The Nox Family of NAD(P)H Oxidases: Host Defense and Beyond

Reactive oxygen species (ROS) 1The abbreviations used are: ROS, reactive oxygen species; phox, phagocyte oxidase; Nox, NADPH oxidase; LPS, lipopolysaccharide; TLR, toll-like receptor; Noxo1, NADPH oxidase organizer 1; Noxa1, NADPH oxidase activator 1; EPO, erythropoietin. play diverse roles in biology, including host defense, hormone biosynthesis, fertilization, and redox signaling involved in mitogenesis, apoptosis, or oxygen sensing. Until recently, much of our understanding of the mechanisms of ROS generation and their functions in man was based on studies of phagocytic cells, where abundant microbicidal oxidants released during engulfment of microbes serve as a first line of host defense. In phagocytic cells the ROS precursor superoxide is produced by a NADPH oxidase complex (1Leto T.L. Gallin J.I. Snyderman R. Inflammation Basic Principles and Clinical Correlates. Lippincott Williams & Wilkins, Philadelphia1999: 769-787Google Scholar, 2Quinn M.T. Gauss K.A. J. Leukocyte Biol. 2004; 76: 760-781Crossref PubMed Scopus (392) Google Scholar, 3Cross A.R. Segal A.W. Biochim. Biophys. Acta. 2004; 1657: 1-22Crossref PubMed Scopus (370) Google Scholar). The phagocytic oxidase (phox) consists of a membrane-bound flavocytochrome b558, several modular cytosolic regulators (p47phox, p67phox, p40phox), and a small GTPase, Rac1 or Rac2. The cytochrome is a complex of two proteins: a flavin- and heme-binding glycoprotein (gp91phox) and a smaller subunit (p22phox). With the recent expansion of information available in human genome databases, several novel gp91phox homologues have been recognized (Fig. 1), suggesting that enzymes similar to the phagocytic oxidase function in a variety of tissues, notably the colon, kidney, thyroid gland, testis, salivary glands, airways, and lymphoid organs (4Suh Y.A. Arnold R.S. Lassegue B. Shi J. Xu X. Sorescu D. Chung A.B. Griendling K.K. Lambeth J.D. Nature. 1999; 401: 79-82Crossref PubMed Scopus (1284) Google Scholar, 5Geiszt M. Kopp J.B. Varnai P. Leto T.L. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 8010-8014Crossref PubMed Scopus (715) Google Scholar, 6Dupuy C. Ohayon R. Valent A. Noel-Hudson M.S. Deme D. Virion A. J. Biol. Chem. 1999; 274: 37265-37269Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 7De Deken X. Wang D. Many M.C. Costagliola S. Libert F. Vassart G. Dumont J.E. Miot F. J. Biol. Chem. 2000; 275: 23227-23233Abstract Full Text Full Text PDF PubMed Scopus (505) Google Scholar, 8Shiose A. Kuroda J. Tsuruya K. Hirai M. Hirakata H. Naito S. Hattori M. Sakaki Y. Sumimoto H. J. Biol. Chem. 2001; 276: 1417-1423Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar, 9Banfi B. Molnar G. Maturana A. Steger K. Hegedus B. Demaurex N. Krause K.H. J. Biol. Chem. 2001; 276: 37594-37601Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). The physiological functions of these novel NADPH oxidases, now designated the Nox family, are currently under intensive investigation. Recent reviews have described in detail the molecular features of the phox system (2Quinn M.T. Gauss K.A. J. Leukocyte Biol. 2004; 76: 760-781Crossref PubMed Scopus (392) Google Scholar, 3Cross A.R. Segal A.W. Biochim. Biophys. Acta. 2004; 1657: 1-22Crossref PubMed Scopus (370) Google Scholar). This review updates our current knowledge about novel members of the Nox family. Nox1, the first recognized homologue of gp91phox, now termed Nox2, is detected in abundance in the colon and at lower levels in uterus, prostate, and vascular smooth muscle cells (4Suh Y.A. Arnold R.S. Lassegue B. Shi J. Xu X. Sorescu D. Chung A.B. Griendling K.K. Lambeth J.D. Nature. 1999; 401: 79-82Crossref PubMed Scopus (1284) Google Scholar). The 564-amino acid protein is 56% identical to gp91phox and contains the essential features of its phagocytic counterpart, including six transmembrane segments and several conserved motifs considered important for binding of NADPH, FAD, and two heme molecules. Two variants of the full-length isoform have been described. Bánfi et al. (10Bánfi B. Maturana A. Jaconi S. Arnaudeau S. Laforge T. Sinha B. Ligeti E. Demaurex N. Krause K.H. Science. 