Neutrophil cytosolic factor 4 explained

Neutrophil cytosol factor 4 is a protein that in humans is encoded by the NCF4 gene.^{[1] [2]}

Function

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]

Interactions

Neutrophil cytosolic factor 4 has been shown to interact with Ku70,^[5] Neutrophil cytosolic factor 1^{[6] [7] [8]} and Moesin.^[9]

Further reading

• Matute JD, Arias AA, Dinauer MC, Patiño PJ . p40phox: the last NADPH oxidase subunit . Blood Cells Mol. Dis. . 35 . 2 . 291–302 . 2006 . 16102984 . 10.1016/j.bcmd.2005.06.010 .
• Jones JH . The essence of operating room nursing. Paramedical personnel . Australas Nurses J . 7 . 1 . 44–5, 63–4 . 1977 . 243433 .
• Leto TL, Adams AG, de Mendez I . Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets . Proc. Natl. Acad. Sci. U.S.A. . 91 . 22 . 10650–4 . 1994 . 7938008 . 45079 . 10.1073/pnas.91.22.10650 . 1994PNAS...9110650L . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Tsunawaki S, Mizunari H, Nagata M, Tatsuzawa O, Kuratsuji T . 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 . 1994 . 8147882 . 10.1006/bbrc.1994.1383 .
• Wientjes FB, Hsuan JJ, Totty NF, Segal AW . p40phox, a third cytosolic component of the activation complex of the NADPH oxidase to contain src homology 3 domains . Biochem. J. . 296 (Pt 3) . 3 . 557–61 . 1993 . 8280052 . 1137734 . 10.1042/bj2960557.
• Dusi S, Donini M, Rossi F . Mechanisms of NADPH oxidase activation: translocation of p40phox, Rac1 and Rac2 from the cytosol to the membranes in human neutrophils lacking p47phox or p67phox . Biochem. J. . 314 (Pt 2) . 2 . 409–12 . 1996 . 8670049 . 1217064 . 10.1042/bj3140409.
• Someya A, Nagaoka I, Nunoi H, Yamashita T . Translocation of guinea pig p40-phox during activation of NADPH oxidase . Biochim. Biophys. Acta . 1277 . 3 . 217–25 . 1996 . 8982388 . 10.1016/s0005-2728(96)00099-0 . free .
• Sathyamoorthy M, de Mendez I, Adams AG, Leto TL . p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain . J. Biol. Chem. . 272 . 14 . 9141–6 . 1997 . 9083043 . 10.1074/jbc.272.14.9141 . free .
• Grogan A, Reeves E, Keep N, Wientjes F, Totty NF, Burlingame AL, Hsuan JJ, Segal AW . Cytosolic phox proteins interact with and regulate the assembly of coronin in neutrophils . J. Cell Sci. . 110 (Pt 24) . 24 . 3071–81 . 1997 . 10.1242/jcs.110.24.3071 . 9365277 .
• Fuchs A, Bouin AP, Rabilloud T, Vignais PV . 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 . 1997 . 9370364 . 10.1111/j.1432-1033.1997.00531.x .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Bouin AP, Grandvaux N, Vignais PV, Fuchs A . 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 . 1998 . 9804763 . 10.1074/jbc.273.46.30097 . free .
• Grandvaux N, Grizot S, Vignais PV, Dagher MC . The Ku70 autoantigen interacts with p40phox in B lymphocytes . J. Cell Sci. . 112 (Pt 4) . 4 . 503–13 . 1999 . 10.1242/jcs.112.4.503 . 9914162 .
• Nishiyama A, Ohno T, Iwata S, Matsui M, Hirota K, Masutani H, Nakamura H, Yodoi J . Demonstration of the interaction of thioredoxin with p40phox, a phagocyte oxidase component, using a yeast two-hybrid system . Immunol. Lett. . 68 . 1 . 155–9 . 1999 . 10397171 . 10.1016/S0165-2478(99)00045-0 .
• Hasebe T, Someya A, Nagaoka I . Identification of a splice variant mRNA of p40phox, an NADPH oxidase component of phagocytes . FEBS Lett. . 455 . 3 . 257–61 . 1999 . 10437784 . 10.1016/S0014-5793(99)00905-9 . 23509959 .
• 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 . The DNA sequence of human chromosome 22 . Nature . 402 . 6761 . 489–95 . 1999 . 10591208 . 10.1038/990031 . 1999Natur.402..489D . free .
• Vergnaud S, Paclet MH, El Benna J, Pocidalo MA, Morel F . Complementation of NADPH oxidase in p67-phox-deficient CGD patients p67-phox/p40-phox interaction . Eur. J. Biochem. . 267 . 4 . 1059–67 . 2000 . 10672014 . 10.1046/j.1432-1327.2000.01097.x .
• Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP, Fuchs A, Vignais PV, Timmins PA, Dagher MC, Pebay-Peyroula E . 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 . 2001 . 11258927 . 10.1021/bi0028439 .

Notes and References

1. Zhan S, Vazquez N, Zhan S, Wientjes FB, Budarf ML, Schrock E, Ried T, Green ED, Chanock SJ . 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 . Nov 1996 . 8839867 . 10.1182/blood.V88.7.2714.bloodjournal8872714. free .
2. Web site: Entrez Gene: NCF4 neutrophil cytosolic factor 4, 40kDa.
3. Muise AM, Xu W, Guo CH, Walters TD, Wolters VM, Fattouh R, Lam GY, Hu P, Murchie R, Sherlock M, Gana JC, Russell RK, Glogauer M, Duerr RH, Cho JH, Lees CW, Satsangi J, Wilson DC, Paterson AD, Griffiths AM, Silverberg MS, Brumell JH . NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2 . Gut . 61 . 7 . 1028–35 . 2012 . 21900546 . 3806486 . 10.1136/gutjnl-2011-300078 .
4. Somasundaram R, Deuring JJ, van der Woude CJ, Peppelenbosch MP, Fuhler GM . Linking risk conferring mutations in NCF4 to functional consequences in Crohn's disease . Gut . 61 . 7 . 1097; author reply 1097–8 . 2012 . 22027479 . 10.1136/gutjnl-2011-301344 . 5315006 .
5. Grandvaux N, Grizot S, Vignais PV, Dagher MC . The Ku70 autoantigen interacts with p40phox in B lymphocytes . J. Cell Sci. . 112 (Pt 4) . 4 . 503–13 . Feb 1999 . 10.1242/jcs.112.4.503 . 9914162 .
6. Lapouge K, Smith SJ, Groemping Y, Rittinger K . 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 . Mar 2002 . 11796733 . 10.1074/jbc.M112065200 . free .
7. Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP, Fuchs A, Vignais PV, Timmins PA, Dagher MC, Pebay-Peyroula E . 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 . Mar 2001 . 11258927 . 10.1021/bi0028439 .
8. Sathyamoorthy M, de Mendez I, Adams AG, Leto TL . p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain . J. Biol. Chem. . 272 . 14 . 9141–6 . Apr 1997 . 9083043 . 10.1074/jbc.272.14.9141 . free .
9. Wientjes FB, Reeves EP, Soskic V, Furthmayr H, Segal AW . The NADPH oxidase components p47(phox) and p40(phox) bind to moesin through their PX domain . Biochem. Biophys. Res. Commun. . 289 . 2 . 382–8 . Nov 2001 . 11716484 . 10.1006/bbrc.2001.5982 .