Abstract
The key purpose of phagocytosis is the destruction of pathogenic microorganisms. The phagocytes exert a wide array of killing mechanisms that allow mastering the vast majority of pathogens. One of these mechanisms consists in the production of reactive oxygen species inside the phagosome by a specific enzyme, the phagocyte NADPH oxidase. This enzyme is composed of 6 proteins that need to assemble to form a complex on the phagosomal membrane. Multiple signaling pathways tightly regulate the assembly. We briefly summarize key features of the enzyme and its regulation. We then focus on several related topics that address the activity of the NADPH oxidase during phagocytosis. Novel fluorescence microscopy techniques combined with fluorescent protein labeling of NADPH oxidase subunits opened the view on the structure and dynamics of these proteins in living cells. This combination revealed details of the role of anionic phospholipids in the control of phagosomal ROS production. It also added critical information to propose a 3D model of the complex between the cytosolic subunits prior to activation, in complement to other structural data on the oxidase.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abo A, Pick E, Hall A et al (1991) Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1. Nature 353:668–670. https://doi.org/10.1038/353668a0
Abo A, Webb MR, Grogan A, Segal AW (1994) Activation of NADPH oxidase involves the dissociation of p21rac from its inhibitory GDP/GTP exchange protein (rhoGDI) followed by its translocation to the plasma membrane. Biochem J 298:585–591. https://doi.org/10.1042/bj2980585
Albrett AM, Ashby LV, Dickerhof N et al (2018) Heterogeneity of hypochlorous acid production in individual neutrophil phagosomes revealed by a rhodamine-based probe. J Biol Chem 293:15715–15724. https://doi.org/10.1074/jbc.RA118.004789
Allen LH, McCaffrey RL (2007) To activate or not to activate: distinct strategies used by Helicobacter pylori and Francisella tularensis to modulate the NADPH oxidase and survive in human neutrophils. Immunol Rev 219:103–117. https://doi.org/10.1111/j.1600-065X.2007.00544.x
Ambasta RK, Kumar P, Griendling KK et al (2004) Direct interaction of the novel nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase. J Biol Chem 279:45935–45941. https://doi.org/10.1074/jbc.M406486200
Bagaitkar J, Barbu EA, Perez-Zapata LJ et al (2017) PI(3)P-p40 phox binding regulates NADPH oxidase activation in mouse macrophages and magnitude of inflammatory responses in vivo. J Leukoc Biol 101:449–457. https://doi.org/10.1189/jlb.3AB0316-139R
Balla T (2013) Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol Rev 93:1019–1137. https://doi.org/10.1152/physrev.00028.2012
Baranov MV, Olea RA, van den Bogaart G (2019) Chasing uptake: super-resolution microscopy in endocytosis and phagocytosis. Trends Cell Biol 29:727–739. https://doi.org/10.1016/j.tcb.2019.05.006
Beaumel S, Picciocchi A, Debeurme F et al (2017) Down-regulation of NOX2 activity in phagocytes mediated by ATM-kinase dependent phosphorylation. Free Radic Biol Med 113:1–15. https://doi.org/10.1016/j.freeradbiomed.2017.09.007
Begley MJ, Dixon JE (2005) The structure and regulation of myotubularin phosphatases. Curr Opin Struct Biol 15:614–620. https://doi.org/10.1016/j.sbi.2005.10.016
Belambri SA, Rolas L, Raad H et al (2018) NADPH oxidase activation in neutrophils: role of the phosphorylation of its subunits. Eur J Clin Investig 48:e12951. https://doi.org/10.1111/eci.12951
Berthier S, Paclet MH, Lerouge S et al (2003) Changing the conformation state of cytochrome b 558 initiates NADPH oxidase activation: MRP8/MRP14 regulation. J Biol Chem 278:25499–25508. https://doi.org/10.1074/jbc.M209755200
Bhardwaj R, Hediger MA, Demaurex N (2016) Redox modulation of STIM-ORAI signaling. Cell Calcium 60:142–152. https://doi.org/10.1016/j.ceca.2016.03.006
Bilan DS, Belousov VV (2018) In vivo imaging of hydrogen peroxide with HyPer probes. Antioxid Redox Signal 29:569–584. https://doi.org/10.1089/ars.2018.7540