2000; 287: 138-142Crossref PubMed Scopus (251) Google Scholar) isolated a short mRNA product of the Nox1 gene encoding a proton-conductive channel, called NOH-1S (10Bánfi B. Maturana A. Jaconi S. Arnaudeau S. Laforge T. Sinha B. Ligeti E. Demaurex N. Krause K.H. Science. 2000; 287: 138-142Crossref PubMed Scopus (251) Google Scholar). They suggested that a unique intraexonic splicing process gives rise to the NOH-1S-coding mRNA. Recent studies showed, however, that the NOH-1S product is not transcribed from the Nox1 gene but is artifactually derived by intramolecular template switching during reverse transcription. 2Geiszt, M., Lekstrom, K., and Leto, T. (2004) 279, 51661–51668. Although RNA splicing does not account for NOH-1S synthesis, RNA splicing does generate another Nox1 transcript in normal colon and in colon carcinoma cells, where it is nearly as abundant as the full-length transcript. This transcript lacks the entire exon 11 (residues 433–482) and does not encode a functional oxidase 2Geiszt, M., Lekstrom, K., and Leto, T. (2004) 279, 51661–51668. (10Bánfi B. Maturana A. Jaconi S. Arnaudeau S. Laforge T. Sinha B. Ligeti E. Demaurex N. Krause K.H. Science. 2000; 287: 138-142Crossref PubMed Scopus (251) Google Scholar). In early work exploring the function of Nox1, heterologous overexpression of Nox1 in NIH-3T3 cells was associated with increased cell proliferation and resulted in tumor formation when these cells were injected into nude mice (4Suh Y.A. Arnold R.S. Lassegue B. Shi J. Xu X. Sorescu D. Chung A.B. Griendling K.K. Lambeth J.D. Nature. 1999; 401: 79-82Crossref PubMed Scopus (1284) Google Scholar). Subsequent reports proposed that hydrogen peroxide (H2O2) formation in these Nox1-expressing cells is responsible for the increased mitogenesis (11Arnold R.S. Shi J. Murad E. Whalen A.M. Sun C.Q. Polavarapu R. Parthasarathy S. Petros J.A. Lambeth J.D. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 5550-5555Crossref PubMed Scopus (423) Google Scholar). These findings were enthusiastically received because enhanced cellular ROS generation has been linked to the enhanced growth triggered by growth factor stimulation or tumorigenesis (12Sundaresan M. Yu Z.-X. Ferrans V.J. Irani K. Finkel T. Science. 1995; 270: 296-299Crossref PubMed Scopus (2322) Google Scholar, 13Irani K. Xia Y. Zweier J. Sollott S. Der C. Rearon E. Sundaresan M. Finkel T. Goldschmidt-Clermont P. Science. 1997; 275: 1649-1652Crossref PubMed Scopus (1441) Google Scholar, 14Szatrowski T.P. Nathan C.F. Cancer Res. 1991; 51: 794-798PubMed Google Scholar). Cells overexpressing Nox1 also showed increased vascular endothelial growth factor expression, suggesting that ROS produced by Nox1 also stimulates angiogenesis in these tumors (15Arbiser J.L. Petros J. Klafter R. Govindajaran B. McLaughlin E.R. Brown L.F. Cohen C. Moses M. Kilroy S. Arnold R.S. Lambeth J.D. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 715-720Crossref PubMed Scopus (404) Google Scholar). Further studies revealed, however, that these Nox1-transfected NIH-3T3 cell lines also carry a mutant form of Ras that can account for the enhanced proliferation and transformation (16Lambeth J.D. Nat. Rev. Immunol. 2004; 4: 181-189Crossref PubMed Scopus (2492) Google Scholar). Observations in colon-derived epithelial cells, which naturally express Nox1, do not support the proposed role of Nox1 as a mitogenic oxidase. In HT29 colon cancer cells, the suppression of Nox1 levels does not affect cell proliferation (17Geiszt M. K. S. R. Leto T.L. J. Immunol. PubMed Scopus Google Scholar). Nox1 when HT29 or cells are to by or by (17Geiszt M. K. S. R. Leto T.L. J. Immunol. PubMed Scopus Google Scholar). a of human showed Nox1 is to colon tumors and the Nox1 in tumors (17Geiszt M. K. S. R. Leto T.L. J. Immunol. PubMed Scopus Google Scholar). these findings that Nox1 function in colon to that Nox1 serve as a host oxidase. Nox1 with increased ROS was detected in cells with T. S. A. T. K. K. 2001; PubMed Scopus Google Scholar). et al. T. Y. S. R. Sumimoto H. K. S. T. K. J. Immunol. 