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P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways

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Abstract

Activation of the P2X7 receptor (P2X7R) triggers a remarkably diverse array of membrane trafficking responses in leukocytes and epithelial cells. These responses result in altered profiles of cell surface lipid and protein composition that can modulate the direct interactions of P2X7R-expressing cells with other cell types in the circulation, in blood vessels, at epithelial barriers, or within sites of immune and inflammatory activation. Additionally, these responses can result in the release of bioactive proteins, lipids, and large membrane complexes into extracellular compartments for remote communication between P2X7R-expressing cells and other cells that amplify or modulate inflammation, immunity, and responses to tissue damages. This review will discuss P2X7R-mediated effects on membrane composition and trafficking in the plasma membrane (PM) and intracellular organelles, as well as actions of P2X7R in controlling various modes of non-classical secretion. It will review P2X7R regulation of: (1) phosphatidylserine distribution in the PM outer leaflet; (2) shedding of PM surface proteins; (3) release of PM-derived microvesicles or microparticles; (4) PM blebbing; (5) cell–cell fusion resulting in formation of multinucleate cells; (6) phagosome maturation and fusion with lysosomes; (7) permeability of endosomes with internalized pathogen-associated molecular patterns; (8) permeability/integrity of mitochondria; (9) exocytosis of secretory lysosomes; and (10) release of exosomes from multivesicular bodies.

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References

  1. Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA, Henson PM (2000) A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405:85–90

    PubMed  CAS  Google Scholar 

  2. Bevers EM, Comfurius P, Zwaal RF (1983) Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys Acta 736:57–66

    PubMed  CAS  Google Scholar 

  3. Comfurius P, Zwaal RF (1977) The enzymatic synthesis of phosphatidylserine and purification by CM-cellulose column chromatography. Biochim Biophys Acta 488:36–42

    PubMed  CAS  Google Scholar 

  4. Bevers EM, Comfurius P, Dekkers DW, Zwaal RF (1999) Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta 1439:317–330

    PubMed  CAS  Google Scholar 

  5. Balasubramanian K, Schroit AJ (2003) Aminophospholipid asymmetry: a matter of life and death. Annu Rev Physiol 65:701–734

    PubMed  CAS  Google Scholar 

  6. Zwaal RF, Schroit AJ (1997) Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 89:1121–1132

    PubMed  CAS  Google Scholar 

  7. Mackenzie AB, Young MT, Adinolfi E, Surprenant A (2005) Pseudoapoptosis induced by brief activation of ATP-gated P2X7 receptors. J Biol Chem 280:33968–33976

    PubMed  CAS  Google Scholar 

  8. van den Eijnde SM, van den Hoff MJ, Reutelingsperger CP, van Heerde WL, Henfling ME, Vermeij-Keers C, Schutte B, Borgers M, Ramaekers FC (2001) Transient expression of phosphatidylserine at cell–cell contact areas is required for myotube formation. J Cell Sci 114:3631–3642

    PubMed  Google Scholar 

  9. de Vries KJ, Wiedmer T, Sims PJ, Gadella BM (2003) Caspase-independent exposure of aminophospholipids and tyrosine phosphorylation in bicarbonate responsive human sperm cells. Biol Reprod 68:2122–2134

    PubMed  Google Scholar 

  10. Frasch SC, Henson PM, Nagaosa K, Fessler MB, Borregaard N, Bratton DL (2004) Phospholipid flip–flop and phospholipid scramblase 1 (PLSCR1) co-localize to uropod rafts in formylated Met-Leu-Phe-stimulated neutrophils. J Biol Chem 279:17625–17633

    PubMed  CAS  Google Scholar 

  11. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321–334

    PubMed  CAS  Google Scholar 

  12. Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM (1998) The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ 5:551–562

    PubMed  CAS  Google Scholar 

  13. Marguet D, Luciani MF, Moynault A, Williamson P, Chimini G (1999) Engulfment of apoptotic cells involves the redistribution of membrane phosphatidylserine on phagocyte and prey. Nat Cell Biol 1:454–456

    PubMed  CAS  Google Scholar 

  14. Hamon Y, Broccardo C, Chambenoit O, Luciani MF, Toti F, Chaslin S, Freyssinet JM, Devaux PF, McNeish J, Marguet D, Chimini G (2000) ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nat Cell Biol 2:399–406