Bogeski I, Kummerow C, Al-Ansary D et al (2010) Differential redox regulation of ORAI ion channels: a mechanism to tune cellular calcium signaling. Sci Signal 3:1–10. https://doi.org/10.1126/scisignal.2000672
Bohdanowicz M, Grinstein S (2013) Role of phospholipids in endocytosis, phagocytosis, and macropinocytosis. Physiol Rev 93:69–106. https://doi.org/10.1152/physrev.00002.2012
Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129:865–877. https://doi.org/10.1016/j.cell.2007.05.018
Boussetta T, Gougerot-Pocidalo M-A, Hayem G et al (2010) The prolyl isomerase Pin1 acts as a novel molecular switch for TNF-α–induced priming of the NADPH oxidase in human neutrophils. Blood 116:5795–5802. https://doi.org/10.1182/blood-2010-03-273094
Bravo J, Karathanassis D, Pacold CM et al (2001) The crystal structure of the PX domain from p40phoxbound to phosphatidylinositol 3-phosphate. Mol Cell 8:829–839. https://doi.org/10.1016/S1097-2765(01)00372-0
Bréchard S, Plançon S, Tschirhart EJ (2013) New insights into the regulation of neutrophil NADPH oxidase activity in the phagosome: a focus on the role of lipid and Ca2+ signaling. Antioxid Redox Signal 18:661–676. https://doi.org/10.1089/ars.2012.4773
Buvelot H, Posfay-Barbe KM, Linder P et al (2017) Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease. FEMS Microbiol Rev 41:139–157. https://doi.org/10.1093/femsre/fuw042
Buvelot H, Jaquet V, Krause K-H (2019) Mammalian NADPH oxidases. Methods Mol Biol 1982:17–36
Cachat J, Deffert C, Hugues S, Krause K-H (2015) Phagocyte NADPH oxidase and specific immunity. Clin Sci 128:635–648. https://doi.org/10.1042/CS20140635
Campa CC, Ciraolo E, Ghigo A et al (2015) Crossroads of PI3K and Rac pathways. Small GTPases 6:71–80. https://doi.org/10.4161/21541248.2014.989789
Campion Y, Jesaitis AJ, Nguyen MVC et al (2009) New p22-phox monoclonal antibodies: identification of a conformational probe for cytochrome b558. J Innate Immun 1:556–569. https://doi.org/10.1159/000231977
Casbon A-J, Allen L-AH, Dunn KW, Dinauer MC (2009) Macrophage NADPH oxidase flavocytochrome b localizes to the plasma membrane and Rab11-positive recycling endosomes. J Immunol 182:2325–2339. https://doi.org/10.4049/jimmunol.0803476
Chen Q, Powell DW, Rane MJ et al (2003) Akt phosphorylates p47 phox and mediates respiratory burst activity in human neutrophils. J Immunol 170:5302–5308. https://doi.org/10.4049/jimmunol.170.10.5302
Chen J, He R, Minshall RD et al (2007) Characterization of a mutation in the Phox homology domain of the NADPH oxidase component p40 phox identifies a mechanism for negative regulation of superoxide production. J Biol Chem 282:30273–30284. https://doi.org/10.1074/jbc.M704416200
Clemens RA, Lowell CA (2019) CRAC channel regulation of innate immune cells in health and disease. Cell Calcium 78:56–65. https://doi.org/10.1016/j.ceca.2019.01.003
Cross AR (2000) p40(phox) participates in the activation of NADPH oxidase by increasing the affinity of p47(phox) for flavocytochrome b558. Biochem J 349:113–117. https://doi.org/10.1042/0264-6021:3490113
Cross AR, Segal AW (2004) The NADPH oxidase of professional phagocytes-prototype of the NOX electron transport chain systems. Biochim Biophys Acta Bioenerg 1657:1–22. https://doi.org/10.1016/j.bbabio.2004.03.008
Dahan I, Issaeva I, Gorzalczany Y et al (2002) Mapping of functional domains in the p22phox subunit of flavocytochrome b559 participating in the assembly of the NADPH oxidase complex by “peptide walking”. J Biol Chem 277:8421–8432. https://doi.org/10.1074/jbc.M109778200
Dana R, Leto TL, Malech HL, Levy R (1998) Essential requirement of cytosolic phospholipase A 2 for activation of the phagocyte NADPH oxidase. J Biol Chem 273:441–445. https://doi.org/10.1074/jbc.273.1.441
DeCoursey TE, Ligeti E (2005) Regulation and termination of NADPH oxidase activity. Cell Mol Life Sci 62:2173–2193. https://doi.org/10.1007/s00018-005-5177-1
