Details for: CLCA4

Gene ID: 22802

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: CLCA4

Ensembl ID: ENSG00000016602

Description: chloride channel accessory 4

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • colon epithelial cell CL0011108
    CSI 21.71
    rCSI 22.75%
    PRS 98.9
  • enterocyte CL0000584
    CSI 7.61
    rCSI 12.28%
    PRS 98.11
  • IgA plasma cell CL0000987
    CSI 7.55
    rCSI 7.73%
    PRS 97.55
  • keratinocyte CL0000312
    CSI 7.22
    rCSI 6.06%
    PRS 98.39
  • enterocyte of epithelium of large intestine CL0002071
    CSI 7.12
    rCSI 37.38%
    PRS 99.08
  • secretory cell CL0000151
    CSI 6.37
    rCSI 6.65%
    PRS 98.9
  • nasal mucosa goblet cell CL0002480
    CSI 5.48
    rCSI 6.35%
    PRS 98.49
  • respiratory suprabasal cell CL4033048
    CSI 5.41
    rCSI 6.94%
    PRS 99.37
  • BEST4+ enteroycte CL4030026
    CSI 5.1
    rCSI 6.35%
    PRS 98.74
  • corneal epithelial cell CL0000575
    CSI 5.02
    rCSI 14.36%
    PRS 98.97
  • conjunctival epithelial cell CL1000432
    CSI 4.8
    rCSI 7.32%
    PRS 98.72
  • dendritic cell CL0000451
    CSI 4.35
    rCSI 5.36%
    PRS 98.9
  • squamous epithelial cell CL0000076
    CSI 4.13
    rCSI 9.8%
    PRS 97.05
  • club cell CL0000158
    CSI 3.48
    rCSI 5.1%
    PRS 99
  • intestine goblet cell CL0019031
    CSI 3.02
    rCSI 2.68%
    PRS 98.64
  • respiratory basal cell CL0002633
    CSI 2.67
    rCSI 2.76%
    PRS 99.32
  • tracheal goblet cell CL1000329
    CSI 2.46
    rCSI 5.37%
    PRS 99.29
  • epithelial cell of esophagus CL0002252
    CSI 1.34
    rCSI 13.21%
    PRS 97.41
  • basal cell of epithelium of trachea CL1000348
    CSI 0.93
    rCSI 6.54%
    PRS 99.07
  • epithelial cell of urethra CL1000296
    CSI 0.75
    rCSI 19.02%
    PRS 99.11

