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Rho GTPases and the Control of the Oxidative Burst in Polymorphonuclear Leukocytes

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 291))

Abstract

Stimulation of quiescent leukocytes activates the NADPH oxidase, a membrane-associated enzyme system that generates superoxide and other reactive oxygen species (ROS) that are used to kill bacteria within the phagosome. This chapter describes this multicomponent NADPH oxidase system, one of the first cellular systems shown to be directly regulated by Rac GTPases. We present current models of NADPH oxidase regulation by Rac2 and describe how Rac2 activation controls the timing of ROS production in adherent neutrophils. The antagonistic role that Cdc42 plays as a competitor of Rac2 for binding to the cytochrome component of the NADPH oxidase is discussed as a possible mechanism for tonic regulation of ROS production during the formation of the phagosome. Finally, we briefly depict mechanisms by which invasive bacteria can alter (inhibit) NADPH oxidase function, focusing on the effects of invasive bacteria on components and assembly of the NADPH oxidase.

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References

  • Abo A, Pick E, Hall A, Totty N, Teahan CG, Segal AW (1991) Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature 353:668–670

    Article  PubMed  CAS  Google Scholar 

  • Ahluwalia J, Tinker A, Clapp LH, Duchen MR, Abramov AY, Pope S, Nobles M, Segal AW (2004) The large-conductance Ca2+-activated K+ channel is essential for innate immunity. Nature 427:853–858

    Article  PubMed  CAS  Google Scholar 

  • Allen LA (2003) Mechanisms of pathogenesis: evasion of killing by polymorphonuclear leukocytes. Microbes Infect 5:1329–1335

    Article  PubMed  CAS  Google Scholar 

  • Aghazadeh B, Lowry WE, Huang XY, Rosen MK (2000) Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell 102:625–633

    Article  PubMed  CAS  Google Scholar 

  • Babior BM (1999) NADPH oxidase: An update. Blood 93:1464–1476

    PubMed  CAS  Google Scholar 

  • Babior BM, Lambeth JD, Nauseef W (2002) The neutrophil NADPH oxidase. Arch Biochem Biophys 397:342–344

    Article  PubMed  CAS  Google Scholar 

  • Banerjee R, Anguita J, Roos D, Fikrig E (2000) Cutting edge: infectionby the agent of human granulocytic ehrlichiosis prevents the respiratory burst by down-regulating gp91phox. J Immunol 164:3946–3949

    PubMed  CAS  Google Scholar 

  • Barbieri JT, Riese MJ, Aktories K (2002) Bacterial toxins that modify the actin cytoskeleton. Annu Rev Cell Dev Biol 18:315–344

    Article  PubMed  CAS  Google Scholar 

  • Belaaouaj A, McCarthy R, Baumann M, Gao Z, Ley TJ, Abraham SN, Shapiro SD (1998) Mice lacking neutrophil elastase reveal impaired host defense against Gramnegative bacterial sepsis. Nat Med 4:614–618

    Article  Google Scholar 

  • Benard V, Bohl BP, Bokoch GM (1999) Characterization of Rac and Cdc42 activation in chemoattractant-stimulated human neutrophils using a novel assay for active GTPases. J Biol Chem 274:13198–13204

    Article  PubMed  CAS  Google Scholar 

  • Bishop AL, Hall A (2000) Rho GTPases and their effector proteins. Biochem J 348:241–255

    Article  PubMed  CAS  Google Scholar 

  • Bliska JB (2000) Yop effectors of Yersinia spp and actin rearrangements. Trends Microbiol 8:205–208

    Article  PubMed  CAS  Google Scholar 

  • Bokoch GM and Diebold BA (2002) Current molecular models for NADPH oxidase regulation by Rac GTPase. Blood 100:2692–2696

    Article  PubMed  CAS  Google Scholar 

  • Bokoch GM, Bohl BP, Chuang TH (1994) Guanine nucleotide exchange regulates membrane translocation of Rac/RhoGTP-binding proteins. J Biol Chem 269:31674–31679

    PubMed  CAS  Google Scholar 

  • Bokoch GM, Knaus UG (2003) NADPH oxidases: not just for leukocytes anymore! Trends Biochem Sci 28:502–508

    Article  PubMed  CAS  Google Scholar 

  • Boyle EC, Finlay BB (2003) Bacterial pathogenesis: exploiting cellular adherence. Curr Opin Cell Biol 15:633–639

    Article  PubMed  CAS  Google Scholar 

  • Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–179

    Article  PubMed  CAS  Google Scholar 

  • Carlyon JA, Chan WT, Galan J, Roos D, Fikrig E (2002) Repression of rac2 mRNA expression by Anaplasma phagocytophila is essential to the inhibition of superoxide production and bacterial proliferation. J Immunol 169:7009–7018

