Neutrophil cytosolic factor 4

Neutrophil cytosolic factor 4, 40kDa
PDB rendering based on 1h6h.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1H6H​, 1OEY​, 1W6X​, 1W70​, 1Z9Q​, 2DYB​
Identifiers
Symbols	NCF4 ; NCF; P40PHOX; SH3PXD4
External IDs	OMIM: 601488 MGI: 109186 HomoloGene: 525 GeneCards: NCF4 Gene
Gene ontology Molecular function • protein binding • superoxide-generating NADPH oxidase activator activity • phosphatidylinositol-3-phosphate binding • protein dimerization activity Cellular component • cytosol • endosome membrane • membrane • phagolysosome • NADPH oxidase complex Biological process • antigen processing and presentation of peptide antigen via MHC class I • antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent • immune response • small GTPase mediated signal transduction • antigen processing and presentation of exogenous peptide antigen via MHC class I • positive regulation of catalytic activity • vascular endothelial growth factor receptor signaling pathway • interaction with host • oxidation-reduction process • phagosome maturation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4689	17972
Ensembl	ENSG00000100365	ENSMUSG00000071715
UniProt	Q15080	P97369
RefSeq (mRNA)	NM_000631	NM_008677
RefSeq (protein)	NP_000622	NP_032703
Location (UCSC)	Chr 22: 36.86 – 36.88 Mb	Chr 15: 78.24 – 78.26 Mb
PubMed search

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]

References

1. 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. PMID 8839867.
2. "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 (2012). "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. doi:10.1136/gutjnl-2011-300078. PMC 3806486. PMID 21900546.
4. 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. PMID 22027479.
5. 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. PMID 9914162.
6. 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. PMID 11796733.
7. 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. PMID 11258927.
8. 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. PMID 9083043.
9. 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. PMID 11716484.

Further reading

• Matute JD, Arias AA, Dinauer MC, Patiño PJ (2006). "p40phox: the last NADPH oxidase subunit". Blood Cells Mol. Dis. 35 (2): 291–302. doi:10.1016/j.bcmd.2005.06.010. PMID 16102984.
• Jones JH (1977). "The essence of operating room nursing. Paramedical personnel". Australas Nurses J 7 (1): 44–5, 63–4. PMID 243433.
• Leto TL, Adams AG, de Mendez I (1994). "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. doi:10.1073/pnas.91.22.10650. PMC 45079. PMID 7938008.
• 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. PMID 8125298.
• 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. PMID 8147882.
• Wientjes FB, Hsuan JJ, Totty NF, Segal AW (1993). "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. PMC 1137734. PMID 8280052.
• Dusi S, Donini M, Rossi F (1996). "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. PMC 1217064. PMID 8670049.
• 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. PMID 8982388.
• 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. PMID 9083043.
• 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. PMID 9365277.
• 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. PMID 9370364.
• 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. PMID 9373149.
• 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. PMID 9804763.
• 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. PMID 9914162.
• 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. PMID 10397171.
• 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. PMID 10437784.
• 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. PMID 10591208.
• 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. PMID 10672014.
• 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. PMID 11258927.