    PubMed  CAS  Google Scholar 

  15. Elliott JI, Surprenant A, Marelli-Berg FM, Cooper JC, Cassady-Cain RL, Wooding C, Linton K, Alexander DR, Higgins CF (2005) Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes. Nat Cell Biol 7:808–816

    PubMed  CAS  Google Scholar 

  16. Manodori AB, Barabino GA, Lubin BH, Kuypers FA (2000) Adherence of phosphatidylserine-exposing erythrocytes to endothelial matrix thrombospondin. Blood 95:1293–1300

    PubMed  CAS  Google Scholar 

  17. Galkina E, Tanousis K, Preece G, Tolaini M, Kioussis D, Florey O, Haskard DO, Tedder TF, Ager A (2003) l-selectin shedding does not regulate constitutive T cell trafficking but controls the migration pathways of antigen-activated T lymphocytes. J Exp Med 198:1323–1335

    PubMed  CAS  Google Scholar 

  18. Kishimoto TK, Jutila MA, Berg EL, Butcher EC (1989) Neutrophil Mac-1 and MEL-14 adhesion proteins inversely regulated by chemotactic factors. Science 245:1238–1241

    PubMed  CAS  Google Scholar 

  19. Jamieson GP, Snook MB, Thurlow PJ, Wiley JS (1996) Extracellular ATP causes of loss of l-selectin from human lymphocytes via occupancy of P2Z purinocepters. J Cell Physiol 166:637–642

    PubMed  CAS  Google Scholar 

  20. Gu B, Bendall LJ, Wiley JS (1998) Adenosine triphosphate-induced shedding of CD23 and l-selectin (CD62L) from lymphocytes is mediated by the same receptor but different metalloproteases. Blood 92:946–951

    PubMed  CAS  Google Scholar 

  21. Labasi JM, Petrushova N, Donovan C, McCurdy S, Lira P, Payette MM, Brissette W, Wicks JR, Audoly L, Gabel CA (2002) Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response. J Immunol 168:6436–6445

    PubMed  CAS  Google Scholar 

  22. Sluyter R, Wiley JS (2002) Extracellular adenosine 5′-triphosphate induces a loss of CD23 from human dendritic cells via activation of P2X7 receptors. Int Immunol 14:1415–1421

    PubMed  CAS  Google Scholar 

  23. Chen JR, Gu BJ, Dao LP, Bradley CJ, Mulligan SP, Wiley JS (1999) Transendothelial migration of lymphocytes in chronic lymphocytic leukaemia is impaired and involved down-regulation of both l-selectin and CD23. Br J Haematol 105:181–189

    PubMed  CAS  Google Scholar 

  24. Moon H, Na HY, Chong KH, Kim TJ (2006) P2X7 receptor-dependent ATP-induced shedding of CD27 in mouse lymphocytes. Immunol Lett 102:98–105

    PubMed  CAS  Google Scholar 

  25. VanWijk MJ, VanBavel E, Sturk A, Nieuwland R (2003) Microparticles in cardiovascular diseases. Cardiovasc Res 59:277–287

    PubMed  CAS  Google Scholar 

  26. Hess C, Sadallah S, Hefti A, Landmann R, Schifferli JA (1999) Ectosomes released by human neutrophils are specialized functional units. J Immunol 163:4564–4573

    PubMed  CAS  Google Scholar 

  27. Eken C, Gasser O, Zenhaeusern G, Oehri I, Hess C, Schifferli JA (2008) Polymorphonuclear neutrophil-derived ectosomes interfere with the maturation of monocyte-derived dendritic cells. J Immunol 180:817–824

    PubMed  CAS  Google Scholar 

  28. Barry OP, Pratico D, Savani RC, FitzGerald GA (1998) Modulation of monocyte–endothelial cell interactions by platelet microparticles. J Clin Invest 102:136–144

    PubMed  CAS  Google Scholar 

  29. Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94:3791–3799

    PubMed  CAS  Google Scholar 

  30. George JN, Thoi LL, McManus LM, Reimann TA (1982) Isolation of human platelet membrane microparticles from plasma and serum. Blood 60:834–840

    PubMed  CAS  Google Scholar 

  31. Zwaal RF, Comfurius P, Bevers EM (2004) Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids. Biochim Biophys Acta 1636:119–128