    PubMed  CAS  Google Scholar 

  • Chuang TH, Bohl BP, Bokoch GM (1993) Biologically active lipids are regulators of Rac-GDI complexation. J Biol Chem 268:26206–26211

    PubMed  CAS  Google Scholar 

  • Cornelis GR (2002) The Yersinia YSC-YOP “Type III” weaponry. Nat Rev Mol Cell Biol 3:742–752

    Article  PubMed  CAS  Google Scholar 

  • Cossart P, Sansonetti PJ (2004) Bacterial invasion: The paradigms of enteroinvasive pathogens. Science 304:242–248

    Article  PubMed  CAS  Google Scholar 

  • DeCoursey TE (2004) During the respiratory burst, do phagocytes need proton channels or potassium channels or both? Sci STKE pp.pe21

    Google Scholar 

  • DeCoursey TE, Morgan D, Cherny VV (2003) The voltage dependence of NADPH oxidase reveals why phagocytes need proton channels. Nature 422:531–534

    Article  PubMed  CAS  Google Scholar 

  • DeLeo FR (2004) Modulation of phagocyte apoptosis by bacterial pathogens. Apoptosis 9:399–413

    Article  PubMed  CAS  Google Scholar 

  • DerMardirossian C, Schnelzer A, Bokoch GM (2004) Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Mol Cell 15:117–127

    Article  PubMed  CAS  Google Scholar 

  • Dharmawardhane S, Bokoch GM (1997) Rho GTPases and leukocyte cytoskeletal regulation. Curr Opin Hematol 4:12–18

    Article  PubMed  CAS  Google Scholar 

  • Diebold BA, Bokoch GM (2001) Molecular basis for Rac2 regulation of phagocyte NADPH oxidase. Nat Immunol 2:211–215

    Article  PubMed  CAS  Google Scholar 

  • Diebold BA, Fowler B, Lu J, Dinauer MC, Bokoch GM (2004) Antagonistic crosstalk between Rac and Cdc42 GTPases regulates generation of reactive oxygen species. J Biol Chem 279:28136–28142

    Article  PubMed  CAS  Google Scholar 

  • Dinauer MC (2003) Regulation of neutrophil function by Rac GTPases. Curr Opin Hematol 10:8–15

    Article  PubMed  CAS  Google Scholar 

  • Dorseuil O, Vazquez A, Lang P, Bertoglio J, Gacon G, Leca G (1992) Inhibition of superoxide production in B lymphocytes by rac antisense oligonucleotides. J Biol Chem 267:20540–20542

    PubMed  CAS  Google Scholar 

  • Dorseuil O, Quinn MT, Bokoch GM (1995) Dissociation of Rac translocation from p47/p67 movements in human neutrophils by tyrosine kinase inhibitors. J. Leukoc Biol 58:108–113

    PubMed  CAS  Google Scholar 

  • Ellson CD, Gobert-Gosse S, Anderson KE, Davidson K, Erdjument-Bromage H, Tempst P, Thuring JW, Cooper MA, Lim ZY, Holmes AB, Gaffney PR, Coadwell J, Chilvers ER, Hawkins PT, Stephens LR (2001) PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox). Nat Cell Biol 3:679–682

    Article  PubMed  CAS  Google Scholar 

  • Freeman JL, Lambeth (1996) NADPH oxidase activity is independent of p47phox in vitro. J Biol Chem 271:22578–22582

    Article  PubMed  CAS  Google Scholar 

  • Gallois A, Klein JR, Allen LA, Jones BD, Nauseef WM (2001) Salmonella pathogenicity island 2-encoded type III secretion system mediates exclusion of NADPH oxidase assembly from the phagosomal membrane. J Immunol 166:5741–5748

    PubMed  CAS  Google Scholar 

  • Groemping Y, Lapouge K, Smerdon SJ, Rittinger K (2003) Molecular basis of phosphorylation-induced activation of the NADPH oxidase. Cell 113:343–355

    Article  PubMed  CAS  Google Scholar 

  • Han CH, Freeman JL, Lee T, Motalebi SA, Lambeth JD (1998) Regulation of the neutrophil respiratory burst oxidase: identification of an activation domain in p67phox. J Biol Chem 273:16663–16668

    Article  PubMed  CAS  Google Scholar 

  • Harrison RE, Touret N, Grinstein S (2002) Microbial killing: oxidants, proteases and ions. Curr Biol 12:R357–R359

    Article  PubMed  CAS  Google Scholar 

  • Henderson LM, Chappell JB, Jones OTG (1988) Internal pH changes associated with the activity of NADPH oxidase of human neutrophils: Further evidence for the presence of an H+ conducting channel. Biochem J 251:563–567

