Chapter 14 : Acidification of Endosomes and Phagosomes

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The phagocytic pathway is a specialized endocytic pathway seen in cells that are capable of phagocytosis. Certain cells, such as macrophages and neutrophils, are termed professional phagocytes since they specialize in phagocytosis as a mechanism for cells to degrade unwanted material, which includes foreign particles such as bacteria, as well as necrotic or apoptotic host cells. Although the emphasis of this chapter is on the phagocytosis of pathogens, phagocytosis is in fact also essential for housekeeping functions in multicellular organisms, by way of clearing the apoptotic and necrotic cells. A comparative study of the properties of phagosomes containing vs. shows that whereas -containing endosomes exhibit several characteristics of early endosomes, such as a delayed clearance of major histocompatibility complex (MHC)-I molecules and a relatively intense staining for MHC-II and transferrin receptor, phagosomes rapidly clear the MHC-I and do not express any of the endolysosomal markers studied. Several groups, using several different cell lines expressing exogenous cystic fibrosis transmembrane conductance regulator (CFTR), have reported that acidification of endosomes or the trans-Golgi network (TGN) are not affected by CFTR expression. In cases where phagosome acidification is needed for killing the pathogens, part of the function of acidification may be the activation of degradative lysosomal enzymes, which have low pH optima.

Citation: Mukherjee S, Maxfield F. 2009. Acidification of Endosomes and Phagosomes, p 225-233. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch14
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Image of FIGURE 1

Schematic representation of various organelles that participate in phagocytic and endocytic processes. Organelles are indicated in shades of gray to represent the degree of acidity. See text for references to studies from which the pH values were taken.

Citation: Mukherjee S, Maxfield F. 2009. Acidification of Endosomes and Phagosomes, p 225-233. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch14
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1. Allison, A. C.,, P. Davies, and, S. De Petris. 1971. Role of contractile microfilaments in macrophage movement and endocytosis. Nat. New Biol. 232: 153155.
2. Atluri, P. P.,, and T. A. Ryan. 2006. The kinetics of synaptic vesicle reacidification at hippocampal nerve terminals. J. Neurosci. 26: 23132320.
3. Au, C. L.,, and P. Y. Wong. 1980. Luminal acidification by the perfused rat cauda epididymidis. J. Physiol. 309: 419427.
4. Blair, H. C.,, S. L. Teitelbaum,, R. Ghiselli, and, S. Gluck. 1989. Osteoclastic bone resorption by a polarized vacuolar proton pump. Science 245: 855857.
5. Breton, S.,, and D. Brown. 2007. New insights into the regulation of V-ATPase-dependent proton secretion. Am. J. Physiol. 292: F1F10.
6. Brett, C. L.,, Y. Wei,, M. Donowitz, and, R. Rao. 2002. Human Na(+)/H(+) exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria. Am. J. Physiol. 282: C1031C1041.
7. Cain, C. C.,, and R. F. Murphy. 1988. A chloroquine-resistant Swiss 3T3 cell line with a defect in late endocytic acidification. J. Cell Biol. 106: 269277.
8. Cain, C. C.,, D. M. Sipe, and, R. F. Murphy. 1989. Regulation of endocytic pH by the Na+,K+-ATPase in living cells. Proc. Natl. Acad. Sci. USA 86: 544548.
9. Chalhoub, N.,, N. Benachenhou,, V. Rajapurohitam,, M. Pata,, M. Ferron,, A. Frattini,, A. Villa, and, J. Vacher. 2003. Greylethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat. Med. 9: 399406.
10. Cleiren, E.,, O. Benichou,, E. Van Hul,, J. Gram,, J. Bollerslev,, F. R. Singer,, K. Beaverson,, A. Aledo,, M. P. Whyte,, T. Yoneyama,, M. C. deVernejoul, and, W. Van Hul. 2001. Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Human Mol. Gen. 10: 28612867.
11. Clemens, D. L.,, and M. A. Horwitz. 1995. Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J. Exp. Med. 181: 257270.
