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

Abstract

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 ca