    PubMed  CAS  Google Scholar 

  32. Gasser O, Schifferli JA (2004) Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood 104:2543–2548

    PubMed  CAS  Google Scholar 

  33. Greco V, Hannus M, Eaton S (2001) Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106:633–645

    PubMed  CAS  Google Scholar 

  34. Pizzirani C, Ferrari D, Chiozzi P, Adinolfi E, Sandona D, Savaglio E, Di Virgilio F (2007) Stimulation of P2 receptors causes release of IL-1beta-loaded microvesicles from human dendritic cells. Blood 109:3856–3864

    PubMed  CAS  Google Scholar 

  35. Bianco F, Pravettoni E, Colombo A, Schenk U, Moller T, Matteoli M, Verderio C (2005) Astrocyte-derived ATP induces vesicle shedding and IL-1{beta} release from microglia. J Immunol 174:7268–7277

    PubMed  CAS  Google Scholar 

  36. MacKenzie A, Wilson HL, Kiss-Toth E, Dower SK, North RA, Surprenant A (2001) Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity 15:825–835

    PubMed  CAS  Google Scholar 

  37. Andrei C, Margiocco P, Poggi A, Lotti LV, Torrisi MR, Rubartelli A (2004) Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: implications for inflammatory processes. Proc Natl Acad Sci U S A 101:9745–9750

    PubMed  CAS  Google Scholar 

  38. Gudipaty L, Munetz J, Verhoef PA, Dubyak GR (2003) Essential role for Ca2+ in regulation of IL-1beta secretion by P2X7 nucleotide receptor in monocytes, macrophages, and HEK-293 cells. Am J Physiol Cell Physiol 285:C286–C99

    PubMed  CAS  Google Scholar 

  39. Carta S, Tassi S, Semino C, Fossati G, Mascagni P, Dinarello CA, Rubartelli A (2006) Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules. Blood 108:1618–1626

    PubMed  CAS  Google Scholar 

  40. Qu Y, Franchi L, Nunez G, Dubyak GR (2007) Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages. J Immunol 179:1913–1925

    PubMed  CAS  Google Scholar 

  41. Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A (2002) The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 3:995–1001

    PubMed  CAS  Google Scholar 

  42. Angelini G, Gardella S, Ardy M, Ciriolo MR, Filomeni G, Di Trapani G, Clarke F, Sitia R, Rubartelli A (2002) Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. Proc Natl Acad Sci U S A 99:1491–1496

    PubMed  CAS  Google Scholar 

  43. Robinson RA, Worfolk L, Tracy PB (1992) Endotoxin enhances the expression of monocyte prothrombinase activity. Blood 79:406–416

    PubMed  CAS  Google Scholar 

  44. Morelli A, Chiozzi P, Chiesa A, Ferrari D, Sanz JM, Falzoni S, Pinton P, Rizzuto R, Olson MF, Di Virgilio F (2003) Extracellular ATP causes ROCK I-dependent bleb formation in P2X7-transfected HEK293 cells. Mol Biol Cell 14:2655–2664

    PubMed  CAS  Google Scholar 

  45. Wilson HL, Wilson SA, Surprenant A, North RA (2002) Epithelial membrane proteins induce membrane blebbing and interact with the P2X7 receptor C terminus. J Biol Chem 277:34017–34023

    PubMed  CAS  Google Scholar 

  46. Pfeiffer ZA, Aga M, Prabhu U, Watters JJ, Hall DJ, Bertics PJ (2004) The nucleotide receptor P2X7 mediates actin reorganization and membrane blebbing in RAW 264.7 macrophages via p38 MAP kinase and Rho. J Leukoc Biol 75:1173–1182

    PubMed  CAS  Google Scholar 

  47. Verhoef PA, Estacion M, Schilling W, Dubyak GR (2003) P2X7 receptor-dependent blebbing and the activation of Rho-effector kinases, caspases, and IL-1 beta release. J Immunol 170:5728–5738

    PubMed  CAS  Google Scholar 

  48. Panupinthu N, Zhao L, Possmayer F, Ke HZ, Sims SM, Dixon SJ (2007) P2X7 nucleotide receptors mediate blebbing in osteoblasts through a pathway involving lysophosphatidic acid. J Biol Chem 282:3403–3412