DeLeo FR, Burritt JB, Yu L et al (2000) Processing and maturation of flavocytochrome b 558 include incorporation of Heme as a prerequisite for heterodimer assembly. J Biol Chem 275:13986–13993. https://doi.org/10.1074/jbc.275.18.13986
Demaurex N, Saul S (2018) The role of STIM proteins in neutrophil functions. J Physiol 596:2699–2708. https://doi.org/10.1113/JP275639
Dewitt S, Laffafian I, Hallett MB (2003) Phagosomal oxidative activity during beta2 integrin (CR3)-mediated phagocytosis by neutrophils is triggered by a non-restricted Ca2+ signal: Ca2+ controls time not space. J Cell Sci 116:2857–2865. https://doi.org/10.1242/jcs.00499
Dewitt S, Francis RJ, Hallett MB (2013) Ca2+ and calpain control membrane expansion during the rapid cell spreading of neutrophils. J Cell Sci 126:4627–4635. https://doi.org/10.1242/jcs.124917
Dinauer MC, Pierce EA, Erickson RW et al (1991) Point mutation in the cytoplasmic domain of the neutrophil p22-phox cytochrome b subunit is associated with a nonfunctional NADPH oxidase and chronic granulomatous disease. Proc Natl Acad Sci 88:11231–11235. https://doi.org/10.1073/pnas.88.24.11231
Dupré-Crochet S, Erard M, Nüβe O (2013) ROS production in phagocytes: why, when, and where? J Leukoc Biol 94:657–670. https://doi.org/10.1189/jlb.1012544
Dupré-Crochet S, Erard M, Nüβe O (2019) Kinetic analysis of phagosomal ROS generation. Methods Mol Biol 1982:301–312
El-Benna J, Dang PM-C, Gougerot-Pocidalo M-A et al (2009) p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases. Exp Mol Med 41:217. https://doi.org/10.3858/emm.2009.41.4.058
Ellson CD, Gobert-Gosse S, Anderson KE et al (2001) PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40phox. Nat Cell Biol 3:679–682. https://doi.org/10.1038/35083076
Ellson C, Davidson K, Anderson K et al (2006) PtdIns3P binding to the PX domain of p40phox is a physiological signal in NADPH oxidase activation. EMBO J 25:4468–4478. https://doi.org/10.1038/sj.emboj.7601346
Erard M, Dupré-Crochet S, Nüße O (2018) Biosensors for spatiotemporal detection of reactive oxygen species in cells and tissues. Am J Physiol Regul Integr Comp Physiol 314:R667–R683. https://doi.org/10.1152/ajpregu.00140.2017
Faure MC, Sulpice J-C, Delattre M et al (2013) The recruitment of p47 phox and Rac2G12V at the phagosome is transient and phosphatidylserine dependent. Biol Cell 105:501–518. https://doi.org/10.1111/boc.201300010
Flannagan RS, Jaumouillé V, Grinstein S (2012) The cell biology of phagocytosis. Annu Rev Pathol Mech Dis 7:61–98. https://doi.org/10.1146/annurev-pathol-011811-132445
Foyouzi-Youssefi R, Petersson F, Lew DP et al (1997) Chemoattractant-induced respiratory burst: increases in cytosolic Ca2+ concentrations are essential and synergize with a kinetically distinct second signal. Biochem J 322:709–718. https://doi.org/10.1042/bj3220709
Fradin T, Bechor E, Berdichevsky Y et al (2018) Binding of p67 phox to Nox2 is stabilized by disulfide bonds between cysteines in the 369 Cys-Gly-Cys 371 triad in Nox2 and in p67 phox. J Leukoc Biol 104:1023–1039. https://doi.org/10.1002/JLB.4A0418-173R
Freeman JL, Abo A, Lambeth JD (1996) Rac “insert region” is a novel effector region that is implicated in the activation of NADPH oxidase, but not PAK65. J Biol Chem 271:19794–19801. https://doi.org/10.1074/jbc.271.33.19794
Goulden BD, Pacheco J, Dull A et al (2019) A high-avidity biosensor reveals plasma membrane PI(3,4)P 2 is predominantly a class I PI3K signaling product. J Cell Biol 218:1066–1079. https://doi.org/10.1083/jcb.201809026
Greenlee-Wacker M, DeLeo FR, Nauseef WM (2015) How methicillin-resistant Staphylococcus aureus evade neutrophil killing. Curr Opin Hematol 22:30–35. https://doi.org/10.1097/MOH.0000000000000096
Greenwald EC, Mehta S, Zhang J (2018) Genetically encoded fluorescent biosensors illuminate the spatiotemporal regulation of signaling networks. Chem Rev 118:11707–11794. https://doi.org/10.1021/acs.chemrev.8b00333
Groemping Y, Rittinger K (2005) Activation and assembly of the NADPH oxidase: a structural perspective. Biochem J 386:401–416. https://doi.org/10.1042/BJ20041835