    PubMed  CAS  Google Scholar 

  • Heyworth PG, Bohl BP, Bokoch GM, Curnutte JT (1994) Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox: Evidence for its interaction with flavocytochrome b558. J Biol Chem 269:30749–30752

    PubMed  CAS  Google Scholar 

  • Heyworth PG, Cross AR, Curnutte JT (2003) Chronic granulomatous disease. Curr Opin Immunol 15:578–584

    Article  PubMed  CAS  Google Scholar 

  • Hoppe AD, Swanson JA (2004) Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol Biol Cell 15:3509–2519

    Article  PubMed  CAS  Google Scholar 

  • Kanai F, Liu H, Field SJ, Akbary H, Matsuo T, Brown GE, Cantley LC, Yaffe MB (2001) The PX domains of p47phox and p40 phox bind to lipid products of PI(3)K Nat Cell Biol 3:675–678

    CAS  Google Scholar 

  • Knaus UG, Heyworth PG, Evans T, Curnutte JT, Bokoch GM (1991) Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac2. Science 254:1512–1515

    PubMed  CAS  Google Scholar 

  • Koshkin V, Lotan O, Pick E (1996) The cytosolic component p47phox is not a sine qua non participant in the activation of NADPH oxidase but is required for optimal superoxide production. J Biol Chem 271:30326–30329

    Article  PubMed  CAS  Google Scholar 

  • Kwong, CH, Adams AG, Leto TL (1995) Characterization of the effector-specifying domain of Rac involved in NADPH oxidase activation. J Biol Chem 270:19868–19872

    Article  PubMed  CAS  Google Scholar 

  • Lapouge K, Smith SJ, Walker PA, Gamblin SJ, Smerdon SJ, Rittinger K (2000) Structure of the TPR domain of p67phox in complex with Rac GTP. Mol Cell 6:899–907

    PubMed  CAS  Google Scholar 

  • Lapouge K, Smith SJ, Groemping Y, Rittinger K (2002) Architecture of the p40-p47-p67phox complex in the resting state of the NADPH oxidase. A central role for p67phox. J Biol Chem 277:10121–10128

    Article  PubMed  CAS  Google Scholar 

  • Laskay T, van Zandbergen G, Solbach W (2003) Neutrophil granulocytes—Trojan horses for Leishmania major and other intracellular microbes? Trends Microbiol 11:210–214

    PubMed  CAS  Google Scholar 

  • Li Z, Hannigan M, Mo Z, Liu B, Lu W, Wu Y, Smrcka AV, Wu G, Li L, Liu M, Huang CK, Wu D (2003) Directional sensing requires Gβγ mediated Pak 1 and Pixαdependent activation of Cdc42. Cell 114:215–227

    Article  PubMed  CAS  Google Scholar 

  • Matozaki T, Nakanishi H, Takai Y (2000) Small G-protein networks: their crosstalk and signal cascades. Cell Signal 12:515–524

    Article  PubMed  CAS  Google Scholar 

  • Moores SL, Selfors LM, Fredericks J, Breit T, Fujikawa K, Alt FW, Brugge JS, Swat W (2000) Vav family proteins couple to diverse cell surface receptors. Mol Cell Biol 20:6364–6373

    Article  PubMed  CAS  Google Scholar 

  • Mott, J, Rikihisa, Y, Tsunawaki S (2002) Effects of Anaplasma phagocytophila on NADPH oxidase components in human neutrophils and HL-60 cells. Infect Immun 70:1359–1366

    Article  PubMed  CAS  Google Scholar 

  • Myers JT, Tsang AW, Swanson JA (2003) Localized reactive oxygen and nitrogen intermediates inhibit escape of Listeria monocytogenes from vacuoles in activated macrophages. J Immunol 171:5447–5453

    PubMed  CAS  Google Scholar 

  • Nisimoto Y, Motalebi S, Han CH, Lambeth JD (1999) The p67phox activation domain regulates electron flowfrom NADPH to flavin in flavocytochrome b558. J Biol Chem 274:22999–23005

    Article  PubMed  CAS  Google Scholar 

  • Prada-Delgado A, Carrasco-Marin E, Bokoch GM, Alvarez-Dominguez C (2001) Interferon-γ listericidal action is mediated by novel Rab5a functions at the phagosomal environment. J Biol Chem 276:19059–19065

    Article  PubMed  CAS  Google Scholar 

  • Price MO, McPhail LC Lambeth JD Han CH, Knaus UG, Dinauer MC (2002) Creation of a genetic system for analysis of the phagocyte respiratory burst high-level reconstitution of the NADPH oxidase in a nonhematopoietic system. Blood 99:2653–2661