    PubMed  CAS  Google Scholar 

  49. Chiozzi P, Sanz JM, Ferrari D, Falzoni S, Aleotti A, Buell GN, Collo G, Di Virgilio F (1997) Spontaneous cell fusion in macrophage cultures expressing high levels of the P2Z/P2X7 receptor. J Cell Biol 138:697–706

    PubMed  CAS  Google Scholar 

  50. Fairbairn IP, Stober CB, Kumararatne DS, Lammas DA (2001) ATP-mediated killing of intracellular mycobacteria by macrophages is a P2X(7)-dependent process inducing bacterial death by phagosome–lysosome fusion. J Immunol 167:3300–3307

    PubMed  CAS  Google Scholar 

  51. Adams DO (1976) The granulomatous inflammatory response. A review. Am J Pathol 84:164–192

    PubMed  CAS  Google Scholar 

  52. Falzoni S, Chiozzi P, Ferrari D, Buell G, Di Virgilio F (2000) P2X(7) receptor and polykarion formation. Mol Biol Cell 11:3169–3176

    PubMed  CAS  Google Scholar 

  53. Lemaire I, Falzoni S, Leduc N, Zhang B, Pellegatti P, Adinolfi E, Chiozzi P, Di Virgilio F (2006) Involvement of the purinergic P2X7 receptor in the formation of multinucleated giant cells. J Immunol 177:7257–7265

    PubMed  CAS  Google Scholar 

  54. Ke HZ, Qi H, Weidema AF, Zhang Q, Panupinthu N, Crawford DT, Grasser WA, Paralkar VM, Li M, Audoly LP, Gabel CA, Jee WS, Dixon SJ, Sims SM, Thompson DD (2003) Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. Mol Endocrinol 17:1356–1367

    PubMed  CAS  Google Scholar 

  55. Gartland A, Buckley KA, Hipskind RA, Perry MJ, Tobias JH, Buell G, Chessell I, Bowler WB, Gallagher JA (2003) Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice. Crit Rev Eukaryot Gene Expr 13:243–253

    PubMed  CAS  Google Scholar 

  56. Gartland A, Buckley KA, Bowler WB, Gallagher JA (2003) Blockade of the pore-forming P2X7 receptor inhibits formation of multinucleated human osteoclasts in vitro. Calcif Tissue Int 73:361–369

    PubMed  CAS  Google Scholar 

  57. Lammas DA, Stober C, Harvey CJ, Kendrick N, Panchalingam S, Kumararatne DS (1997) ATP-induced killing of mycobacteria by human macrophages is mediated by purinergic P2Z(P2X7) receptors. Immunity 7:433–444

    PubMed  CAS  Google Scholar 

  58. Kusner DJ, Adams J (2000) ATP-induced killing of virulent Mycobacterium tuberculosis within human macrophages requires phospholipase D. J Immunol 164:379–388

    PubMed  CAS  Google Scholar 

  59. Coutinho-Silva R, Stahl L, Raymond MN, Jungas T, Verbeke P, Burnstock G, Darville T, Ojcius DM (2003) Inhibition of chlamydial infectious activity due to P2X7R-dependent phospholipase D activation. Immunity 19:403–412

    PubMed  CAS  Google Scholar 

  60. Darville T, Welter-Stahl L, Cruz C, Sater AA, Andrews CW Jr, Ojcius DM (2007) Effect of the purinergic receptor P2X7 on Chlamydia infection in cervical epithelial cells and vaginally infected mice. J Immunol 179:3707–3714

    PubMed  CAS  Google Scholar 

  61. Humphreys BD, Dubyak GR (1996) Induction of the P2z/P2X7 nucleotide receptor and associated phospholipase D activity by lipopolysaccharide and IFN-gamma in the human THP-1 monocytic cell line. J Immunol 157:5627–5637

    PubMed  CAS  Google Scholar 

  62. Pochet S, Gomez-Munoz A, Marino A, Dehaye JP (2003) Regulation of phospholipase D by P2X7 receptors in submandibular ductal cells. Cell Signal 15:927–935

    PubMed  CAS  Google Scholar 

  63. Fernando KC, Gargett CE, Wiley JS (1999) Activation of the P2Z/P2X7 receptor in human lymphocytes produces a delayed permeability lesion: involvement of phospholipase D. Arch Biochem Biophys 362:197–202