Hammond GRV, Balla T (2015) Polyphosphoinositide binding domains: key to inositol lipid biology. Biochim Biophys Acta Mol Cell Biol Lipids 1851:746–758. https://doi.org/10.1016/j.bbalip.2015.02.013
Han CH, Lee MH (2000) Activation domain in P67phox regulates the steady state reduction of FAD in gp91phox. J Vet Sci 1:27–31
Han C-H, Freeman JLR, Lee T et al (1998) Regulation of the neutrophil respiratory burst oxidase. J Biol Chem 273:16663–16668. https://doi.org/10.1074/jbc.273.27.16663
Henríquez-Olguín C, Renani LB, Arab-Ceschia L et al (2019) Adaptations to high-intensity interval training in skeletal muscle require NADPH oxidase 2. Redox Biol 24:101188. https://doi.org/10.1016/j.redox.2019.101188
Honbou K, Minakami R, Yuzawa S et al (2007) Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding. EMBO J 26:1176–1186. https://doi.org/10.1038/sj.emboj.7601561
Hsu F, Mao Y (2015) The structure of phosphoinositide phosphatases: insights into substrate specificity and catalysis. Biochim Biophys Acta Mol Cell Biol Lipids 1851:698–710. https://doi.org/10.1016/j.bbalip.2014.09.015
Imlay JA (2008) Cellular defenses against superoxide and hydrogen peroxide. Annu Rev Biochem 77:755–776. https://doi.org/10.1146/annurev.biochem.77.061606.161055
Immler R, Simon SI, Sperandio M (2018) Calcium signalling and related ion channels in neutrophil recruitment and function. Eur J Clin Investig 48:e12964. https://doi.org/10.1111/eci.12964
Ito T (2001) Novel modular domain PB1 recognizes PC motif to mediate functional protein-protein interactions. EMBO J 20:3938–3946. https://doi.org/10.1093/emboj/20.15.3938
Kalyanaraman B, Hardy M, Podsiadly R et al (2017) Recent developments in detection of superoxide radical anion and hydrogen peroxide: opportunities, challenges, and implications in redox signaling. Arch Biochem Biophys 617:38–47. https://doi.org/10.1016/j.abb.2016.08.021
Kamen LA, Levinsohn J, Cadwallader A et al (2008) SHIP-A increases early oxidative burst and regulates phagosome maturation in macrophages. J Immunol 180:7497–7505. https://doi.org/10.4049/jimmunol.180.11.7497
Kami K (2002) Diverse recognition of non-PxxP peptide ligands by the SH3 domains from p67phox, Grb2 and Pex13p. EMBO J 21:4268–4276. https://doi.org/10.1093/emboj/cdf428
Kanai F, Liu H, Field SJ et al (2001) The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nat Cell Biol 3:675–678. https://doi.org/10.1038/35083070
Karathanassis D, Stahelin RV, Bravo J et al (2002) Binding of the PX domain of p47phox to phosphatidylinositol 3,4-bisphosphate and phosphatidic acid is masked by an intramolecular interaction. EMBO J 21:5057–5068. https://doi.org/10.1093/emboj/cdf519
Kim GHE, Dayam RM, Prashar A et al (2014) PIKfyve inhibition interferes with phagosome and endosome maturation in macrophages. Traffic 15:1143–1163. https://doi.org/10.1111/tra.12199
Klebanoff SJ, Kettle AJ, Rosen H et al (2013) Myeloperoxidase: a front-line defender against phagocytosed microorganisms. J Leukoc Biol 93:185–198. https://doi.org/10.1189/jlb.0712349
Knaus UG, Heyworth PG, Kinsella BT et al (1992) Purification and characterization of Rac 2. A cytosolic GTP-binding protein that regulates human neutrophil NADPH oxidase. J Biol Chem 267:23575–23582
Koga H, Terasawa H, Nunoi H et al (1999) Tetratricopeptide repeat (TPR) motifs of p67 phox participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase. J Biol Chem 274:25051–25060. https://doi.org/10.1074/jbc.274.35.25051
Kreck ML, Freeman JL, Abo A, Lambeth JD (1996) Membrane association of Rac is required for high activity of the respiratory burst oxidase †. Biochemistry 35:15683–15692. https://doi.org/10.1021/bi962064l
Kuribayashi F, Nunoi H, Wakamatsu K et al (2002) The adaptor protein p40 phox as a positive regulator of the superoxide-producing phagocyte oxidase. EMBO J 21:6312–6320. https://doi.org/10.1093/emboj/cdf642
Lambert TJ (2019) FPbase: a community-editable fluorescent protein database. Nat Methods 16:277–278. https://doi.org/10.1038/s41592-019-0352-8
