaander MCW, Biermann K et al (2011) Role of acid suppression in the development and progression of dysplasia in patients with Barrett’s esophagus. Dig Dis Basel Switz 29:499–506

    Article  CAS  Google Scholar 

  255. Krop M, Lu X, Danser AH et al (2013) The (Pro)renin receptor. A decade of research: what have we learned. Pflugers Arch 465:87–97

    Article  CAS  PubMed  Google Scholar 

  256. Kinouchi K, Ichihara A, Sano M et al (2010) The (Pro)renin receptor/ATP6AP2 is essential for vacuolar H + -ATPase assembly in murine cardiomyocytes. Circ Res 107:30–34

    Article  CAS  PubMed  Google Scholar 

  257. Jewell JL, Russell RC, Guan K-L (2013) Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14:133–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H + -ATPase. Science 334:678–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Peña-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC et al (2011) Regulation of TFEB and V-ATPases by mTORC1. EMBO J 30:3242–3258

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Fitz Hall, Room 249, 1 University of New Mexico MSC 08, Albuquerque, NM, 4670, USA

    Colleen A. Fordyce, Martha M. Grimes, Yamhilette Licon-Munoz, Chun-Yuan Chan & Karlett J. Parra

Authors
  1. Colleen A. Fordyce
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martha M. Grimes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yamhilette Licon-Munoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-Yuan Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karlett J. Parra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karlett J. Parra .

Editor information

Editors and Affiliations

  1. Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. University of Manitoba, Institute of Cardiovascular Science St. Boniface Hospital Research, Winnipeg, Manitoba, Canada

    Naranjan S Dhalla

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Fordyce, C.A., Grimes, M.M., Licon-Munoz, Y., Chan, CY., Parra, K.J. (2016). Vacuolar ATPase in Physiology and Pathology: Roles in Neurobiology, Infectious Disease, and Cancer. In: Chakraborti, S., Dhalla, N. (eds) Regulation of Ca2+-ATPases,V-ATPases and F-ATPases. Advances in Biochemistry in Health and Disease, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-24780-9_17

Download citation

Publish with us

Policies and ethics

Search

Navigation