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The Neutrophil NADPH Oxidase
Archives of Biochemistry and Biophysics Vol. 397, No. 2, January 15, pp. 342–344, 2002 doi:10.1006/abbi.2001.2642, available online at http://www.idealibrary.com on
MINIREVIEW The Neutrophil NADPH Oxidase B. M. Babior,* ,1 J. D. Lambeth,† and W. Nauseef ‡ *The Scripps Research Institute, La Jolla, California 92037; †Emory University Medical School, Atlanta, Georgia 30322; and ‡University of Iowa, Iowa City, Iowa 52246
Received September 20, 2001, and in revised form October 12, 2001; published online December 19, 2002
The NADPH oxidase of phagocytes catalyzes the conversion of oxygen to O 2ⴚ. This multicomponent enzyme complex contains five essential protein components, two in the membrane and three in the cytosol. Unassembled and inactive in resting phagocytes, the oxidase becomes active after translocation of cytosolic components to the membrane to assemble a functional oxidase. Multiple factors regulate its assembly and activity, thus serving to maintain this highly reactive system under spatial and temporal control until recruited for antimicrobial or proinflammatory events. The recent identification of homologs of one of the membrane components in nonphagocytic cells will expand understanding of the biological contexts in which this system may function. © 2002 Elsevier Science Key Words: NADPH oxidase; cytochrome b 558; p67 PHOX; p47 PHOX.
NADPH oxidase (1) is an enzyme that is located in neutrophils (2), eosinophils (3), and mononuclear phagocytes (4) and catalyzes the generation of superoxide (O 2⫺) 2 from oxygen and NADPH (5): NADPH ⫹ O2 3 NADP ⫹ ⫹ H ⫹ ⫹ O 2⫺ . O 2⫺ is converted to H 2O 2, which represents stoichiometrically the bulk of oxygen consumed by stimulated phagocytes (6, 7). Concurrent with activation of the NADPH oxidase, intracellular granules fuse with the plasma membrane or phagosomal membrane to release a broad array of biologically active molecules, including 1
To whom correspondence should be addressed. Abbreviations used: MPO, myeloperoxidase; O 2⫺, superoxide; M, metal. 2
342
proteases, antimicrobial proteins, and peroxidases. The H 2O 2 generated by the oxidase serves as a cosubstrate for peroxidases, either myeloperoxidase (MPO) in neutrophils and monocytes (8) or eosinophil peroxidase in eosinophils (9), in the oxidation of halides to generate hypohalous acids. In the case of neutrophils (10), the HOCl produced is a potent antimicrobial agent that in turn spawns long-lived chloramines that are in themselves cytotoxic (reviewed in Ref. 11). In addition to these reactive products, the NADPH oxidase also generates hydroxyl radical, made by the following metal (M)-catalyzed reaction (12, 13): H2 O2 ⫹ M ⫹ 3 OH 䡠 ⫹ OH ⫺ ⫹ M 2⫹ M 2⫹ 3 M ⫹ . Finally, the reaction H 2O 2 ⫹ HOCl can produce singlet oxygen ( 1O 2) (14), a more energetic form of oxygen that can attack double bonds. The phagocyte oxidase consists of four components that are essential for activity: the heterodimeric membrane-associated flavocytochrome b 588 protein, which is composed of gp91 PHOX (15) and p22 PHOX (15); the cytosolic components p47 PHOX (16) and p67 PHOX; and the small GTPase(s) Rac 1 or Rac2 (17). An additional component, p40 PHOX, is also associated with the oxidase, but its functional role is unclear (see below). The stability of each subunit of flavocytochrome b558 depends on heterodimer formation (18), so mutations in either gp91 PHOX or p22 PHOX result in the absence of both subunits from the cell surface. Flavocytochrome b558 has two heme groups, each buried in or near the membrane, and sequences consistent with binding motifs for binding flavin (19) and for NADPH. When considering potential roles of the individual components of the NADPH oxidase during stimulation 0003-9861/02 $35.00 © 2002 Elsevier Science All rights reserved.