12. Clemens, D. L.,, B. Y. Lee, and, M. A. Horwitz. 2000a. Deviant expression of Rab5 on phagosomes containing the intracellular pathogens Mycobacterium tuberculosis and Legionella pneumophila is associated with altered phagosomal fate. Infect. Immun. 68: 26712684.
13. Clemens, D. L.,, B. Y. Lee, and, M. A. Horwitz. 2000b. Mycobacterium tuberculosis and Legionella pneumophila phagosomes exhibit arrested maturation despite acquisition of Rab7. Infect. Immun. 68: 51545166.
14. Demaurex, N.,, W. Furuya,, S. D’Souza,, J. S. Bonifacino, and, S. Grinstein. 1998. Mechanism of acidification of the transGolgi network (TGN). In situ measurements of pH using retrieval of TGN38 and furin from the cell surface. J. Biol. Chem. 273: 20442051.
15. Di, A.,, M. E. Brown,, L. V. Deriy,, C. Li,, F. L. Szeto,, Y. Chen,, P. Huang,, J. Tong,, A. P. Naren,, V. Bindokas,, H. C. Palfrey, and, D. J. Nelson. 2006. CFTR regulates phagosome acidification in macrophages and alters bactericidal activity. Nat. Cell Biol. 8: 933944.
16. Dunn, K. W.,, and F. R. Maxfield. 2003. Ratio imaging instrumentation. Methods Cell Biol. 72: 389413.
17. Dunn, K. W.,, S. Mayor,, J. N. Myers, and, F. R. Maxfield. 1994. Applications of ratio fluorescence microscopy in the study of cell physiology. FASEB J. 8: 573582.
18. Dunn, K. W.,, T. E. McGraw, and, F. R. Maxfield. 1989. Iterative fractionation of recycling receptors from lysosomally destined ligands in an early sorting endosome. J. Cell Biol. 109: 33033314.
19. Dunn, K. W.,, J. Park,, C. E. Semrad,, D. L. Gelman,, T. Shevell, and, T. E. McGraw. 1994. Regulation of endocytic trafficking and acidification are independent of the cystic fibrosis transmembrane regulator. J. Biol. Chem. 269: 53365345.
20. Fagotto, F.,, and F. R. Maxfield. 1994. Changes in yolk platelet pH during Xenopus laevis development correlate with yolk utilization. A quantitative confocal microscopy study. J. Cell Sci. 107: 33253337.
21. Faundez, V.,, and H. C. Hartzell. 2004. Intracellular chloride channels: determinants of function in the endosomal pathway. Science STKE 2004: re8.
22. Fuchs, R.,, S. Schmid, and, I. Mellman. 1989. A possible role for Na+,K+-ATPase in regulating ATP-dependent endosome acidification. Proc. Natl. Acad. Sci. USA 86: 539543.
23. Gunther, W.,, A. Luchow,, F. Cluzeaud,, A. Vandewalle, and, T. J. Jentsch. 1998. ClC-5, the chloride channel mutated in Dent’s disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc. Natl. Acad. Sci. USA 95: 80758080.
24. Hao, M.,, and F. R. Maxfield. 2000. Characterization of rapid membrane internalization and recycling. J. Biol. Chem. 275: 1527915286.
25. Inoue, T.,, Y. Wang,, K. Jefferies,, J. Qi,, A. Hinton, and, M. Forgac. 2005. Structure and regulation of the V-ATPases. J. Bioenerg. Biomemb. 37: 393398.
26. Jentsch, T. J. 2007. Chloride and the endosomal-lysosomal pathway: emerging roles of CLC chloride transporters. J. Physiol. 578: 633640.
27. Kasper, D.,, R. Planells-Cases,, J. C. Fuhrmann,, O. Scheel,, O. Zeitz,, K. Ruether,, A. Schmitt,, M. Poet,, R. Steinfeld,, M. Schweizer,, U. Kornak, and, T. J. Jentsch. 2005. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J. 24: 10791091.
28. Kaufmann, S. H.,, and U. E. Schaible. 2005. Antigen presentation and recognition in bacterial infections. Curr. Opin. Immunol. 17: 7987.