Lapouge K, Smith SJM, 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. https://doi.org/10.1074/jbc.M112065200
Levin R, Grinstein S, Schlam D (2015) Phosphoinositides in phagocytosis and macropinocytosis. Biochim Biophys Acta Mol Cell Biol Lipids 1851:805–823. https://doi.org/10.1016/j.bbalip.2014.09.005
Levin R, Hammond GRV, Balla T et al (2017) Multiphasic dynamics of phosphatidylinositol 4-phosphate during phagocytosis. Mol Biol Cell 28:128–140. https://doi.org/10.1091/mbc.e16-06-0451
Li XJ, Tian W, Stull ND et al (2009) A fluorescently tagged C-terminal fragment of p47 phox detects NADPH oxidase dynamics during phagocytosis. Mol Biol Cell 20:1520–1532. https://doi.org/10.1091/mbc.e08-06-0620
Li XJ, Marchal CC, Stull ND et al (2010) p47 phox Phox homology domain regulates plasma membrane but not phagosome neutrophil NADPH oxidase activation. J Biol Chem 285:35169–35179. https://doi.org/10.1074/jbc.M110.164475
Lopes LR, Dagher MC, Gutierrez A et al (2004) Phosphorylated p40PHOXAs a negative regulator of NADPH oxidase. Biochemistry 43:3723–3730. https://doi.org/10.1021/bi035636s
Magalhaes MAO, Glogauer M (2010) Pivotal advance: phospholipids determine net membrane surface charge resulting in differential localization of active Rac1 and Rac2. J Leukoc Biol 87:545–555. https://doi.org/10.1189/jlb.0609390
Magnani F, Nenci S, Fananas EM et al (2017) Crystal structures and atomic model of NADPH oxidase. Proc Natl Acad Sci U S A 114:6764–6769. https://doi.org/10.1073/pnas.1702293114
Makni-Maalej K, Boussetta T, Hurtado-Nedelec M et al (2012) The TLR7/8 agonist CL097 primes N -formyl-methionyl-leucyl-phenylalanine-stimulated NADPH oxidase activation in human neutrophils: critical role of p47phox phosphorylation and the proline isomerase Pin1. J Immunol 189:4657–4665. https://doi.org/10.4049/jimmunol.1201007
Marion S, Mazzolini J, Herit F et al (2012) The NF-κB signaling protein Bcl10 regulates actin dynamics by controlling AP1 and OCRL-bearing vesicles. Dev Cell 23:954–967. https://doi.org/10.1016/j.devcel.2012.09.021
Martynov VI, Pakhomov AA, Deyev IE, Petrenko AG (2018) Genetically encoded fluorescent indicators for live cell pH imaging. Biochim Biophys Acta Gen Subj 1862:2924–2939. https://doi.org/10.1016/j.bbagen.2018.09.013
Masoud R, Serfaty X, Erard M et al (2017) Conversion of NOX2 into a constitutive enzyme in vitro and in living cells, after its binding with a chimera of the regulatory subunits. Free Radic Biol Med 113:470–477. https://doi.org/10.1016/j.freeradbiomed.2017.10.376
Massenet C, Chenavas S, Cohen-Addad C et al (2005) Effects of p47 phox C terminus phosphorylations on binding interactions with p40 phox and p67 phox. J Biol Chem 280:13752–13761. https://doi.org/10.1074/jbc.M412897200
Matute JD, Arias AA, Wright NAM et al (2009) A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity. Blood 114:3309–3315. https://doi.org/10.1182/blood-2009-07-231498
Meijles DN, Howlin BJ, Li JM (2012) Consensus in silico computational modelling of the p22phox subunit of the NADPH oxidase. Comput Biol Chem 39:6–13. https://doi.org/10.1016/j.compbiolchem.2012.05.001
Miller JL, Velmurugan K, Cowan MJ, Briken V (2010) The type I NADH dehydrogenase of mycobacterium tuberculosis counters phagosomal NOX2 activity to inhibit TNF-α-mediated host cell apoptosis. PLoS Pathog 6:e1000864. https://doi.org/10.1371/journal.ppat.1000864
Minakami R, Maehara Y, Kamakura S et al (2010) Membrane phospholipid metabolism during phagocytosis in human neutrophils. Genes Cells 15:409–424. https://doi.org/10.1111/j.1365-2443.2010.01393.x
Murillo I, Henderson LM (2005) Expression of gp91phox/Nox2 in COS-7 cells: cellular localization of the protein and the detection of outward proton currents. Biochem J 385:649–657. https://doi.org/10.1042/BJ20040829
Nault L, Bouchab L, Dupré-Crochet S et al (2016) Environmental effects on reactive oxygen species detection—learning from the phagosome. Antioxid Redox Signal 25:564–576. https://doi.org/10.1089/ars.2016.6747