THE NEUTROPHIL NADPH OXIDASE
of phagocytes, it is convenient to recognize that agonist exposure triggers both its assembly and activation. Whereas gp91 PHOX serves as the electron transporter of the NADPH oxidase (20), the functions of the cytosolic components are less precisely defined. p47 PHOX appears to serve as an adaptor protein, providing a platform for the assembly of a functional enzyme at the cytoplasmic face of cytochrome b 558. Serving as a switch to trigger oxidase assembly, phosphorylation of p47 PHOX (21, 22) results in a conformational rearrangement, exposing otherwise cryptic SH3 motifs, proline-rich regions, and a PX domain (see below) that together mediate interactions both with cytochrome b 558 and p67 PHOX. P47 PHOX translocation and oxidase activity appear to require the phosphorylation of one of a specific pair of serines on p47 PHOX: the conversion of S303 and S304 to the alanine equivalents eliminates oxidase activity (23), as does the conversion of S359 and S370 to the alanine equivalents (24). The kinase that seems to be responsible for most of the phosphorylation is protein kinase C (25), although it is not known which specific isoform(s) of protein kinase C is responsible. Another protein kinase that also phosphorylates p47 PHOX is Akt, but with weaker activity (unpublished). Like p47 PHOX, p22 PHOX and p67 PHOX are also phosphorylated upon cell activation, although the functional significance of these phosphorylations is uncertain. Guanine nucleotide exchange of Rac–GDP to form Rac–GTP also occurs, and this also appears to be an essential trigger for initiating oxidase assembly and activation. P47 PHOX contains tandem SH3 (26) domains one of which is bound to a remote polyproline domain, forming a fold that opens when the protein is activated (27). The amino terminus of p47 PHOX contains also a region of ⬃130 amino acids previously described as a PX domain, being first recognized in the phagocyte oxidase proteins p40 PHOX and p47 PHOX (28). The PX domains of p47 PHOX and p40 PHOX have been demonstrated to bind to specific phosphoinositides and may thus mediate in part the assembly of the oxidase at the plasma or phagosomal membrane (29 –31). P67 PHOX (26) likewise contains two SH3 domains and a NADPH binding domain of mysterious function. The function of p67 PHOX is thought to be to regulate the transfer electrons from NADPH to flavin (32, 33). P67 PHOX contains an “activation domain” (amino acids ⬃200 –210) that is essential for activation of the electron flow within flavocytochrome b558. This region is thought to regulate the hydride transfer from NADPH to FAD. Rac likewise participates in electron transfer and independently of p67 PHOX regulates transfer from NADPH to FAD by flavocytochrome b 558 (34). According to one view, the functions of both p47 PHOX and Rac are to bind and orient p67 PHOX so as to arrange properly its activation domain to regulate the electron flow within the flavocytochrome b558. This is consistent with recent data show-
343
ing that when high concentrations of p67 PHOX and Rac are present in a cell-free system then p47 PHOX is not needed to reconstitute high NADPH oxidase activity (35, 36). A fourth soluble component is p40 PHOX, whose function is not clear, although there is evidence both for its potentiating (37) and for its terminating (38) oxidase activity. P47 PHOX, p67 PHOX, and p40 PHOX form a cytosolic complex in which p47 PHOX is about 1:1, but the amount of p47 PHOX is three to four times the quantity of p67 PHOX (39). Superoxide production by the NADPH oxidase is an electrogenic process (40) and is accompanied by proton channel activity, attributed in several studies to gp91 PHOX (41– 43). Although the capacity of gp91 PHOX to mediate proton efflux is generally accepted, there is spirited controversy as to whether gp91 PHOX is the predominant voltage-gated proton channel activated