Neutrophil cytosolic factor 4

Last updated
NCF4
Protein NCF4 PDB 1h6h.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NCF4 , NCF, P40PHOX, SH3PXD4, Neutrophil cytosolic factor 4, CGD3
External IDs OMIM: 601488 MGI: 109186 HomoloGene: 525 GeneCards: NCF4
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000631
NM_013416

NM_008677

RefSeq (protein)

NP_000622
NP_038202

NP_032703

Location (UCSC) Chr 22: 36.86 – 36.88 Mb Chr 15: 78.13 – 78.15 Mb
PubMed search [3] [4]
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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Chronic granulomatous disease</span> Hereditary disease group

Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens. This leads to the formation of granulomas in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.

Respiratory burst is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types.

NADPH oxidase is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.

<span class="mw-page-title-main">NOX2</span> Protein-coding gene in the species Homo sapiens

NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene. The protein is a superoxide generating enzyme which forms reactive oxygen species (ROS).

Anthony (Tony) Segal MD PhD FRS FMedSci is a British physician/scientist.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

<span class="mw-page-title-main">PX domain</span>

The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.

<span class="mw-page-title-main">NCF1C</span>

Putative neutrophil cytosol factor 1C is a protein that in humans is encoded by the NCF1C gene. It relates to a type of white blood cell called a neutrophil. The Neutrophil Cytosolic Factor 1C (NCF1C) gene is responsible for encoding the 47 kDA cytosolic subunit of NADPH oxidase. The NCF1C gene is located near two pseudogenes and when the NCF1C gene recombines with them, the NCF1C gene will inactivate and can lead to chronic granulomatous disease.

<span class="mw-page-title-main">Neutrophil cytosolic factor 2</span> Protein-coding gene in the species Homo sapiens

Neutrophil cytosol factor 2 is a protein that in humans is encoded by the NCF2 gene.

<span class="mw-page-title-main">Neutrophil cytosolic factor 1</span> Protein-coding gene in the species Homo sapiens

Neutrophil cytosol factor 1, also known as p47phox, is a protein that in humans is encoded by the NCF1 gene.

<span class="mw-page-title-main">NOX1</span> Protein-coding gene in the species Homo sapiens

NADPH oxidase 1 is an enzyme that in humans is encoded by the NOX1 gene.

<span class="mw-page-title-main">Cytochrome b-245, alpha polypeptide</span> Protein-coding gene in the species Homo sapiens

Cytochrome b-245 light chain is a protein that in humans is encoded by the CYBA gene involved in superoxide production and phagocytosis.

<span class="mw-page-title-main">RHO protein GDP dissociation inhibitor</span>

RHO protein GDP dissociation inhibitor of Rho proteins, regulates GDP/GTP exchange.

<span class="mw-page-title-main">RAC2</span> Protein-coding gene in the species Homo sapiens

Rac2 is a small signaling G protein, and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RAC2.

<span class="mw-page-title-main">Dual oxidase 2</span> Protein-coding gene in the species Homo sapiens

Dual oxidase 2, also known as DUOX2 or ThOX2, is an enzyme that in humans is encoded by the DUOX2 gene. Dual oxidase is an enzyme that was first identified in the mammalian thyroid gland. In humans, two isoforms are found; hDUOX1 and hDUOX2. The protein location is not exclusive to thyroid tissue; hDUOX1 is prominent in airway epithelial cells and hDUOX2 in the salivary glands and gastrointestinal tract.

<span class="mw-page-title-main">NOX5</span> Protein-coding gene in the species Homo sapiens

NADPH oxidase, EF-hand calcium binding domain 5, also known as NOX5, is a protein which in humans is encoded by the NOX5 gene.

<span class="mw-page-title-main">NOXO1</span> Protein-coding gene in the species Homo sapiens

NADPH oxidase organizer 1 is an enzyme that in humans is encoded by the NOXO1 gene.

<span class="mw-page-title-main">NOX3</span> Protein-coding gene in the species Homo sapiens

NADPH oxidase 3 is an enzyme that in humans is encoded by the NOX3 gene.

p22phox Protein, also known as the human neutrophil cytochrome b light chain (CYBA), is an essential component of the membrane-associated enzyme phagocyte NADPH-oxidase This enzyme uses NADH or NADPH as the electron donor for the one electron reduction of oxygen to produce superoxide anion, a reactive oxygen species (ROS), and a functionally important step for the antimicrobial activity of phagocytic cells. p22phox is also expressed in many other human cells such as endothelial and vascular smooth muscle cells, including those within the coronary arteries. Specific polymorphisms of the CYBA gene have been identified that are associated with a decreased risk of coronary artery disease (CAD).

Edgar Pick is an Israeli immunologist who is Professor Emeritus of Immunology in the Department of Clinical Microbiology and Immunology at the Sackler Faculty of Medicine at Tel Aviv University, Israel.

References

  1. 1 2 3 ENSG00000100365 GRCh38: Ensembl release 89: ENSG00000275990, ENSG00000100365 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000071715 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. "Entrez Gene: NCF4 neutrophil cytosolic factor 4, 40kDa".
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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