29. Kawasaki-Nishi, S.,, K. Bowers,, T. Nishi,, M. Forgac, and, T. H. Stevens. 2001a. The amino-terminal domain of the vacuolar proton-translocating ATPase a subunit controls targeting and in vivo dissociation, and the carboxyl-terminal domain affects coupling of proton transport and ATP hydrolysis. J. Biol. Chem. 276: 4741147420.
30. Kawasaki-Nishi, S.,, T. Nishi, and, M. Forgac. 2001b. 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: 1794117948.
31. Kielian, M. C.,, M. Marsh, and, A. Helenius. 1986. Kinetics of endosome acidification detected by mutant and wild-type Semliki Forest virus. EMBO J. 5: 31033109.
32. Killisch, I.,, P. Steinlein,, K. Romisch,, R. Hollinshead,, H. Beug, and, G. Griffiths. 1992. Characterization of early and late endocytic compartments of the transferrin cycle. Transferrin receptor antibody blocks erythroid differentiation by trapping the receptor in the early endosome. J. Cell Sci. 103: 211232.
33. Kim, J. H.,, L. Johannes,, B. Goud,, C. Antony,, C. A. Ling-wood,, R. Daneman, and, S. Grinstein. 1998. Noninvasive measurement of the pH of the endoplasmic reticulum at rest and during calcium release. Proc. Natl. Acad. Sci. USA 95: 29973002.
34. Kornak, U.,, D. Kasper,, M. R. Bosl,, E. Kaiser,, M. Schweizer,, A. Schulz,, W. Friedrich,, G. Delling, and, T. J. Jentsch. 2001. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104: 205215.
35. Krysko, D. V.,, K. D’Herde, and, P. Vandenabeele. 2006. Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis 11: 17091726.
36. Lange, P. F.,, L. Wartosch,, T. J. Jentsch, and, J. C. Fuhrmann. 2006. ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature 440: 220223.
37. Lee, R. J.,, S. Wang, and, P. S. Low. 1996. Measurement of endosome pH following folate receptor-mediated endocytosis. Biochim. Biophys. Acta 1312: 237242.
38. Lin, H. J.,, H. Szmacinski, and, J. R. Lakowicz. 1999. Lifetime-based pH sensors: indicators for acidic environments. Anal. Biochem. 269: 162167.
39. Lloyd, S. E.,, S. H. Pearce,, S. E. Fisher,, K. Steinmeyer,, B. Schwappach,, S. J. Scheinman,, B. Harding,, A. Bolino,, M. Devoto,, P. Goodyer,, S. P. Rigden,, O. Wrong,, T. J. Jentsch,, I. W. Craig, and, R. V. Thakker. 1996. A common molecular basis for three inherited kidney stone diseases. Nature 379: 445449.
40. Lowrie, D. B.,, P. W. Andrew, and, T. J. Peters. 1979. Analytical subcellular fractionation of alveolar macrophages from normal and BCG-vaccinated rabbits with particular reference to heterogeneity of hydrolase-containing granules. Biochem. J. 178: 761767.
41. Majumdar, A.,, D. Cruz,, N. Asamoah,, A. Buxbaum,, I. Sohar,, P. Lobel, and, F. R. Maxfield. 2007. Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol. Biol. Cell 18: 14901496.
42. Maxfield, F. R.,, and T. E. McGraw. 2004. Endocytic recycling. Nat. Rev. Mol. Cell Biol. 5: 121132.
43. Mellman, I. 1992. The importance of being acid: the role of acidification in intracellular membrane traffic. J. Exp. Biol. 172: 3945.
44. Miesenbock, G.,, D. A. De Angelis, and, J. E. Rothman. 1998. Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394: 192195.
45. Mukherjee, S.,, R. N. Ghosh, and, F. R. Maxfield. 1997. Endocytosis. Physiol. Rev. 77: 759803.
46. Nakamura, N.,, S. Tanaka,, Y. Teko,, K. Mitsui, and, H. Kanazawa. 2005. Four Na+/H+ exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation. J. Biol. Chem. 280: 15611572.
47. Nathan, C.,, and S. Ehrt. 2003. Nitric Oxide in Tuberculosis, 2nd ed. Lippincott Williams & Wilkins, Philadelphia, PA.