during phagocyte stimulation (44, 45). The relatively recent appreciation that gp91 PHOX is a member of a protein family whose members are expressed widely in nonphagocytic cells and likely mediate a wide array of functions unrelated to antimicrobial activity (reviewed in Ref. 46) may provide important insights pertinent to this controversy. A splice variant of NOX1 (47) functions as a proton channel despite the absence of heme groups or oxidase activity. Ongoing studies of gp91 PHOX homologs may provide important insights into the coupling and functional significance of electron and proton transport activities attributed to the phagocyte oxidase. REFERENCES 1. Park, J.-W., Scott, K. E., and Babior, B. M. (1999) Exp. Hematol. 26, 37– 44. 2. Batot, G., Martel, C., Capdeville, N., Wientjes, F., and Morel, F. (1995) Eur. J. Biochem. 234, 208 –215. 3. Bolscher, B. G. J. M., Koenderman, L., Tool, A. T. J., Stokman, P. M., and Roos, D. (1990) FEBS Lett. 268, 269 –273. 4. Brozna, J. P., Hauff, N. F., Phillips, W. A., and Johnston, R. B., Jr. (1988) J. Immunol. 141, 1642–1647. 5. Babior, B. M., Kipnes, R. S., and Curnutte, J. T. (1973) J. Clin. Invest. 52, 741–744. 6. Roos, D., Eckmann, C. M., Yazdanbakhsh, M., Hamers, M. N., and de Boer, M. (1984) J. Biol. Chem. 259, 1770 –1775. 7. Makino, R., Tanaka, T., Iizuka, T., Ishimura, Y., and Kanagesaki, S. (1986) J. Biol. Chem. 261, 11444 –11447. 8. Furtmuller, P. G., Burner, U., and Obinger, C. (1998) Biochemistry 37, 17923–17930. 9. Horton, M. A., Larson, K. A., Lee, J. J., and Lee, N. A. (1996) J. Leukocyte Biol. 60, 285–294. 10. Albrich, J. M., McCarthy, C. A., and Hurst, J. K. (1981) Proc. Natl. Acad. Sci. USA 78, 210 –214. 11. Hampton, M. B., Kettle, A. J., and Winterbourn, C. C. (1998) Blood 92, 3007–3017. 12. Kadiiska, M. B., Burkitt, M. J., Xiang, Q.-H., and Mason, R. P. (1995) J. Clin. Invest. 96, 1653–1657. 13. Liochev, S. I. (1996) Free Radical. Res. 25, 369 –384.
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14. Allen, R. C., Yevich, S. J., Orth, R. W., and Steele, R. H. (1974) Biochem. Biophys. Res. Commun. 60, 909 –917. 15. Volpp, B. D., Nauseef, W. M., and Clark, R. A. (1988) Science 242, 1295–1297. 16. Nunoi, H., Rotrosen, D., Gallin, J. I., and Malech, H. L. (1988) Science 242, 1298 –1301. 17. Kwong, C. H., Malech, H. L., Rotrosen, D., and Leto, T. L. (1993) Biochemistry 32, 5711–5717. 18. DeLeo, F. R., Burritt, J. B., Yu, L., Jesaitis, A. J., Dinauer, M. C., and Nauseef, W. M. (2000) J. Biol. Chem. 275, 13986 –13993. 19. Cross, A. R., Jones, O. T. G., Garcia, R., and Segal, A. W. (1982) Biochem. J. 208, 759 –763. 20. Cross, A. R., Parkinson, J. F., and Jones, O. T. G. (1985) Biochem. J. 226, 881– 884. 21. El Benna, J., Park, J.-W., Ruedi, J. M., and Babior, B. M. (1995) Blood Cells Mol. Dis. 21, 201–206. 22. Faust, L. P., El Benna, J., Babior, B. M., and Chanock, S. J. (1995) J. Clin. Invest. 96, 1499 –1505. 23. Inanami, O., Johnson, J. L., McAdara, J. K., El Benna, J., Faust, L. P., Newburger, P. E., and Babior, B. M. (1998) J. Biol. Chem. 273, 9539 –9543. 24. Johnson, J. L., Park, J. W., El Benna, J., Faust, L. P., Inanami, O., and Babior, B. M. (1998) J. Biol. Chem. 273, 35147–35152. 25. El Benna, J., Faust, L. P., and Babior, B. M. (1994) J. Biol. Chem. 269, 23431–23436. 26. Leto, T. L., Lomax, K. J., Volpp, B. D., Nunoi, H., Sechler, J. M. G., Nauseef, W. M., Clark, R. A., Gallin, J. I., and Malech, H. L. (1990) Science 248, 727–730. 27. Sumimoto, H., Kage, Y., Nunoi, H., Sasaki, H., Nose, T., Fukumaki, Y., Ohno, M., Minakami, S., and Takeshige, K. (1994) Proc. Natl. Acad. Sci. USA 91, 5345–5349. 28. Ponting, C. F. (1996) Protein Sci. 5, 2353–2357. 29. Kanai, F., Liu, H., Field, S., Akbary, H., Matsuo, T., Brown, G., Cantley, L., and Yaffe, M. (2001) Nature Cell Biol. 3, 675– 678. 30. Hiroaki, H., Ago, T., Ito, T., Sumimoto, H., and Kohda, D. (2001) Nature Struct. Biol. 8, 526 –530.
