Details for: NCF2

Gene ID: 4688

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: NCF2

Ensembl ID: ENSG00000116701

Description: neutrophil cytosolic factor 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD14-low, CD16-positive monocyte CL0002396
    CSI 73.88
    rCSI 56.92%
    PRS 97.52
  • elicited macrophage CL0000861
    CSI 31.82
    rCSI 29.22%
    PRS 97.99
  • Hofbauer cell CL3000001
    CSI 23.9
    rCSI 45.12%
    PRS 97.93
  • alveolar macrophage CL0000583
    CSI 19.17
    rCSI 31.58%
    PRS 96.38
  • CD14-positive monocyte CL0001054
    CSI 18.98
    rCSI 23.64%
    PRS 98.5
  • classical monocyte CL0000860
    CSI 14.87
    rCSI 22.05%
    PRS 97.14
  • intermediate monocyte CL0002393
    CSI 14.59
    rCSI 22.01%
    PRS 97.89
  • dendritic cell, human CL0001056
    CSI 13.32
    rCSI 20.45%
    PRS 98.31
  • granulocyte CL0000094
    CSI 11.75
    rCSI 17.95%
    PRS 97.58
  • non-classical monocyte CL0000875
    CSI 11.44
    rCSI 18.34%
    PRS 97.85
  • mononuclear phagocyte CL0000113
    CSI 10.29
    rCSI 22.66%
    PRS 97.06
  • CD14-positive, CD16-negative classical monocyte CL0002057
    CSI 9.6
    rCSI 58.1%
    PRS 98.23
  • myeloid leukocyte CL0000766
    CSI 8.41
    rCSI 7.76%
    PRS 96.51
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 7.73
    rCSI 10.13%
    PRS 98.63
  • promonocyte CL0000559
    CSI 7.7
    rCSI 13.19%
    PRS 96.33
  • conventional dendritic cell CL0000990
    CSI 6.95
    rCSI 5.8%
    PRS 89.85
  • pro-B cell CL0000826
    CSI 5.85
    rCSI 4.84%
    PRS 96.16
  • monocyte CL0000576
    CSI 5.7
    rCSI 10.31%
    PRS 96.24
  • Kupffer cell CL0000091
    CSI 5.64
    rCSI 12.89%
    PRS 96.25
  • alternatively activated macrophage CL0000890
    CSI 5.44
    rCSI 6.84%
    PRS 98.39
  • lung macrophage CL1001603
    CSI 5.07
    rCSI 11.33%
    PRS 98.16
  • pancreatic ductal cell CL0002079
    CSI 4.56
    rCSI 8.86%
    PRS 95.94
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 4.34
    rCSI 5.24%
    PRS 97.93
  • lung ciliated cell CL1000271
    CSI 4.23
    rCSI 4.89%
    PRS 91.74
  • mature NK T cell CL0000814
    CSI 3.92
    rCSI 5.02%
    PRS 97.15
  • inflammatory macrophage CL0000863
    CSI 3.62
    rCSI 6.19%
    PRS 99.35
  • lung interstitial macrophage CL4033043
    CSI 3.55
    rCSI 7.96%
    PRS 99.08
  • professional antigen presenting cell CL0000145
    CSI 3.44
    rCSI 11.85%
    PRS 96.35
  • neutrophil CL0000775
    CSI 3.01
    rCSI 16.84%
    PRS 93.04
  • dendritic cell CL0000451
    CSI 2.87
    rCSI 3.53%
    PRS 94.83
  • multi-ciliated epithelial cell CL0005012
    CSI 2.63
    rCSI 2.62%
    PRS 91.45
  • colon macrophage CL0009038
    CSI 2.56
    rCSI 11.82%
    PRS 98.84
  • Langerhans cell CL0000453
    CSI 2.51
    rCSI 3.83%
    PRS 98.4
  • myeloid dendritic cell CL0000782
    CSI 2.27
    rCSI 3.29%
    PRS 99.1
  • promyelocyte CL0000836
    CSI 1.8
    rCSI 2.59%
    PRS 96.18
  • myeloid dendritic cell, human CL0001057
    CSI 0.93
    rCSI 5.21%
    PRS 98.95
  • myelocyte CL0002193
    CSI 0.62
    rCSI 4.06%
    PRS 97.92