48. Nathan, C.,, and M. U. Shiloh. 2000. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc. Natl. Acad. Sci. USA 97: 88418848.
49. Nguyen, L.,, and J. Pieters. 2005. The Trojan horse: survival tactics of pathogenic mycobacteria in macrophages. Trends Cell Biol. 15: 269276.
50. Oka, T.,, Y. Murata,, M. Namba,, T. Yoshimizu,, T. Toyomura,, A. Yamamoto,, G. H. Sun-Wada,, N. Hamasaki,, Y. Wada, and, M. Futai. 2001. a4, a unique kidney-specific isoform of mouse vacuolar H+-ATPase subunit a. J. Biol. Chem. 276: 4005040054.
51. Parra, K. J.,, and P. M. Kane. 1998. Reversible association between the V1 and V0 domains of yeast vacuolar H+-ATPase is an unconventional glucose-induced effect. Mol. Cell Biol. 18: 70647074.
52. Picollo, A.,, and M. Pusch. 2005. Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature 436: 420423.
53. Pizarro-Cerda, J.,, and P. Cossart. 2006. Subversion of cellular functions by Listeria monocytogenes. J. Pathol. 208: 215223.
54. Poet, M.,, U. Kornak,, M. Schweizer,, A. A. Zdebik,, O. Scheel,, S. Hoelter,, W. Wurst,, A. Schmitt,, J. C. Fuhrmann,, R. Planells-Cases,, S. E. Mole,, C. A. Hubner, and, T. J. Jentsch. 2006. Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6. Proc. Natl. Acad. Sci. USA 103: 1385413859.
55. Rathman, M.,, M. D. Sjaastad, and, S. Falkow. 1996. Acidification of phagosomes containing Salmonella typhimurium in murine macrophages. Infect. Immun. 64: 27652773.
56. Root, K. V.,, J. F. Engelhardt,, M. Post,, J. W. Wilson, and, R. W. Van Dyke. 1994. CFTR does not alter acidification of L cell endosomes. Biochem. Biophys. Res. Commun. 205: 396401.
57. Roy, C. R.,, and L. G. Tilney. 2002. The road less traveled: transport of Legionella to the endoplasmic reticulum. J. Cell Biol. 158: 415419.
58. Rybak, S. L.,, and R. F. Murphy. 1998. Primary cell cultures from murine kidney and heart differ in endosomal pH. J. Cell Physiol. 176: 216222.
59. Sandvig, K.,, and B. van Deurs. 2005. Delivery into cells: lessons learned from plant and bacterial toxins. Gene Ther. 12: 865872.
60. Sandvig, K.,, and B. van Deurs. 2002. Membrane traffic exploited by protein toxins. Annu. Rev. Cell Dev. Biol. 18: 124.
61. Scheel, O.,, A. A. Zdebik,, S. Lourdel, and, T. J. Jentsch. 2005. Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature 436: 424427.
62. Schmid, S. R.,, M. Fuchs,, A. Kielian, and, I. Mellman. 1989. Acidification of endosome subpopulations in wild-type Chinese hamster ovary cells and temperature-sensitive acidification-defective mutants. J. Cell Biol. 108: 12911300.
63. Schmidt, W. K.,, and H. P. Moore. 1995. Ionic milieu controls the compartment-specific activation of pro-opiomelanocortin processing in AtT-20 cells. Mol. Biol. Cell 6: 12711285.
64. Scott, C. C.,, R. J. Botelho, and, S. Grinstein. 2003. Phagosome maturation: a few bugs in the system. J. Memb. Biol. 193: 137152.
65. Seksek, O.,, J. Biwersi, and, A. S. Verkman. 1996. Evidence against defective trans-Golgi acidification in cystic fibrosis. J. Biol. Chem. 271: 1554215548.
66. Seol, J. H.,, A. Shevchenko,, A. Shevchenko, and, R. J. Deshaies. 2001. Skp1 forms multiple protein complexes, including RAVE, a regulator of V-ATPase assembly. Nat. Cell Biol. 3: 384391.