    PubMed  CAS  Google Scholar 

  64. Sikora A, Liu J, Brosnan C, Buell G, Chessel I, Bloom BR (1999) Cutting edge: purinergic signaling regulates radical-mediated bacterial killing mechanisms in macrophages through a P2X7-independent mechanism. J Immunol 163:558–561

    PubMed  CAS  Google Scholar 

  65. Malik ZA, Thompson CR, Hashimi S, Porter B, Iyer SS, Kusner DJ (2003) Cutting edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase. J Immunol 170:2811–2815

    PubMed  CAS  Google Scholar 

  66. Thompson CR, Iyer SS, Melrose N, VanOosten R, Johnson K, Pitson SM, Obeid LM, Kusner DJ (2005) Sphingosine kinase 1 (SK1) is recruited to nascent phagosomes in human macrophages: inhibition of SK1 translocation by Mycobacterium tuberculosis. J Immunol 174:3551–3561

    PubMed  CAS  Google Scholar 

  67. Connolly SF, Kusner DJ (2007) The regulation of dendritic cell function by calcium-signaling and its inhibition by microbial pathogens. Immunol Res 39:115–127

    PubMed  CAS  Google Scholar 

  68. Mancino G, Placido R, Di Virgilio F (2001) P2X7 receptors and apoptosis in tuberculosis infection. J Biol Regul Homeost Agents 15:286–293

    PubMed  CAS  Google Scholar 

  69. Li CM, Campbell SJ, Kumararatne DS, Bellamy R, Ruwende C, McAdam KP, Hill AV, Lammas DA (2002) Association of a polymorphism in the P2X7 gene with tuberculosis in a Gambian population. J Infect Dis 186:1458–1462

    PubMed  CAS  Google Scholar 

  70. Myers AJ, Eilertson B, Fulton SA, Flynn JL, Canaday DH (2005) The purinergic P2X7 receptor is not required for control of pulmonary Mycobacterium tuberculosis infection. Infect Immun 73:3192–3195

    PubMed  CAS  Google Scholar 

  71. Fernando SL, Saunders BM, Sluyter R, Skarratt KK, Goldberg H, Marks GB, Wiley JS, Britton WJ (2007) A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis. Am J Respir Crit Care Med 175:360–366

    PubMed  CAS  Google Scholar 

  72. Franco-Martinez S, Nino-Moreno P, Bernal-Silva S, Baranda L, Rocha-Meza M, Portales-Cervantes L, Layseca-Espinosa E, Gonzalez-Amaro R, Portales-Perez D (2006) Expression and function of the purinergic receptor P2X7 in patients with pulmonary tuberculosis. Clin Exp Immunol 146:253–261

    PubMed  CAS  Google Scholar 

  73. Britton WJ, Fernando SL, Saunders BM, Sluyter R, Wiley JS (2007) The genetic control of susceptibility to Mycobacterium tuberculosis. Novartis Found Symp 281:79–89 discussion 89–92, 208–9

    PubMed  CAS  Google Scholar 

  74. Nino-Moreno P, Portales-Perez D, Hernandez-Castro B, Portales-Cervantes L, Flores-Meraz V, Baranda L, Gomez-Gomez A, Acuna-Alonzo V, Granados J, Gonzalez-Amaro R (2007) P2X7 and NRAMP1/SLC11 A1 gene polymorphisms in Mexican mestizo patients with pulmonary tuberculosis. Clin Exp Immunol 148:469–477

    PubMed  CAS  Google Scholar 

  75. Mokrousov I, Sapozhnikova N, Narvskaya O (2008) Mycobacterium tuberculosis co-existence with humans: making an imprint on the macrophage P2X7 receptor gene? J Med Microbiol 57:581–584

    PubMed  CAS  Google Scholar 

  76. Lu H, Shen C, Brunham RC (2000) Chlamydia trachomatis infection of epithelial cells induces the activation of caspase-1 and release of mature IL-18. J Immunol 165:1463–1469

    PubMed  CAS  Google Scholar 

  77. Balcewicz-Sablinska MK, Keane J, Kornfeld H, Remold HG (1998) Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha. J Immunol 161:2636–2641