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [NCF2](/details-gene/4688) (Neutrophil Cytosolic Factor 2), also known as p67phox, is a protein-coding gene located on chromosome 1q25.3. It encodes a critical cytosolic subunit of the multi-protein NADPH oxidase complex. This complex is responsible for generating superoxide, a key component of the respiratory burst in phagocytic cells, which is essential for microbial killing. The expression profile of [NCF2](/details-gene/4688) is highly specific to cells of the myeloid lineage, with particularly high significance in various monocyte and macrophage populations. Functionally, it is integral to the [innate immune response (GO:0045087)](https://www.ebi.ac.uk/QuickGO/term/GO:0045087) and [phagocytosis (GO:0006909)](https://www.ebi.ac.uk/QuickGO/term/GO:0006909). Mutations in this gene are a cause of autosomal recessive chronic granulomatous disease (CGD), an immunodeficiency disorder characterized by an inability of phagocytes to kill certain pathogens ([Link](https://omim.org/entry/233710)). ## Cellular Roles and Expression Landscape The expression pattern of [NCF2](/details-gene/4688) firmly establishes its role as a key functional component of the mononuclear phagocyte system and granulocytes. **Overall**, the gene shows the highest significance in [CD14-low, CD16-positive monocyte](/details-cell/CL0002396) (CSI: 73.88), indicating it is a defining marker of this non-classical monocyte subset, which is involved in patrolling blood vessels and responding to inflammation. The gene's prominence extends across a spectrum of phagocytic cells, highlighting its fundamental role in innate immunity. It is highly significant in various macrophage populations, including [elicited macrophage](/details-cell/CL0000861), placental [Hofbauer cell](/details-cell/CL3000001), and [alveolar macrophage](/details-cell/CL0000583). Furthermore, its high CSI values in other monocyte subsets such as [CD14-positive monocyte](/details-cell/CL0001054) and [classical monocyte](/details-cell/CL0000860), as well as in [granulocyte](/details-cell/CL0000094) and [dendritic cell, human](/details-cell/CL0001056), underscore its broad importance across the myeloid lineage. This collective expression profile suggests that [NCF2](/details-gene/4688) is not merely a lineage marker but a crucial "workhorse" gene essential for the primary microbicidal functions of these cells. ## Pathways and Molecular Function [NCF2](/details-gene/4688) is functionally annotated as a central player in the host's [cellular defense response (GO:0006968)](https://www.ebi.ac.uk/QuickGO/term/GO:0006968). Its protein product is a key component of the [Nadph oxidase complex (GO:0043020)](https://www.ebi.ac.uk/QuickGO/term/GO:0043020), where it acts as an activator ([superoxide-generating nadph oxidase activator activity (GO:0016176)](https://www.ebi.ac.uk/QuickGO/term/GO:0016176)). This role is central to the process of [respiratory burst (GO:0045730)](https://www.ebi.ac.uk/QuickGO/term/GO:0045730), leading to [superoxide anion generation (GO:0042554)](https://www.ebi.ac.uk/QuickGO/term/GO:0042554) within the phagolysosome to destroy ingested pathogens. This is strongly supported by its involvement in the Reactome pathway [Ros and rns production in phagocytes (R-HSA-1222556)](https://reactome.org/content/detail/R-HSA-1222556). Mechanistically, [NCF2](/details-gene/4688) functions as an adaptor protein that facilitates the assembly of the active NADPH oxidase at the membrane. It achieves this through its ability for [protein