67. Shao, E.,, and M. Forgac. 2004. Involvement of the nonhomologous region of subunit A of the yeast V-ATPase in coupling and in vivo dissociation. J. Biol. Chem. 279: 4866348670.
68. Shao, E.,, T. Nishi,, S. Kawasaki-Nishi, and, M. Forgac. 2003. Mutational analysis of the non-homologous region of subunit A of the yeast V-ATPase. J. Biol. Chem. 278: 1298512991.
69. Sheterline, P.,, J. E. Rickard, and, R. C. Richards. 1984. Fc receptor-directed phagocytic stimuli induce transient actin assembly at an early stage of phagocytosis in neutrophil leukocytes. Eur. J. Cell Biol. 34: 8087.
70. Shu, Z.,, M. Jung,, H. G. Beger,, M. Marzinzig,, F. Han,, U. Butzer,, U. B. Bruckner, and, A. K. Nussler. 1997. pH-dependent changes of nitric oxide, peroxynitrite, and reactive oxygen species in hepatocellular damage. Am. J. Physiol. 273: G1118G1126.
71. Sipe, D. M.,, A. Jesurum, and, R. F. Murphy. 1991. Absence of Na+,K(+)-ATPase regulation of endosomal acidification in K562 erythroleukemia cells. Analysis via inhibition of transferrin recycling by low temperatures. J. Biol. Chem. 266: 34693474.
72. Sipe, D. M.,, and R. F. Murphy. 1987. High resolution kinetics of transferrin acidification in Balb/c 3T3 cells: exposure to pH 6 followed by temperature sensitive alkalinization during recycling. Proc. Natl. Acad. Sci. USA 84: 71197123.
73. Slepkov, E. R.,, J. K. Rainey,, B. D. Sykes, and, L. Fliegel. 2007. Structural and functional analysis of the Na+/H+ exchanger. Biochem. J. 401: 623633.
74. Stobrawa, S. M.,, T. Breiderhoff,, S. Takamori,, D. Engel,, M. Schweizer,, A. A. Zdebik,, M. R. Bosl,, K. Ruether,, H. Jahn,, A. Draguhn,, R. Jahn, and, T. J. Jentsch. 2001. Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29: 185196.
75. Sugita, M.,, M. Cernadas, and, M. B. Brenner. 2004. New insights into pathways for CD1-mediated antigen presentation. Curr. Opin. Immunol. 16: 9095.
76. Tjelle, T. E.,, T. Lovdal, and, T. Berg. 2000. Phagosome dynamics and function. BioEssays 22: 255263.
77. Toyomura, T.,, T. Oka,, C. Yamaguchi,, Y. Wada, and, M. Futai. 2000. Three subunit a isoforms of mouse vacuolar H(+)-ATPase. Preferential expression of the a3 isoform during osteoclast differentiation. J. Biol. Chem. 275: 87608765.
78. Vieira, O. V.,, R. J. Botelho, and, S. Grinstein. 2002. Phagosome maturation: aging gracefully. Biochem. J. 366: 689704.
79. Wagner, C. A.,, K. E. Finberg,, S. Breton,, V. Marshansky,, D. Brown, and, J. P. Geibel. 2004. Renal vacuolar H+-ATPase. Physiol. Rev. 84: 12631314.
80. Xu, T.,, and M. Forgac. 2001. Microtubules are involved in glucose-dependent dissociation of the yeast vacuolar [H+]-ATPase in vivo. J. Biol. Chem. 276: 2485524861.
81. Yamashiro, D. J.,, and F. R. Maxfield. 1987. Kinetics of endosome acidification in mutant and wild-type Chinese hamster ovary cells. J. Cell Biol. 105: 27132721.
82. Yu, S. P. 2003. Na(+), K(+)-ATPase: the new face of an old player in pathogenesis and apoptotic/hybrid cell death. Biochem. Pharmacol. 66: 16011609.
83. Yun, C. H.,, C. M. Tse,, S. K. Nath,, S. A. Levine,, S. R. Brant, and, M. Donowitz. 1995. Mammalian Na+/H+ exchanger gene family: structure and function studies. Am. J. Physiol. 269: G1G11.

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