The protein encoded by this gene is a cytosolic regulatory component of the superoxide-producing phagocyte NADPH-oxidase, a multicomponent enzyme system important for host defense. This protein is preferentially expressed in cells of myeloid lineage. It interacts primarily with neutrophil cytosolic factor 2 (NCF2/p67-phox) to form a complex with neutrophil cytosolic factor 1 (NCF1/p47-phox), which further interacts with the small G protein RAC1 and translocates to the membrane upon cell stimulation. This complex then activates flavocytochrome b, the membrane-integrated catalytic core of the enzyme system. The PX domain of this protein can bind phospholipid products of the PI(3) kinase, which suggests its role in PI(3) kinase-mediated signaling events. The phosphorylation of this protein was found to negatively regulate the enzyme activity. Alternatively spliced transcript variants encoding distinct isoforms have been observed.
Clinical significance
GWAS studies showed that Crohn's disease patient with certain SNPs in NCF4 are more susceptible to get Crohn's disease.[3] Crohn's patient with rs4821544 variants showed a decreased reactive oxygen species after stimulation with GM-CSF which is a proinflammtory cytokine.[4]
↑Zhan S, Vazquez N, Zhan S, Wientjes FB, Budarf ML, Schrock E, Ried T, Green ED, Chanock SJ (Nov 1996). "Genomic structure, chromosomal localization, start of transcription, and tissue expression of the human p40-phox, a new component of the nicotinamide adenine dinucleotide phosphate-oxidase complex". Blood. 88 (7): 2714–21. PMID8839867.
↑Somasundaram R, Deuring JJ, van der Woude CJ, Peppelenbosch MP, Fuhler GM (2012). "Linking risk conferring mutations in NCF4 to functional consequences in Crohn's disease". Gut. 61 (7): 1097, author reply 1097–8. doi:10.1136/gutjnl-2011-301344. PMID22027479.
↑Grandvaux N, Grizot S, Vignais PV, Dagher MC (Feb 1999). "The Ku70 autoantigen interacts with p40phox in B lymphocytes". J. Cell Sci. 112 ( Pt 4) (4): 503–13. PMID9914162.
↑Lapouge K, Smith SJ, Groemping Y, Rittinger K (Mar 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 (12): 10121–8. doi:10.1074/jbc.M112065200. PMID11796733.
↑Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP, Fuchs A, Vignais PV, Timmins PA, Dagher MC, Pebay-Peyroula E (Mar 2001). "Small angle neutron scattering and gel filtration analyses of neutrophil NADPH oxidase cytosolic factors highlight the role of the C-terminal end of p47phox in the association with p40phox". Biochemistry. 40 (10): 3127–33. doi:10.1021/bi0028439. PMID11258927.
↑Sathyamoorthy M, de Mendez I, Adams AG, Leto TL (Apr 1997). "p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain". J. Biol. Chem. 272 (14): 9141–6. doi:10.1074/jbc.272.14.9141. PMID9083043.
↑Wientjes FB, Reeves EP, Soskic V, Furthmayr H, Segal AW (Nov 2001). "The NADPH oxidase components p47(phox) and p40(phox) bind to moesin through their PX domain". Biochem. Biophys. Res. Commun. 289 (2): 382–8. doi:10.1006/bbrc.2001.5982. PMID11716484.
Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Tsunawaki S, Mizunari H, Nagata M, Tatsuzawa O, Kuratsuji T (1994). "A novel cytosolic component, p40phox, of respiratory burst oxidase associates with p67phox and is absent in patients with chronic granulomatous disease who lack p67phox". Biochem. Biophys. Res. Commun. 199 (3): 1378–87. doi:10.1006/bbrc.1994.1383. PMID8147882.
Someya A, Nagaoka I, Nunoi H, Yamashita T (1996). "Translocation of guinea pig p40-phox during activation of NADPH oxidase". Biochim. Biophys. Acta. 1277 (3): 217–25. doi:10.1016/s0005-2728(96)00099-0. PMID8982388.
Sathyamoorthy M, de Mendez I, Adams AG, Leto TL (1997). "p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain". J. Biol. Chem. 272 (14): 9141–6. doi:10.1074/jbc.272.14.9141. PMID9083043.
Grogan A, Reeves E, Keep N, Wientjes F, Totty NF, Burlingame AL, Hsuan JJ, Segal AW (1997). "Cytosolic phox proteins interact with and regulate the assembly of coronin in neutrophils". J. Cell Sci. 110 ( Pt 24) (24): 3071–81. PMID9365277.
Fuchs A, Bouin AP, Rabilloud T, Vignais PV (1997). "The 40-kDa component of the phagocyte NADPH oxidase (p40phox) is phosphorylated during activation in differentiated HL60 cells". Eur. J. Biochem. 249 (2): 531–9. doi:10.1111/j.1432-1033.1997.00531.x. PMID9370364.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Bouin AP, Grandvaux N, Vignais PV, Fuchs A (1998). "p40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process". J. Biol. Chem. 273 (46): 30097–103. doi:10.1074/jbc.273.46.30097. PMID9804763.
Grandvaux N, Grizot S, Vignais PV, Dagher MC (1999). "The Ku70 autoantigen interacts with p40phox in B lymphocytes". J. Cell Sci. 112 ( Pt 4) (4): 503–13. PMID9914162.
Nishiyama A, Ohno T, Iwata S, Matsui M, Hirota K, Masutani H, Nakamura H, Yodoi J (1999). "Demonstration of the interaction of thioredoxin with p40phox, a phagocyte oxidase component, using a yeast two-hybrid system". Immunol. Lett. 68 (1): 155–9. doi:10.1016/S0165-2478(99)00045-0. PMID10397171.
Hasebe T, Someya A, Nagaoka I (1999). "Identification of a splice variant mRNA of p40phox, an NADPH oxidase component of phagocytes". FEBS Lett. 455 (3): 257–61. doi:10.1016/S0014-5793(99)00905-9. PMID10437784.
Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE, Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O, Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD, O'Brien KP (1999). "The DNA sequence of human chromosome 22". Nature. 402 (6761): 489–95. doi:10.1038/990031. PMID10591208.
Vergnaud S, Paclet MH, El Benna J, Pocidalo MA, Morel F (2000). "Complementation of NADPH oxidase in p67-phox-deficient CGD patients p67-phox/p40-phox interaction". Eur. J. Biochem. 267 (4): 1059–67. doi:10.1046/j.1432-1327.2000.01097.x. PMID10672014.
Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP, Fuchs A, Vignais PV, Timmins PA, Dagher MC, Pebay-Peyroula E (2001). "Small angle neutron scattering and gel filtration analyses of neutrophil NADPH oxidase cytosolic factors highlight the role of the C-terminal end of p47phox in the association with p40phox". Biochemistry. 40 (10): 3127–33. doi:10.1021/bi0028439. PMID11258927.