31. Ellson, C., Gobert-Gosse, S., Anderson, K., Davidson, K., Erdjument-Bromage, H., Tempst, P., Thuring, J., Cooper, M., Lim, Z.-Y., Holmes, A., Gaffney, P., Chilvers, E., Hawkins, P., and Stephens, L. (2001) Nature Cell Biol. 3, 679 – 682. 32. Nisimoto, Y., Motalebi, S., Han, C. H., and Lambeth, J. D. (1999) J. Biol. Chem. 274, 22999 –23005. 33. Han, C. H., Freeman, J. L., Lee, T., Motalebi, S. A., and Lambeth, J. D. (1998) J. Biol. Chem. 273, 16663–16668. 34. Diebold, B. A., and Bokoch, G. M. (2001) Nature Immunol. 2, 211–215. 35. Freeman, J. L., and Lambeth, J. D. (1996) J. Biol. Chem. 271, 19794 –19801. 36. Koshkin, V., Lotan, O., and Pick, E. (1996) J. Biol. Chem. 271, 30326 –30329. 37. Cross, A. R. (2000) Biochem. J. 349, 113–117. 38. Sathyamoorthy, M., de Mendez, I., Adams, A. G., and Leto, T. L. (1997) J. Biol. Chem. 272, 9141–9146. 39. Park, J.-W., Ma, M., Ruedi, J. M., Smith, R. M., and Babior, B. M. (1992) J. Biol. Chem. 267, 17327–17332. 40. Nanda, A., Curnutte, J. T., and Grinstein, S. (1994) J. Clin. Invest. 93, 1770 –1775. 41. Henderson, L. M. (1998) J. Biol. Chem. 273, 33216 –33223. 42. Schrenzel, J., Serrander, L., Banfi, B., Nusse, O., Fouyouzi, R., Lew, D. P., Demaurex, N., and Krause, K. H. (1998) Nature 392, 734 –737. 43. Maturana, A., Arnaudeau, S., Ryser, S., Banfi, B., Hossle, J. P., Schlegel, W., Krause, K. H., and Demaurex, N. (2001) J. Biol. Chem. 276, 30277–30284. 44. DeCoursey, T. E., Cherny, V. V., Morgan, D., Katz, B. Z., and Dinauer, M. C. (2001) J. Biol. Chem. 276, 36063–36066. 45. DeCoursey, T. E., Cheny, V. V., Zhou, W., and Thomas, J. L. (2000) Proc. Natl. Acad. Sci. USA 97, 6885– 6889. 46. Lambeth, J. D., Cheng, G., Arnold, R. S., and Edens, W. A. (2000) Trends Biochem. Sci. 25, 459 – 461. 47. Banfi, B., Maturana, A., Jaconi, S., Arnaudeau, S., Laforge, T., Sinha, B., Ligeti, E., Demaurex, N., and Krause, K. H. (2000) Science 287, 138 –142.