    Article  PubMed  CAS  Google Scholar 

  • Quinn MT, Evans T, Loetterle LR, Jesaitis AJ and Bokoch GM (1993) Translocation of Rac correlates with NADPH oxidase activation. J Biol Chem 268:20983–20987

    PubMed  CAS  Google Scholar 

  • Reeves EP, Lu H, Jacobs HL, Messina CG, Bolsover S, Gabella G, Potma EO, Warley A, Roes J, Segal AW (2002) Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416:291–297

    Article  PubMed  CAS  Google Scholar 

  • Roberts AW, Kim C, Zhen L, Lowe JB, Kapur R, Petryniak B, Spaetti A, Pollock JD, Borneo JB, Bradford GB, Atkinson SJ, Dinauer MC, Williams DA (1999) Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 10:183–196

    Article  PubMed  CAS  Google Scholar 

  • Roos D, Winterbourn CC (2002) Lethal weapons. Science 296:669–671

    Article  PubMed  CAS  Google Scholar 

  • Roos D, van Bruggen R, Meischl C (2003) Oxidative killing of microbes by neutrophils. Microbes Infect 5:1307–1315

    Article  PubMed  CAS  Google Scholar 

  • Rosen H (2004) Bacterial responses to neutrophil phagocytosis. Curr Opin Hematol 11:1–6

    Article  PubMed  Google Scholar 

  • Sibley, LD (2004) Intracellular parasite invasion strategies. Science 304:248–253

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan S., Wang F, Glavas S, Ott A, Hofmann F, Aktories K, Kalman D, Bourne HR (2003) Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis. J Cell Biol 160:375–385

    Article  PubMed  CAS  Google Scholar 

  • Stebbins CE, Galan JE (2001) Structural mimicry in bacterial virulence. Nature 412:701–705

    Article  PubMed  CAS  Google Scholar 

  • Touret N, Grinstein S (2002) Voltage-gated proton “channels”: a spectator's viewpoint. J Gen Physiol 120:767–771

    Article  PubMed  CAS  Google Scholar 

  • Tkalcevic J, Novelli M, Phylactides M, Iredale JP, Segal AW, Roes J (2000) Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity 12:201–210

    Article  PubMed  CAS  Google Scholar 

  • Vazquez-Boland JA, Kuhn M, Berche P, Chakraborty T, Dominguez-Bernal G, Goebel W, Gonzalez-Zorn B, Wehland J, Kreft J (2001) Listeria pathogenesis and molecular virulence determinants. Clin Microbio Rev 14:584–640

    Article  CAS  Google Scholar 

  • Vazquez-Torres A, Xu Y, Jones-Carson J, Holden DW, Lucia SM, Dinauer MC, Mastroeni P, Fang FC (2000) Salmonella pathogenicity island 2-dependent evasion of the phagocyte NADPH oxidase. Science 287:1655–1658

    Article  PubMed  CAS  Google Scholar 

  • Voncken JW, van Schaick H, Kaartinen V, Deemer K, Coates T, Landing B, Pattengale P, Dorseuil O, Bokoch GM, Groffen J, Heisterkamp N (1995) Increased neutrophil respiratory burst in bcr-null mutants. Cell 80:719–728

    Article  PubMed  CAS  Google Scholar 

  • Wentworth, Jr P, McDunn JE, Wentworth AD, Takeuchi C, Nieva J, Jones T, Bautista C, Ruedi JM, Gutierrez A, Janda KD, Babior BM, Eschenmoser A, Lerner RA (2002) Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation. Science 298:2195–2199

    Article  PubMed  CAS  Google Scholar 

  • Wientjes FB, Segal AW (2003) PX domain takes shape. Curr Opin Hematol 10:2–7

    Article  PubMed  CAS  Google Scholar 

  • Yuzawa S, Suzuki NN, Fujioka Y, Ogura K, Sumimoto H, Inagaki F (2004) A molecular mechanism for autoinhibition of the tandem SH3 domains of p47phox, the regulatory subunit of the phagocyte NADPH oxidase. Genes Cells 9:443–456

    Article  PubMed  CAS  Google Scholar 

  • Zhao T, Benard V, Bohl BP, Bokoch GM (2003) The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils. J Clin Invest 112:1732–1740

    Article  PubMed  CAS  Google Scholar 

  • Zhao X, Carnevale KA, Cathcart MK (2003) Human monocytes use Rac1, not Rac2, in the NADPH oxidase complex. J Biol Chem 278:40788–40792

    Article  PubMed  CAS  Google Scholar 

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Diebold, B.A., Bokoch, G.M. (2005). Rho GTPases and the Control of the Oxidative Burst in Polymorphonuclear Leukocytes. In: Boquet, P., Lemichez, E. (eds) Bacterial Virulence Factors and Rho GTPases. Current Topics in Microbiology and Immunology, vol 291. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27511-8_6

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