Nauseef WM (2004) Assembly of the phagocyte NADPH oxidase. Histochem Cell Biol 122:277–291. https://doi.org/10.1007/s00418-004-0679-8
Nauseef WM (2007) How human neutrophils kill and degrade microbes: an integrated view. Immunol Rev 219:88–102. https://doi.org/10.1111/j.1600-065X.2007.00550.x
Nauseef WM (2019) The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling. Curr Opin Immunol 60:130–140. https://doi.org/10.1016/j.coi.2019.05.006
Niedergang F, Grinstein S (2018) How to build a phagosome: new concepts for an old process. Curr Opin Cell Biol 50:57–63. https://doi.org/10.1016/j.ceb.2018.01.009
Nigorikawa K, Hazeki K, Sasaki J et al (2015) Inositol polyphosphate-4-phosphatase type I negatively regulates phagocytosis via dephosphorylation of phagosomal PtdIns(3,4)P2. PLoS One 10:e0142091. https://doi.org/10.1371/journal.pone.0142091
Nisimoto Y, Freeman JLR, Motalebi SA et al (1997) Rac binding to p67(phox). Structural basis for interactions of the Rac1 effector region and insert region with components of the respiratory burst oxidase. J Biol Chem 272:18834–18841. https://doi.org/10.1074/jbc.272.30.18834
Nisimoto Y, Motalebi S, Han C-H, Lambeth JD (1999) The p67 phox activation domain regulates electron flow from NADPH to flavin in flavocytochrome b 558. J Biol Chem 274:22999–23005. https://doi.org/10.1074/jbc.274.33.22999
Nunes P, Cornut D, Bochet V et al (2012) STIM1 juxtaposes ER to phagosomes, generating Ca2+ hotspots that boost phagocytosis. Curr Biol 22:1990–1997. https://doi.org/10.1016/j.cub.2012.08.049
Nunes P, Demaurex N, Dinauer MC (2013) Regulation of the NADPH oxidase and associated ion fluxes during phagocytosis. Traffic 14:1118–1131. https://doi.org/10.1111/tra.12115
O’Neill S, Mathis M, Kovačič L et al (2018) Quantitative interaction analysis permits molecular insights into functional NOX4 NADPH oxidase heterodimer assembly. J Biol Chem 293:8750–8760. https://doi.org/10.1074/jbc.RA117.001045
Ohayon D, De Chiara A, Dang PM-C et al (2019) Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils. J Exp Med 216:2669–2687. https://doi.org/10.1084/jem.20180371
Ostuni MA, Gelinotte M, Bizouarn T et al (2010) Targeting NADPH-oxidase by reactive oxygen species reveals an initial sensitive step in the assembly process. Free Radic Biol Med 49:900–907. https://doi.org/10.1016/j.freeradbiomed.2010.06.021
Pal R, Basu Thakur P, Li S et al (2013) Real-time imaging of NADPH oxidase activity in living cells using a novel fluorescent protein reporter. PLoS One 8:e63989. https://doi.org/10.1371/journal.pone.0063989
Pozzan T, Lew DP, Wollheim CB, Tsien RY (1983) Is cytosolic ionized calcium regulating neutrophil activation? Science 221:1413–1415. https://doi.org/10.1126/science.6310757
Price MO, McPhail LC, Lambeth JD et al (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. https://doi.org/10.1182/blood.V99.8.2653
Regier DS, Waite KA, Wallin R, McPhail LC (1999) A phosphatidic acid-activated protein kinase and conventional protein kinase C isoforms phosphorylate p22 phox, an NADPH oxidase component. J Biol Chem 274:36601–36608. https://doi.org/10.1074/jbc.274.51.36601
Roma LP, Deponte M, Riemer J, Morgan B (2018) Mechanisms and applications of redox-sensitive green fluorescent protein-based hydrogen peroxide probes. Antioxid Redox Signal 29:552–568. https://doi.org/10.1089/ars.2017.7449
Roos D (2019) Chronic granulomatous disease. Methods Mol Biol 1982:531–542. https://doi.org/10.1007/978-1-4939-9424-3_32
Rosales C, Uribe-Querol E (2017) Phagocytosis: a fundamental process in immunity. Biomed Res Int 2017:1–18. https://doi.org/10.1155/2017/9042851
Sarfstein R, Gorzalczany Y, Mizrahi A et al (2004) Dual role of Rac in the assembly of NADPH oxidase, tethering to the membrane and activation of p67 phox. J Biol Chem 279:16007–16016. https://doi.org/10.1074/jbc.M312394200