MINIREVIEW The Neutrophil NADPH Oxidase B. M. Babior,* ,1 J. D. Lambeth,† and W. Nauseef ‡ *The Scripps Research Institute, La Jolla, California 92037; †Emory University Medical School, Atlanta, Georgia 30322; and ‡University of Iowa, Iowa City, Iowa 52246
Received September 20, 2001, and in revised form October 12, 2001; published online December 19, 2002
The NADPH oxidase of phagocytes catalyzes the conversion of oxygen to O 2ⴚ. This multicomponent enzyme complex contains five essential protein components, two in the membrane and three in the cytosol. Unassembled and inactive in resting phagocytes, the oxidase becomes active after translocation of cytosolic components to the membrane to assemble a functional oxidase. Multiple factors regulate its assembly and activity, thus serving to maintain this highly reactive system under spatial and temporal control until recruited for antimicrobial or proinflammatory events. The recent identification of homologs of one of the membrane components in nonphagocytic cells will expand understanding of the biological contexts in which this system may function. © 2002 Elsevier Science Key Words: NADPH oxidase; cytochrome b 558; p67 PHOX; p47 PHOX.
NADPH oxidase (1) is an enzyme that is located in neutrophils (2), eosinophils (3), and mononuclear phagocytes (4) and catalyzes the generation of superoxide (O 2⫺) 2 from oxygen and NADPH (5): NADPH ⫹ O2 3 NADP ⫹ ⫹ H ⫹ ⫹ O 2⫺ . O 2⫺ is converted to H 2O 2, which represents stoichiometrically the bulk of oxygen consumed by stimulated phagocytes (6, 7). Concurrent with activation of the NADPH oxidase, intracellular granules fuse with the plasma membrane or phagosomal membrane to release a broad array of biologically active molecules, including 1
To whom correspondence should be addressed. Abbreviations used: MPO, myeloperoxidase; O 2⫺, superoxide; M, metal. 2
342
proteases, antimicrobial proteins, and peroxidases. The H 2O 2 generated by the oxidase serves as a cosubstrate for peroxidases, either myeloperoxidase (MPO) in neutrophils and monocytes (8) or eosinophil peroxidase in eosinophils (9), in the oxidation of halides to generate hypohalous acids. In the case of neutrophils (10), the HOCl produced is a potent antimicrobial agent that in turn spawns long-lived chloramines that are in themselves cytotoxic (reviewed in Ref. 11). In addition to these reactive products, the NADPH oxidase also generates hydroxyl radical, made by the following metal (M)-catalyzed reaction (12, 13): H2 O2 ⫹ M ⫹ 3 OH 䡠 ⫹ OH ⫺ ⫹ M 2⫹ M 2⫹ 3 M ⫹ . Finally, the reaction H 2O 2 ⫹ HOCl can produce singlet oxygen ( 1O 2) (14), a more energetic form of oxygen that can attack double bonds. The phagocyte oxidase consists of four components that are essential for activity: the heterodimeric membrane-associated flavocytochrome b 588 protein, which is composed of gp91 PHOX (15) and p22 PHOX (15); the cytosolic components p47 PHOX (16) and p67 PHOX; and the small GTPase(s) Rac 1 or Rac2 (17). An additional component, p40 PHOX, is also associated with the oxidase, but its functional role is unclear (see below). The stability of each subunit of flavocytochrome b558 depends on heterodimer formation (18), so mutations in either gp91 PHOX or p22 PHOX result in the absence of both subunits from the cell surface. Flavocytochrome b558 has two heme groups, each buried in or near the membrane, and sequences consistent with binding motifs for binding flavin (19) and for NADPH. When considering potential roles of the individual components of the NADPH oxidase during stimulation 0003-9861/02 $35.00 © 2002 Elsevier Science All rights reserved.
