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NCF4
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1H6H, 1OEY, 1W6X, 1W70, 1Z9Q, 2DYB
Identifiers
Aliases	NCF4, NCF, P40PHOX, SH3PXD4, Neutrophil cytosolic factor 4, CGD3
External IDs	OMIM: 601488; MGI: 109186; HomoloGene: 525; GeneCards: NCF4; OMA:NCF4 - orthologs
Gene location (Human)
Chr.	Chromosome 22 (human)
End	36,878,017 bp
Gene location (Mouse)
Chr.	Chromosome 15 (mouse)
End	78,146,780 bp
RNA expression pattern
	Top expressed in
	blood; ; spleen; ; granulocyte; ; bone marrow; ; monocyte; ; bone marrow cells; ; appendix; ; lymph node; ; synovial membrane; ; placenta;
	Top expressed in
	granulocyte; ; blood; ; tibiofemoral joint; ; spleen; ; mesenteric lymph nodes; ; bone marrow; ; fetal liver hematopoietic progenitor cell; ; stroma of bone marrow; ; embryo; ; internal carotid artery;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	protein dimerization activity; phosphatidylinositol-3-phosphate binding; protein binding; phosphatidylinositol binding; lipid binding; superoxide-generating NADPH oxidase activator activity;
Cellular component	cytoplasm; cytosol; endosome; membrane; phagolysosome; endosome membrane; trans-Golgi network; NADPH oxidase complex;
Biological process	vascular endothelial growth factor receptor signaling pathway; immune response; positive regulation of catalytic activity; vesicle-mediated transport; phagocytosis; respiratory burst; superoxide metabolic process; antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent; cellular response to oxidative stress; cell redox homeostasis;
	Sources:Amigo / QuickGO
Orthologs
	4689
	17972
	ENSG00000275990; ENSG00000100365
	ENSMUSG00000071715
	Q15080
	P97369
	NM_000631; NM_013416
	NM_008677
	NP_000622; NP_038202
	NP_032703
	Wikidata
View/Edit Human	View/Edit Mouse

Neutrophil cytosol factor 4 is a protein that in humans is encoded by the NCF4 gene.^[5]^[6]

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.^[7] Crohn's patient with rs4821544 variants showed a decreased reactive oxygen species after stimulation with GM-CSF which is a proinflammtory cytokine.^[8]

Interactions

Neutrophil cytosolic factor 4 has been shown to interact with Ku70,^[9] Neutrophil cytosolic factor 1^[10]^[11]^[12] and Moesin.^[13]

References

^ ^a ^b ^c ENSG00000100365 GRCh38: Ensembl release 89: ENSG00000275990, ENSG00000100365 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000071715 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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. doi:10.1182/blood.V88.7.2714.bloodjournal8872714. PMID 8839867.
^ "Entrez Gene: NCF4 neutrophil cytosolic factor 4, 40kDa".
^ 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.
^ 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. S2CID 5315006.
^ 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. doi:10.1242/jcs.112.4.503. PMID 9914162.
^ 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.
^ 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.
^ 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.
^ 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.

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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. doi:10.1242/jcs.110.24.3071. 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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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.