2004; PubMed Scopus Google Scholar) proposed that from H. stimulates ROS a toll-like In colon epithelial cells, which and do not to LPS, ROS in to from T. Y. S. R. Sumimoto H. K. S. T. K. J. Immunol. 2004; PubMed Scopus Google Scholar). role for Nox1 in was also suggested by that Nox1 (gp91phox) in the of the in superoxide in (17Geiszt M. K. S. R. Leto T.L. J. Immunol. PubMed Scopus Google Scholar). these findings that Nox1 is similar to Nox1 has a role in colon epithelial or in host investigation. Although reports have the role of Nox1 in the colon, where it is several have the of Nox1 in ROS in vascular Nox1 in smooth muscle cells was described by et al. (4Suh Y.A. Arnold R.S. Lassegue B. Shi J. Xu X. Sorescu D. Chung A.B. Griendling K.K. Lambeth J.D. Nature. 1999; 401: 79-82Crossref PubMed Scopus (1284) Google and several these findings in B. J. PubMed Scopus Google Scholar). including growth and to Nox1 mRNA levels in smooth muscle cells (4Suh Y.A. Arnold R.S. Lassegue B. 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PubMed Scopus Google Scholar). in several cell lines to ROS suggesting oxidase are for Deken X. D. Dumont J.E. Miot F. Res. 2002; PubMed Scopus Google Scholar). In thyroid the are detected on the where for and of is essential for because in in H. F. T. C. N. J. 2002; PubMed Scopus Google Scholar). The role of in thyroid has not been are also by the of lower as G. R. T. X. C. Lambeth J.D. J. Biol. 2001; PubMed Scopus Google Scholar). formation was during C. of by RNA G. R. T. X. C. Lambeth J.D. J. Biol. 2001; PubMed Scopus Google Scholar). was proposed that the ROS for of in a to the The isolated C. produced in to of in G. R. T. X. C. Lambeth J.D. J. Biol. 2001; PubMed Scopus Google Scholar). roles for enzymes in host were proposed in several M. J. J. K. Leto T.L. J. PubMed Scopus Google Scholar). on the levels of in epithelial cells of salivary and of colon, and airways, these enzymes were proposed to serve as of the of abundant in and to to and species J.D. Nature. PubMed Scopus Google Scholar). the that microbicidal system that has been recognized in In phagocytic cells, gp91phox is the of a complex (1Leto T.L. Gallin J.I. Snyderman R. Inflammation Basic Principles and Clinical Correlates. Lippincott Williams & Wilkins, Philadelphia1999: 769-787Google Scholar, 2Quinn M.T. Gauss K.A. J. Leukocyte Biol. 2004; 76: 760-781Crossref PubMed Scopus (392) Google Scholar, 3Cross A.R. Segal A.W. Biochim. Biophys. Acta. 2004; 1657: 1-22Crossref PubMed Scopus (370) Google Scholar). and are also essential for superoxide as is in where or the of of these in oxidase a into the and to J.L. T. Lambeth J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Sci. Full Text Full Text PDF PubMed Scopus Google Scholar). essential role for in oxidase was in A. E. A. N. Segal A.W. Nature. 1991; PubMed Scopus Google Scholar) and was in mutant C. J. A. G. C. A. M. R. D. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar) and in mice in A.W. C. J.B. R. B. A. J.D. J.B. M.C. Williams 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The molecular of the are a of as that of the homologues of gp91phox also function as et al. (4Suh Y.A. Arnold R.S. Lassegue B. Shi J. Xu X. Sorescu D. Chung A.B. Griendling K.K. Lambeth J.D. Nature. 1999; 401: 79-82Crossref PubMed Scopus (1284) Google Scholar) that Nox1 overexpression superoxide not superoxide when Nox1 was in several (17Geiszt M. K. S. R. Leto T.L. J. Immunol. PubMed Scopus Google Scholar, M. K. J. Leto T.