THE NEUTROPHIL NADPH OXIDASE
of phagocytes, it is convenient to recognize that agonist exposure triggers both its assembly and activation. Whereas gp91 PHOX serves as the electron transporter of the NADPH oxidase (20), the functions of the cytosolic components are less precisely defined. p47 PHOX appears to serve as an adaptor protein, providing a platform for the assembly of a functional enzyme at the cytoplasmic face of cytochrome b 558. Serving as a switch to trigger oxidase assembly, phosphorylation of p47 PHOX (21, 22) results in a conformational rearrangement, exposing otherwise cryptic SH3 motifs, proline-rich regions, and a PX domain (see below) that together mediate interactions both with cytochrome b 558 and p67 PHOX. P47 PHOX translocation and oxidase activity appear to require the phosphorylation of one of a specific pair of serines on p47 PHOX: the conversion of S303 and S304 to the alanine equivalents eliminates oxidase activity (23), as does the conversion of S359 and S370 to the alanine equivalents (24). The kinase that seems to be responsible for most of the phosphorylation is protein kinase C (25), although it is not known which specific isoform(s) of protein kinase C is responsible. Another protein kinase that also phosphorylates p47 PHOX is Akt, but with weaker activity (unpublished). Like p47 PHOX, p22 PHOX and p67 PHOX are also phosphorylated upon cell activation, although the functional significance of these phosphorylations is uncertain. Guanine nucleotide exchange of Rac–GDP to form Rac–GTP also occurs, and this also appears to be an essential trigger for initiating oxidase assembly and activation. P47 PHOX contains tandem SH3 (26) domains one of which is bound to a remote polyproline domain, forming a fold that opens when the protein is activated (27). The amino terminus of p47 PHOX contains also a region of ⬃130 amino acids previously described as a PX domain, being first recognized in the phagocyte oxidase proteins p40 PHOX and p47 PHOX (28). The PX domains of p47 PHOX and p40 PHOX have been demonstrated to bind to specific phosphoinositides and may thus mediate in part the assembly of the oxidase at the plasma or phagosomal membrane (29 –31). P67 PHOX (26) likewise contains two SH3 domains and a NADPH binding domain of mysterious function. The function of p67 PHOX is thought to be to regulate the transfer electrons from NADPH to flavin (32, 33). P67 PHOX contains an “activation domain” (amino acids ⬃200 –210) that is essential for activation of the electron flow within flavocytochrome b558. This region is thought to regulate the hydride transfer from NADPH to FAD. Rac likewise participates in electron transfer and independently of p67 PHOX regulates transfer from NADPH to FAD by flavocytochrome b 558 (34). According to one view, the functions of both p47 PHOX and Rac are to bind and orient p67 PHOX so as to arrange properly its activation domain to regulate the electron flow within the flavocytochrome b558. This is consistent with recent data show-
343
ing that when high concentrations of p67 PHOX and Rac are present in a cell-free system then p47 PHOX is not needed to reconstitute high NADPH oxidase activity (35, 36). A fourth soluble component is p40 PHOX, whose function is not clear, although there is evidence both for its potentiating (37) and for its terminating (38) oxidase activity. P47 PHOX, p67 PHOX, and p40 PHOX form a cytosolic complex in which p47 PHOX is about 1:1, but the amount of p47 PHOX is three to four times the quantity of p67 PHOX (39). Superoxide production by the NADPH oxidase is an electrogenic process (40) and is accompanied by proton channel activity, attributed in several studies to gp91 PHOX (41– 43). Although the capacity of gp91 PHOX to mediate proton efflux is generally accepted, there is spirited controversy as to whether gp91 PHOX is the predominant voltage-gated proton channel activated during phagocyte stimulation (44, 45). The relatively recent appreciation that gp91 PHOX is a member of a protein family whose members are expressed widely in nonphagocytic cells and likely mediate a wide array of functions unrelated to antimicrobial activity (reviewed in Ref. 46) may provide important insights pertinent to this controversy. A splice variant of NOX1 (47) functions as a proton channel despite the absence of heme groups or oxidase activity. Ongoing studies of gp91 PHOX homologs may provide important insights into the coupling and functional significance of electron and proton transport activities attributed to the phagocyte oxidase. REFERENCES 1. Park, J.-W., Scott, K. E., and Babior, B. M. (1999) Exp. Hematol. 26, 37– 44. 2. Batot, G., Martel, C., Capdeville, N., Wientjes, F., and Morel, F. (1995) Eur. J. Biochem. 234, 208 –215. 3. Bolscher, B. G. J. M., Koenderman, L., Tool, A. T. J., Stokman, P. M., and Roos, D. (1990) FEBS Lett. 268, 269 –273. 4. Brozna, J. P., Hauff, N. F., Phillips, W. A., and Johnston, R. B., Jr. (1988) J. Immunol. 141, 1642–1647. 5. Babior, B. M., Kipnes, R. S., and Curnutte, J. T. (1973) J. Clin. Invest. 52, 741–744. 6. Roos, D., Eckmann, C. M., Yazdanbakhsh, M., Hamers, M. N., and de Boer, M. (1984) J. Biol. Chem. 259, 1770 –1775. 7. Makino, R., Tanaka, T., Iizuka, T., Ishimura, Y., and Kanagesaki, S. (1986) J. Biol. Chem. 261, 11444 –11447. 8. Furtmuller, P. G., Burner, U., and Obinger, C. (1998) Biochemistry 37, 17923–17930. 9. Horton, M. A., Larson, K. A., Lee, J. J., and Lee, N. A. (1996) J. Leukocyte Biol. 60, 285–294. 10. Albrich, J. M., McCarthy, C. A., and Hurst, J. K. (1981) Proc. Natl. Acad. Sci. USA 78, 210 –214. 11. Hampton, M. B., Kettle, A. J., and Winterbourn, C. C. (1998) Blood 92, 3007–3017. 12. Kadiiska, M. B., Burkitt, M. J., Xiang, Q.-H., and Mason, R. P. (1995) J. Clin. Invest. 96, 1653–1657. 13. Liochev, S. I. (1996) Free Radical. Res. 25, 369 –384.
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14. Allen, R. C., Yevich, S. J., Orth, R. W., and Steele, R. H. (1974) Biochem. Biophys. Res. Commun. 60, 909 –917. 15. Volpp, B. D., Nauseef, W. M., and Clark, R. A. (1988) Science 242, 1295–1297. 16. Nunoi, H., Rotrosen, D., Gallin, J. I., and Malech, H. L. (1988) Science 242, 1298 –1301. 17. Kwong, C. H., Malech, H. L., Rotrosen, D., and Leto, T. L. (1993) Biochemistry 32, 5711–5717. 18. DeLeo, F. R., Burritt, J. B., Yu, L., Jesaitis, A. J., Dinauer, M. C., and Nauseef, W. M. (2000) J. Biol. Chem. 275, 13986 –13993. 19. Cross, A. R., Jones, O. T. G., Garcia, R., and Segal, A. W. (1982) Biochem. J. 208, 759 –763. 20. Cross, A. R., Parkinson, J. F., and Jones, O. T. G. (1985) Biochem. J. 226, 881– 884. 21. El Benna, J., Park, J.-W., Ruedi, J. M., and Babior, B. M. (1995) Blood Cells Mol. Dis. 21, 201–206. 22. Faust, L. P., El Benna, J., Babior, B. M., and Chanock, S. J. (1995) J. Clin. Invest. 96, 1499 –1505. 23. Inanami, O., Johnson, J. L., McAdara, J. K., El Benna, J., Faust, L. P., Newburger, P. E., and Babior, B. M. (1998) J. Biol. Chem. 273, 9539 –9543. 24. Johnson, J. L., Park, J. W., El Benna, J., Faust, L. P., Inanami, O., and Babior, B. M. (1998) J. Biol. Chem. 273, 35147–35152. 25. El Benna, J., Faust, L. P., and Babior, B. M. (1994) J. Biol. Chem. 269, 23431–23436. 26. Leto, T. L., Lomax, K. J., Volpp, B. D., Nunoi, H., Sechler, J. M. G., Nauseef, W. M., Clark, R. A., Gallin, J. I., and Malech, H. L. (1990) Science 248, 727–730. 27. Sumimoto, H., Kage, Y., Nunoi, H., Sasaki, H., Nose, T., Fukumaki, Y., Ohno, M., Minakami, S., and Takeshige, K. (1994) Proc. Natl. Acad. Sci. USA 91, 5345–5349. 28. Ponting, C. F. (1996) Protein Sci. 5, 2353–2357. 29. Kanai, F., Liu, H., Field, S., Akbary, H., Matsuo, T., Brown, G., Cantley, L., and Yaffe, M. (2001) Nature Cell Biol. 3, 675– 678. 30. Hiroaki, H., Ago, T., Ito, T., Sumimoto, H., and Kohda, D. (2001) Nature Struct. Biol. 8, 526 –530.
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