Neutrophil cytosolic factor 4

Neutrophil cytosolic factor 4, 40kDa

PDB rendering based on 1h6h.

Available structures

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 • antigen processing and presentation of exogenous peptide antigen via MHC class I • positive regulation of catalytic activity • interaction with host • oxidation-reduction process • phagosome maturation
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 22:
37.26 – 37.27 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

↑ Zhan S, Vazquez N, Zhan S, Wientjes FB, Budarf ML, Schrock E et al. (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. CS1 maint: Date and year (link)
↑ "Entrez Gene: NCF4 neutrophil cytosolic factor 4, 40kDa".
↑ Muise AM, Xu W, Guo CH, Walters TD, Wolters VM, Fattouh R et al. (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.
↑ 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.
↑ 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. CS1 maint: Date and year (link)
↑ 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. CS1 maint: Date and year (link)
↑ Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP et al. (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. CS1 maint: Date and year (link)
↑ 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. CS1 maint: Date and year (link)
↑ 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. CS1 maint: Date and year (link)

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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 et al. (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.
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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 et al. (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.
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Grizot S, Grandvaux N, Fieschi F, Fauré J, Massenet C, Andrieu JP et al. (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.