Schlam D, Bohdanowicz M, Chatilialoglu A et al (2013) Diacylglycerol kinases terminate diacylglycerol signaling during the respiratory burst leading to heterogeneous phagosomal NADPH oxidase activation. J Biol Chem 288:23090–23104. https://doi.org/10.1074/jbc.M113.457606
Schlam D, Bagshaw RD, Freeman SA et al (2015) Phosphoinositide 3-kinase enables phagocytosis of large particles by terminating actin assembly through Rac/Cdc42 GTPase-activating proteins. Nat Commun 6:8623. https://doi.org/10.1038/ncomms9623
Schrenzel J, Serrander L, Bánfi B et al (1998) Electron currents generated by the human phagocyte NADPH oxidase. Nature 392:734–737. https://doi.org/10.1038/33725
Schürmann N, Forrer P, Casse O et al (2017) Myeloperoxidase targets oxidative host attacks to Salmonella and prevents collateral tissue damage. Nat Microbiol 2:16268. https://doi.org/10.1038/nmicrobiol.2016.268
Shao C, Novakovic VA, Head JF et al (2008) Crystal structure of lactadherin C2 domain at 1.7 Å resolution with mutational and computational analyses of its membrane-binding motif. J Biol Chem 283:7230–7241. https://doi.org/10.1074/jbc.M705195200
Someya A, Nagaoka I, Yamashita T (1993) Purification of the 260 kDa cytosolic complex involved in the superoxide production of guinea pig neutrophils. FEBS Lett 330:215–218. https://doi.org/10.1016/0014-5793(93)80276-Z
Song ZM, Bouchab L, Hudik E et al (2017) Phosphoinositol 3-phosphate acts as a timer for reactive oxygen species production in the phagosome. J Leukoc Biol 101:1155–1168. https://doi.org/10.1189/jlb.1A0716-305R
Staerck C, Gastebois A, Vandeputte P et al (2017) Microbial antioxidant defense enzymes. Microb Pathog 110:56–65. https://doi.org/10.1016/j.micpath.2017.06.015
Stasia MJ, Li XJ (2008) Genetics and immunopathology of chronic granulomatous disease. Semin Immunopathol 30:209–235
Steinckwich N, Frippiat J-P, Stasia M-J et al (2007) Potent inhibition of store-operated Ca2+ influx and superoxide production in HL60 cells and polymorphonuclear neutrophils by the pyrazole derivative BTP2. J Leukoc Biol 81:1054–1064. https://doi.org/10.1189/jlb.0406248
Steinckwich N, Schenten V, Melchior C et al (2011) An essential role of STIM1, Orai1, and S100A8–A9 proteins for Ca2+ signaling and FcγR-mediated phagosomal oxidative activity. J Immunol 186:2182–2191. https://doi.org/10.4049/jimmunol.1001338
Suh C-I, Stull ND, Li XJ et al (2006) The phosphoinositide-binding protein p40 phox activates the NADPH oxidase during FcγIIA receptor–induced phagocytosis. J Exp Med 203:1915–1925. https://doi.org/10.1084/jem.20052085
Sumimoto H (2008) Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species. FEBS J 275:3249–3277. https://doi.org/10.1111/j.1742-4658.2008.06488.x
Sumimoto H, Minakami R, Miyano K (2019) Soluble regulatory proteins for activation of NOX family NADPH oxidases. Methods Mol Biol 1982:121–137
Sun J, Singh V, Lau A et al (2013) Mycobacterium tuberculosis nucleoside diphosphate kinase inactivates small GTPases leading to evasion of innate immunity. PLoS Pathog 9:e1003499. https://doi.org/10.1371/journal.ppat.1003499
Taylor WR, Jones DT, Segal AW (1993) A structural model for the nucleotide binding domains of the flavocytochrome b -245 β-chain. Protein Sci 2:1675–1685. https://doi.org/10.1002/pro.5560021013
Thomas DC (2018) How the phagocyte NADPH oxidase regulates innate immunity. Free Radic Biol Med 125:44–52. https://doi.org/10.1016/j.freeradbiomed.2018.06.011
Tian W, Li XJ, Stull ND et al (2008) Fc gamma R-stimulated activation of the NADPH oxidase: phosphoinositide-binding protein p40phox regulates NADPH oxidase activity after enzyme assembly on the phagosome. Blood 112:3867–3877
Tlili A, Dupré-Crochet S, Erard M, Nüße O (2011) Kinetic analysis of phagosomal production of reactive oxygen species. Free Radic Biol Med 50:438–447. https://doi.org/10.1016/j.freeradbiomed.2010.11.024
Tlili A, Erard M, Faure MC et al (2012) Stable accumulation of p67(phox) at the phagosomal membrane and ROS production within the phagosome. J Leukoc Biol 91:83–95. https://doi.org/10.1189/jlb.1210701