    PubMed  CAS  Google Scholar 

  78. Di Virgilio F (2007) Liaisons dangereuses: P2X(7) and the inflammasome. Trends Pharmacol Sci 28:465–472

    PubMed  Google Scholar 

  79. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241

    PubMed  CAS  Google Scholar 

  80. Martinon F (2008) Detection of immune danger signals by NALP3. J Leukoc Biol 83:507–511

    PubMed  CAS  Google Scholar 

  81. Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7:31–40

    PubMed  CAS  Google Scholar 

  82. Martinon F (2007) Orchestration of pathogen recognition by inflammasome diversity: variations on a common theme. Eur J Immunol 37:3003–3006

    PubMed  CAS  Google Scholar 

  83. McDermott MF, Tschopp J (2007) From inflammasomes to fevers, crystals and hypertension: how basic research explains inflammatory diseases. Trends Mol Med 13:381–388

    PubMed  CAS  Google Scholar 

  84. Ye Z, Ting JP (2008) NLR, the nucleotide-binding domain leucine-rich repeat containing gene family. Curr Opin Immunol 20:3–9

    PubMed  CAS  Google Scholar 

  85. Franchi L, Kanneganti TD, Dubyak GR, Nunez G (2007) Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J Biol Chem 282:18810–18818

    PubMed  CAS  Google Scholar 

  86. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232

    PubMed  CAS  Google Scholar 

  87. Kahlenberg JM, Dubyak GR (2004) Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol Cell Physiol 286:C1100–C1108

    PubMed  CAS  Google Scholar 

  88. Pelegrin P, Surprenant A (2006) Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J 25:5071–5082

    PubMed  CAS  Google Scholar 

  89. Pelegrin P, Surprenant A (2007) Pannexin-1 couples to maitotoxin- and nigericin-induced interleukin-1beta release through a dye uptake-independent pathway. J Biol Chem 282:2386–2394

    PubMed  CAS  Google Scholar 

  90. Marina-Garcia N, Franchi L, Kim YG, Miller D, McDonald C, Boons GJ, Nunez G (2008) Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via Cryopyrin/NLRP3 independently of Nod2. J Immunol 180:4050–4057

    PubMed  CAS  Google Scholar 

  91. Kanneganti TD, Lamkanfi M, Kim YG, Chen G, Park JH, Franchi L, Vandenabeele P, Nunez G (2007) Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26:433–443

    PubMed  CAS  Google Scholar 

  92. Adinolfi E, Callegari MG, Ferrari D, Bolognesi C, Minelli M, Wieckowski MR, Pinton P, Rizzuto R, Di Virgilio F (2005) Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 16(7):3260–3272

    PubMed  CAS  Google Scholar 

  93. Garcia-Marcos M, Fontanils U, Aguirre A, Pochet S, Dehaye JP, Marino A (2005) Role of sodium in mitochondrial membrane depolarization induced by P2X7 receptor activation in submandibular glands. FEBS Lett 579:5407–5413

    PubMed  CAS  Google Scholar 

  94. Adinolfi E, Melchiorri L, Falzoni S, Chiozzi P, Morelli A, Tieghi A, Cuneo A, Castoldi G, Di Virgilio F, Baricordi OR (2002) P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia. Blood 99:706–708

    PubMed  CAS  Google Scholar 

  95. Greig AV, Linge C, Healy V, Lim P, Clayton E, Rustin MH, McGrouther DA, Burnstock G (2003) Expression of purinergic receptors in non-melanoma skin cancers and their functional roles in A431 cells. J Invest Dermatol 121:315–327

    PubMed  CAS  Google Scholar 

  96. Slater M, Scolyer RA, Gidley-Baird A, Thompson JF, Barden JA (2003) Increased expression of apoptotic markers in melanoma. Melanoma Res 13:137–145

    PubMed  CAS  Google Scholar 

  97. Slater M, Danieletto S, Gidley-Baird A, Teh LC, Barden JA (2004) Early prostate cancer detected using expression of non-functional cytolytic P2X7 receptors. Histopathology 44:206–215

    PubMed  CAS  Google Scholar 

  98. Cockcroft S, Gomperts BD (1979) ATP induces nucleotide permeability in rat mast cells. Nature 279:541–542

    PubMed  CAS  Google Scholar 

  99. Cockcroft S, Gomperts BD (1979) Activation and inhibition of calcium-dependent histamine secretion by ATP ions applied to rat mast cells. J Physiol 296:229–243