binding (GO:0005515)](https://www.ebi.ac.uk/QuickGO/term/GO:0005515) and specifically [small gtpase binding (GO:0031267)](https://www.ebi.ac.uk/QuickGO/term/GO:0031267). This is consistent with its role in pathways like [Signaling by rho gtpases (R-HSA-194315)](https://reactome.org/content/detail/R-HSA-194315), particularly the [Rac1 gtpase cycle (R-HSA-9013149)](https://reactome.org/content/detail/R-HSA-9013149) and [Rac2 gtpase cycle (R-HSA-9013404)](https://reactome.org/content/detail/R-HSA-9013404), where it links GTPase activation to the recruitment and activation of the oxidase complex ([Link](https://doi.org/10.1016/s1097-2765(05)00091-2)). This core function places it as an indispensable node within the broader [Innate immune system (R-HSA-168249)](https://reactome.org/content/detail/R-HSA-168249) pathway. ## Research Directions The well-established role of [NCF2](/details-gene/4688) in phagocyte-mediated immunity provides a foundation for more nuanced investigations into its regulation and context-specific functions. **Proposed Hypotheses:** 1. Given the diverse array of macrophage subtypes where [NCF2](/details-gene/4688) is highly expressed (e.g., [alveolar macrophage](/details-cell/CL0000583), [Hofbauer cell](/details-cell/CL3000001)), it is hypothesized that the assembly and activation of the [NCF2](/details-gene/4688)-containing NADPH oxidase complex are differentially regulated in these tissue-resident macrophages to tailor the intensity and duration of the oxidative burst to their specific microenvironments (e.g., sterile inflammation vs. pathogen clearance). 2. Considering [NCF2](/details-gene/4688)'s function as a binding partner for Rho GTPases and other oxidase subunits, it is hypothesized that pathogen-specific signaling pathways induce distinct post-translational modifications on the [NCF2](/details-gene/4688) protein, which in turn dictate the composition and subcellular localization of the active NADPH oxidase complex, leading to specialized antimicrobial responses. **Experimental Approach:** To test the first hypothesis, one could isolate primary macrophages from distinct tissues, such as alveolar macrophages from bronchoalveolar lavage fluid and Hofbauer cells from placental tissue. These cell populations would be stimulated *ex vivo* with a panel of microbial ligands (e.g., LPS, zymosan). The resulting oxidative burst could be quantified using assays for reactive oxygen species (ROS) production. Parallel analysis of [NCF2](/details-gene/4688) expression, phosphorylation status, and its interaction with other oxidase components (e.g., NCF1, RAC2) could be performed via immunoprecipitation followed by mass spectrometry to determine if tissue-specific regulatory mechanisms correlate with functional differences in ROS production. **Therapeutic Potential:** [NCF2](/details-gene/4688) is not a candidate for therapeutic inhibition, as loss-of-function mutations cause chronic granulomatous disease ([233710](https://omim.org/entry/233710)), a severe immunodeficiency. Therapeutic strategies would therefore focus on restoring its function. The gene represents a prime target for gene therapy, where a functional copy of the [NCF2](/details-gene/4688) gene could be introduced into autologous hematopoietic stem cells, which would then be re-infused into the patient. This approach aims to permanently correct the genetic defect in all subsequent myeloid progeny, including neutrophils and macrophages, thereby restoring the patient's ability to mount an effective oxidative burst against pathogens.