Ueyama T, Nakakita J, Nakamura T et al (2011) Cooperation of p40 phox with p47 phox for Nox2-based NADPH oxidase activation during Fcγ receptor (FcγR)-mediated phagocytosis. J Biol Chem 286:40693–40705. https://doi.org/10.1074/jbc.M111.237289
van Manen H-J, Verkuijlen P, Wittendorp P et al (2008) Refractive index sensing of green fluorescent proteins in living cells using fluorescence lifetime imaging microscopy. Biophys J 94:L67–L69. https://doi.org/10.1529/biophysj.107.127837
Vareechon C, Zmina SE, Karmakar M et al (2017) Pseudomonas aeruginosa effector ExoS inhibits ROS production in human neutrophils. Cell Host Microbe 21:611–618.e5. https://doi.org/10.1016/j.chom.2017.04.001
Westman J, Grinstein S, Maxson ME (2019) Revisiting the role of calcium in phagosome formation and maturation. J Leukoc Biol 106:837–851. https://doi.org/10.1002/JLB.MR1118-444R
Wientjes FB, Reeves EP, Soskic V et al (2001) The NADPH oxidase components p47phox and p40phox bind to moesin through their PX domain. Biochem Biophys Res Commun 289:382–388. https://doi.org/10.1006/bbrc.2001.5982
Wilson MI, Gill DJ, Perisic O et al (2003) PB1 domain-mediated heterodimerization in NADPH oxidase and signaling complexes of atypical protein kinase C with Par6 and p62. Mol Cell 12:39–50. https://doi.org/10.1016/S1097-2765(03)00246-6
Winterbourn CC, Hampton MB, Livesey JH, Kettle AJ (2006) Modeling the reactions of superoxide and myeloperoxidase in the neutrophil phagosome. J Biol Chem 281:39860–39869. https://doi.org/10.1074/jbc.M605898200
Wrona D, Siler U, Reichenbach J (2017) CRISPR/Cas9-generated p47 phox -deficient cell line for chronic granulomatous disease gene therapy vector development. Sci Rep 7:6–11. https://doi.org/10.1038/srep44187
Yeung T (2006) Receptor activation alters inner surface potential during phagocytosis. Science 313:347–351. https://doi.org/10.1126/science.1129551
Yeung T, Grinstein S (2007) Lipid signaling and the modulation of surface charge during phagocytosis. Immunol Rev 219:17–36. https://doi.org/10.1111/j.1600-065X.2007.00546.x
Yeung T, Gilbert GE, Shi J et al (2008) Membrane phosphatidylserine regulates surface charge and protein localization. Science 319:210–213. https://doi.org/10.1126/science.1152066
Yeung T, Heit B, Dubuisson J-F et al (2009) Contribution of phosphatidylserine to membrane surface charge and protein targeting during phagosome maturation. J Cell Biol 185:917–928. https://doi.org/10.1083/jcb.200903020
Yu L, Quinn MT, Cross AR, Dinauer MC (1998) Gp91phox is the heme binding subunit of the superoxide-generating NADPH oxidase. Proc Natl Acad Sci 95:7993–7998. https://doi.org/10.1073/pnas.95.14.7993
Zhao X, Carnevale KA, Cathcart MK (2003) Human monocytes use Rac1, Not Rac2, in the NADPH oxidase complex. J Biol Chem 278:40788–40792. https://doi.org/10.1074/jbc.M302208200
Zhao X, Xu B, Bhattacharjee A et al (2005) Protein kinase Cδ regulates p67phox phosphorylation in human monocytes. J Leukoc Biol 77:414–420. https://doi.org/10.1189/jlb.0504284
Zhen L, King AA, Xiao Y et al (1993) Gene targeting of X chromosome-linked chronic granulomatous disease locus in a human myeloid leukemia cell line and rescue by expression of recombinant gp91phox. Proc Natl Acad Sci 90:9832–9836. https://doi.org/10.1073/pnas.90.21.9832
Ziegler CS, Bouchab L, Tramier M et al (2019) Quantitative live-cell imaging and 3D modeling reveal critical functional features in the cytosolic complex of phagocyte NADPH oxidase. J Biol Chem 294:3824–3836. https://doi.org/10.1074/jbc.RA118.006864
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Valenta, H., Erard, M., Dupré-Crochet, S., Nüβe, O. (2020). The NADPH Oxidase and the Phagosome. In: Hallett, M. (eds) Molecular and Cellular Biology of Phagocytosis . Advances in Experimental Medicine and Biology, vol 1246. Springer, Cham. https://doi.org/10.1007/978-3-030-40406-2_9
Download citation
DOI: https://doi.org/10.1007/978-3-030-40406-2_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-40405-5
Online ISBN: 978-3-030-40406-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)