    PubMed  CAS  Google Scholar 

  100. Cockcroft S, Gomperts BD (1980) The ATP4- receptor of rat mast cells. Biochem J 188:789–798

    PubMed  CAS  Google Scholar 

  101. Tatham PE, Cusack NJ, Gomperts BD (1988) Characterisation of the ATP4- receptor that mediates permeabilisation of rat mast cells. Eur J Pharmacol 147:13–21

    PubMed  CAS  Google Scholar 

  102. Alzola E, Perez-Etxebarria A, Kabre E, Fogarty DJ, Metioui M, Chaib N, Macarulla JM, Matute C, Dehaye JP, Marino A (1998) Activation by P2X7 agonists of two phospholipases A2 (PLA2) in ductal cells of rat submandibular gland. Coupling of the calcium-independent PLA2 with kallikrein secretion. J Biol Chem 273:30208–30217

    PubMed  CAS  Google Scholar 

  103. Blott EJ, Griffiths GM (2002) Secretory lysosomes. Nat Rev Mol Cell Biol 3:122–131

    PubMed  CAS  Google Scholar 

  104. Andrews NW (2000) Regulated secretion of conventional lysosomes. Trends Cell Biol 10:316–321

    PubMed  CAS  Google Scholar 

  105. Holt OJ, Gallo F, Griffiths GM (2006) Regulating secretory lysosomes. J Biochem (Tokyo) 140:7–12

    CAS  Google Scholar 

  106. Fowler KT, Andrews NW, Huleatt JW (2007) Expression and function of synaptotagmin VII in CTLs. J Immunol 178:1498–1504

    PubMed  CAS  Google Scholar 

  107. Andrei C, Dazzi C, Lotti L, Torrisi MR, Chimini G, Rubartelli A (1999) The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles. Mol Biol Cell 10:1463–1475

    PubMed  CAS  Google Scholar 

  108. Brough D, Rothwell NJ (2007) Caspase-1-dependent processing of pro-interleukin-1beta is cytosolic and precedes cell death. J Cell Sci 120:772–781

    PubMed  CAS  Google Scholar 

  109. Clark R, Griffiths GM (2003) Lytic granules, secretory lysosomes and disease. Curr Opin Immunol 15:516–521

    PubMed  CAS  Google Scholar 

  110. Griffiths G (2002) What’s special about secretory lysosomes? Semin Cell Dev Biol 13:279–284

    PubMed  CAS  Google Scholar 

  111. Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579

    PubMed  CAS  Google Scholar 

  112. Johnstone RM (2006) Exosomes biological significance: a concise review. Blood Cells Mol Dis 36:315–321

    PubMed  CAS  Google Scholar 

  113. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172

    PubMed  CAS  Google Scholar 

  114. Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, Garin J, Amigorena S (2001) Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol 166:7309–7318

    PubMed  CAS  Google Scholar 

  115. Muntasell A, Berger AC, Roche PA (2007) T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. Embo J 26:4263–4272

    PubMed  CAS  Google Scholar 

  116. Thery C, Duban L, Segura E, Veron P, Lantz O, Amigorena S (2002) Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol 3:1156–1162

    PubMed  CAS  Google Scholar 

  117. Quah BJ, O’Neill HC (2005) The immunogenicity of dendritic cell-derived exosomes. Blood Cells Mol Dis 35:94–110

    PubMed  CAS  Google Scholar 

  118. Li XB, Zhang ZR, Schluesener HJ, Xu SQ (2006) Role of exosomes in immune regulation. J Cell Mol Med 10:364–375

    PubMed  CAS  Google Scholar 

  119. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

    PubMed  CAS  Google Scholar 

  120. Sanderson MP, Keller S, Alonso A, Riedle S, Dempsey PJ, Altevogt P (2008) Generation of novel, secreted epidermal growth factor receptor (EGFR/ErbB1) isoforms via metalloprotease-dependent ectodomain shedding and exosome secretion. J Cell Biochem 103:1783–1797

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44120, USA

    George R. Dubyak

  2. Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, USA

    Yan Qu

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  1. Yan Qu
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  2. George R. Dubyak
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Correspondence to George R. Dubyak.

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This work was supported by NIH grants R01-GM36387 and P01-HLHL18708 (G.R.D.).

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Qu, Y., Dubyak, G.R. P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways. Purinergic Signalling 5, 163–173 (2009). https://doi.org/10.1007/s11302-009-9132-8

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  • DOI: https://doi.org/10.1007/s11302-009-9132-8

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