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. K. M. M. T. H. Sumimoto H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of and superoxide in cells Nox1 (17Geiszt M. K. S. R. Leto T.L. J. Immunol. PubMed Scopus Google Scholar, B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a protein to that was in several M. K. J. Leto T.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. K. M. M. T. H. Sumimoto H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G. Lambeth J.D. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). was in which is designated oxidase organizer or The mRNA for is detected at levels colon where Nox1 is also M. K. J. Leto T.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The and is contains of the functional considered essential in its phagocytic two and a that as a binding M. K. J. Leto T.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. K. M. M. T. H. Sumimoto H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). lacks a to the of a with several during and of the phagocytic oxidase complex (1Leto T.L. Gallin J.I. Snyderman R. Inflammation Basic Principles and Clinical Correlates. Lippincott Williams & Wilkins, Philadelphia1999: 769-787Google Scholar, 2Quinn M.T. Gauss K.A. J. Leukocyte Biol. 2004; 76: 760-781Crossref PubMed Scopus (392) Google Scholar, 3Cross A.R. Segal A.W. Biochim. Biophys. Acta. 2004; 1657: 1-22Crossref PubMed Scopus (370) Google Scholar). The of also lacks the in and has a binding that is from that of G. Lambeth J.D. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). on these was to a M. K. J. Leto T.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. K. M. M. T. H. Sumimoto H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G. Lambeth J.D. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). with these with Nox1 on the when in cells, in the of cell stimulation G. Lambeth J.D. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). protein with to p67phox, called for NADPH oxidase activator 1), was also in colon M. K. J. Leto T.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. K. M. M. T. H. Sumimoto H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). p67phox, contains that a and a that M. K. J. Leto T.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. K. M. M. T. H. Sumimoto H. J. Biol. Chem. 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J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google with its to gp91phox and the of have not been roles for as a of are because its is detected in several tissues, notably thyroid and salivary glands, kidney, and M. K. J. Leto T.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. K. M. M. T. H. Sumimoto H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of also of its with Nox because transcript is abundant in H. M. H. K. Sakaki Y. S. Biophys. Res. PubMed Scopus Google Scholar). of with is however, because have in thyroid to are not detected in the genome of C. which is another of the novel Nox of the that NADPH function in cells were based on in cells overexpressing mutant (12Sundaresan M. Yu Z.-X. Ferrans V.J. Irani K. Finkel T. Science. 1995; 270: 296-299Crossref PubMed Scopus (2322) Google Scholar, 13Irani K. Xia Y. Zweier J. Sollott S. Der C. Rearon E. Sundaresan M. Finkel T. Goldschmidt-Clermont P. Science. 1997; 275: 1649-1652Crossref PubMed Scopus (1441) Google however, is that the novel Nox enzymes D. Biol. 2004; PubMed Scopus Google Scholar). The to the Nox enzymes to recent of binding to B. Steger K. Krause K.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the Nox enzymes by Noxa1, or its homologue p67phox, are for by With the recent of members it that ROS in cells can from signaling roles for these enzymes have been proposed in a variety of where are detected at their levels at epithelial cells, that have functions in to host defense, as in hormone biosynthesis, fertilization, oxygen and is that host are not to and that epithelial cells can also are to the molecular of these novel and to their physiological With of these functions the that these enzymes also have roles in a variety of to or of