Genular Protein ID: 2143487864

Symbol: NCF2_HUMAN

Name: Neutrophil cytosol factor 2

UniProtKB Accession Codes:

P19878 B2R6Q1 B4DKQ7 B4DQA7 E9PHJ2 E9PHX3 Q2PP06 Q8NFC7 Q9BV51

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 3 CTD 1 ChiTaRS 1 ComplexPortal 3 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 EMBL 23 Ensembl 5 EvolutionaryTrace 1 ExpressionAtlas 1 GO 16 Gene3D 2 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 IDEAL 1 InParanoid 1 IntAct 1 InterPro 10 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 7 PDBsum 7 PIR 1 PRIDE 1 PRINTS 2 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 Reactome 8 RefSeq 6 SASBDB 1 SIGNOR 1 SMART 3 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 1692159

Title: Cloning of a 67-kD neutrophil oxidase factor with similarity to a noncatalytic region of p60c-src.

PubMed ID: 1692159

DOI: 10.1126/science.1692159

PubMed ID: 7903171

Title: Characterization of the p67phox gene: genomic organization and restriction fragment length polymorphism analysis for prenatal diagnosis in chronic granulomatous disease.

PubMed ID: 7903171

PubMed ID: 12207919

Title: Expression of a p67(phox) homolog in Caco-2 cells giving O(2)(-)-reconstituting ability to cytochrome b(558) together with recombinant p47(phox).

PubMed ID: 12207919

DOI: 10.1016/s0006-291x(02)02059-4

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 11278853

Title: JFC1, a novel tandem C2 domain-containing protein associated with the leukocyte NADPH oxidase.

PubMed ID: 11278853

DOI: 10.1074/jbc.m011167200

PubMed ID: 12716910

Title: Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases.

PubMed ID: 12716910

DOI: 10.1074/jbc.m212856200

PubMed ID: 15642721

Title: The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase activation by interaction with p67phox and Rac-2.

PubMed ID: 15642721

DOI: 10.1096/fj.04-2377fje

PubMed ID: 17290225

Title: Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding.

PubMed ID: 17290225

DOI: 10.1038/sj.emboj.7601561

PubMed ID: 11090627

Title: Structure of the TPR domain of p67phox in complex with Rac.GTP.

PubMed ID: 11090627

DOI: 10.1016/s1097-2765(05)00091-2

PubMed ID: 12169629

Title: Diverse recognition of non-PxxP peptide ligands by the SH3 domains from p67(phox), Grb2 and Pex13p.

PubMed ID: 12169629

DOI: 10.1093/emboj/cdf428

PubMed ID: 12887891

Title: PB1 domain-mediated heterodimerization in NADPH oxidase and signaling complexes of atypical protein kinase C with Par6 and p62.

PubMed ID: 12887891

DOI: 10.1016/s1097-2765(03)00246-6

PubMed ID: 8286749

Title: Autosomal recessive chronic granulomatous disease with absence of the 67-kD cytosolic NADPH oxidase component: identification of mutation and detection of carriers.

PubMed ID: 8286749

PubMed ID: 9070911

Title: Identification of a double mutation (D160V-K161E) (sic) in the p67phox gene of a chronic granulomatous disease patient.

PubMed ID: 9070911

DOI: 10.1006/bbrc.1997.6204

PubMed ID: 10498624

Title: Molecular characterization of autosomal recessive chronic granulomatous disease caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase component p67-phox.

PubMed ID: 10498624

PubMed ID: 10598813

Title: Autosomal recessive chronic granulomatous disease caused by novel mutations in NCF-2, the gene encoding the p67-phox component of phagocyte NADPH oxidase.

PubMed ID: 10598813

DOI: 10.1007/s004390051131

PubMed ID: 11112388

Title: Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (first update).

PubMed ID: 11112388

DOI: 10.1006/bcmd.2000.0333

PubMed ID: 16937026

Title: Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia.

PubMed ID: 16937026

DOI: 10.1007/s10038-006-0039-8

PubMed ID: 18625437

Title: Focus on FOCIS: the continuing diagnostic challenge of autosomal recessive chronic granulomatous disease.

PubMed ID: 18625437

DOI: 10.1016/j.clim.2008.05.008

PubMed ID: 19624736

Title: Four different NCF2 mutations in six families from Turkey and an overview of NCF2 gene mutations.

PubMed ID: 19624736

DOI: 10.1111/j.1365-2362.2009.02195.x

PubMed ID: 20167518

Title: Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update).

PubMed ID: 20167518

DOI: 10.1016/j.bcmd.2010.01.009

PubMed ID: 23910690

Title: Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients.

PubMed ID: 23910690

DOI: 10.1016/j.jaci.2013.05.039

PubMed ID: 27535533

Title: Analysis of protein-coding genetic variation in 60,706 humans.

PubMed ID: 27535533

DOI: 10.1038/nature19057

Sequence Information:

  • Length: 526
  • Mass: 59762
  • Checksum: EC136766E1915376
  • Sequence:
    • MSLVEAISLW NEGVLAADKK DWKGALDAFS AVQDPHSRIC FNIGCMYTIL KNMTEAEKAF 
TRSINRDKHL AVAYFQRGML YYQTEKYDLA IKDLKEALIQ LRGNQLIDYK ILGLQFKLFA 
CEVLYNIAFM YAKKEEWKKA EEQLALATSM KSEPRHSKID KAMECVWKQK LYEPVVIPVG 
KLFRPNERQV AQLAKKDYLG KATVVASVVD QDSFSGFAPL QPQAAEPPPR PKTPEIFRAL 
EGEAHRVLFG FVPETKEELQ VMPGNIVFVL KKGNDNWATV MFNGQKGLVP CNYLEPVELR 
IHPQQQPQEE SSPQSDIPAP PSSKAPGRPQ LSPGQKQKEE PKEVKLSVPM PYTLKVHYKY 
TVVMKTQPGL PYSQVRDMVS KKLELRLEHT KLSYRPRDSN ELVPLSEDSM KDAWGQVKNY 
CLTLWCENTV GDQGFPDEPK ESEKADANNQ TTEPQLKKGS QVEALFSYEA TQPEDLEFQE 
GDIILVLSKV NEEWLEGECK GKVGIFPKVF VEDCATTDLE STRREV

Genular Protein ID: 1770991100

Symbol: A0A8V8TMB9_HUMAN

Name: N/A

UniProtKB Accession Codes:

A0A8V8TMB9

Database IDs:

ARBA 3 CDD 3 CTD 1 EMBL 1 Ensembl 2 GO 4 Gene3D 2 GeneTree 1 HGNC 1 InterPro 10 NCBI Taxonomy 1 PANTHER 2 PRINTS 2 PROSITE 5 PROSITE-ProRule 2 PeptideAtlas 2 Pfam 3 Proteomes 2 ProteomicsDB 1 RefSeq 1 SAM 1 SMART 3 SMR 1 SUPFAM 3

Citations:

PubMed ID: 11237011

Title: Initial sequencing and analysis of the human genome.

PubMed ID: 11237011

DOI: 10.1038/35057062

PubMed ID: 15496913

Title: Finishing the euchromatic sequence of the human genome.

PubMed ID: 15496913

DOI: 10.1038/nature03001

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

Sequence Information:

  • Length: 490
  • Mass: 55653
  • Checksum: 35A09739FEE7E402
  • Sequence:
    • MSLVEAISLW NEGVLAADKK DWKGALDAFS AVQDPHSRIC FNIGCMYTIL KNMTEAEKAF 
TRSINRDKHL AVAYFQRGML YYQTEKYDLA IKDLKEALIQ LRGNQLIDYK ILGLQFKLFA 
CEVLYNIAFM YAKKEEWKKA EEQLALATSM KSEPRHSKID KAMECVWVVA SVVDQDSFSG 
FAPLQPQAAE PPPRPKTPEI FRALEGEAHR VLFGFVPETK EELQVMPGNI VFVLKKGNDN 
WATVMFNGQK GLVPCNYLEP VELRIHPQQQ PQEESSPQSD IPAPPSSKAP GRPQLSPGQK 
QKEEPKEVKL SVPMPYTLKV HYKYTVVMKT QPGLPYSQVR DMVSKKLELR LEHTKLSYRP 
RDSNELVPLS EDSMKDAWGQ VKNYCLTLWC ENTVGDQGFP DEPKESEKAD ANNQTTEPQL 
KKGSQVEALF SYEATQPEDL EFQEGDIILV LSKVNEEWLE GECKGKVGIF PKVFVEDCAT 
TDLESTRREV