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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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 [CLCA4](/details-gene/22802) (Chloride Channel Accessory 4) encodes a protein that belongs to the calcium-activated chloride channel (CaCC) family. While annotated as a channel accessory protein, members of this family are known to function as regulators of chloride transport and may also possess metalloprotease activity. **Overall**, expression data reveals that [CLCA4](/details-gene/22802) is a highly specific marker for epithelial cells, particularly those lining mucosal surfaces of the gastrointestinal and respiratory tracts. Its function is primarily associated with [ion channel transport (R-HSA-983712)](https://reactome.org/content/detail/R-HSA-983712) and [chloride transmembrane transport (GO:1902476)](https://www.ebi.ac.uk/QuickGO/term/GO:1902476), consistent with a crucial role in maintaining mucosal homeostasis and secretion. ## Cellular Roles and Expression Landscape The expression profile of [CLCA4](/details-gene/22802) demonstrates a highly restricted and significant role in specialized epithelial cell populations. **Overall**, the gene shows the highest significance in [colon epithelial cell](/details-cell/CL0011108)s (CSI: 21.71), underscoring its prominent role in the large intestine. Functionally, its expression is concentrated in several key epithelial systems: * **Gastrointestinal Tract:** [CLCA4](/details-gene/22802) is a key gene in various intestinal epithelial cells, including [enterocyte](/details-cell/CL0000584)s (CSI: 7.61), [enterocyte of epithelium of large intestine](/details-cell/CL0002071)s (CSI: 7.12), [BEST4+ enteroycte](/details-cell/CL4030026)s (CSI: 5.10), and [intestine goblet cell](/details-cell/CL0019031)s (CSI: 3.02). This pattern is consistent with early research identifying it as predominantly expressed in the digestive tract ([Link](https://doi.org/10.1016/s0014-5793(99)00891-1)). * **Respiratory and Ocular Surfaces:** The gene is also significantly expressed in the epithelial linings of other mucosal surfaces, including [nasal mucosa goblet cell](/details-cell/CL0002480)s (CSI: 5.48), [respiratory suprabasal cell](/details-cell/CL4033048)s (CSI: 5.41), [club cell](/details-cell/CL0000158)s (CSI: 3.48), [corneal epithelial cell](/details-cell/CL0000575)s (CSI: 5.02), and [conjunctival epithelial cell](/details-cell/CL1000432)s (CSI: 4.80). This expression in secretory cells like goblet and club cells suggests a role in regulating airway surface liquid. * **Other Barrier Tissues:** High significance in [keratinocyte](/details-cell/CL0000312)s (CSI: 7.22) and [squamous epithelial cell](/details-cell/CL0000076)s (CSI: 4.13) indicates a broader role in maintaining ion balance across stratified epithelia. Interestingly, [CLCA4](/details-gene/22802) also shows significance in [IgA plasma cell](/details-cell/CL0000987)s (CSI: 7.55), which are typically located in mucosal tissues. This may suggest a secondary role related to the mucosal immune system, although the predominant signal points to a primary function within the epithelial barrier itself. ## Pathways and Molecular Function The functional annotations for [CLCA4](/details-gene/22802) strongly align with its expression pattern in secretory epithelia. It is a key component of [stimuli-sensing channels (R-HSA-2672351)](https://reactome.org/content/detail/R-HSA-2672351) and is directly involved in [chloride channel activity (GO:0005254)](https://www.ebi.ac.uk/QuickGO/term/GO:0005254), specifically [intracellularly calcium-gated chloride channel activity (GO:0005229)](https://www.ebi.ac.uk/QuickGO/term/GO:0005229). This molecular function is critical for processes like fluid and mucus secretion at the [apical plasma membrane (GO:0016324)](https://www.ebi.ac.uk/QuickGO/term/GO:0016324) of epithelial cells. In addition to its role in ion transport, [CLCA4](/details-gene/22802) is annotated with [metalloendopeptidase activity (GO:0004222)](https://www.ebi.ac.uk/QuickGO/term/GO:0004222) and involvement in [proteolysis (GO:0006508)](https://www.ebi.ac.uk/QuickGO/term/GO:0006508). This suggests a potential dual function where the protein may undergo proteolytic processing to become active, or it may itself cleave other substrates in the extracellular environment. This enzymatic function, combined with its localization to the [extracellular region (GO:0005576)](https://www.ebi.ac.uk/QuickGO/term/GO:0005576), could be important for modifying the cellular microenvironment or other membrane-associated proteins. ## Research Directions The highly specific expression of [CLCA4](/details-gene/22802) in mucosal epithelial cells, combined with its function as a chloride channel regulator, points toward a critical role in diseases characterized by defective ion transport and mucus secretion. **Proposed Hypotheses:** 1. Given its high significance in [colon epithelial cell](/details-cell/CL0011108)s and [intestine goblet cell](/details-cell/CL0019031)s, and the established role of CLCA family members in cystic fibrosis pathophysiology ([Link](https://doi.org/10.1007/s00439-004-1190-y)), [CLCA4](/details-gene/22802) is a key modulator of intestinal fluid secretion and mucus hydration. Its dysregulation may contribute to barrier dysfunction in inflammatory bowel disease (IBD) or the pathophysiology of secretory diarrheas. 2. The annotated [metalloendopeptidase activity (GO:0004222)](https://www.ebi.ac.uk/QuickGO/term/GO:0004222) of [CLCA4](/details-gene/22802) is required for its function in modulating ion transport. This proteolytic activity might be directed at itself (auto-processing) or at other components of the ion transport machinery at the apical membrane of enterocytes and respiratory epithelial cells. **Key Experimental Approach:** To test the hypothesis that [CLCA4](/details-gene/22802) regulates intestinal barrier function and mucus properties, one could utilize an *in vitro* model of the human intestinal epithelium. Specifically, CRISPR-Cas9 could be used to knock out [CLCA4](/details-gene/22802) in Caco-2 or HT29-MTX co-cultures, which can be grown on transwell inserts to form polarized monolayers with a mucus layer. The impact of the knockout could be assessed by measuring transepithelial electrical resistance (TEER) to evaluate barrier integrity, performing Ussing chamber experiments to quantify calcium-activated chloride currents, and using confocal microscopy with fluorescent lectins to visualize and quantify changes in mucus layer thickness and structure. **Therapeutic Potential:** The restricted expression of [CLCA4](/details-gene/22802) to specific epithelial tissues makes it an attractive therapeutic target with a potentially low risk of off-target effects. For diseases of mucus hypersecretion, such as chronic bronchitis or certain forms of asthma, developing small-molecule inhibitors of [CLCA4](/details-gene/22802) could reduce chloride and water secretion, thereby decreasing mucus volume. Conversely, for conditions of deficient chloride transport and mucus dehydration, such as cystic fibrosis, developing a small-molecule activator or potentiator of [CLCA4](/details-gene/22802) could provide a therapeutic benefit by promoting mucosal hydration. The strategy would therefore be one of functional modulation rather than simple inhibition.

Genular Protein ID: 3215605791

Symbol: CLCA4_HUMAN

Name: Calcium-activated chloride channel regulator 4

UniProtKB Accession Codes:

Q14CN2 A8MQC9 B7Z1Q5 Q6UX81 Q9UNF7

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 3 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 1 GO 9 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 2 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10437792

Title: Identification of three novel members of the calcium-dependent chloride channel (CaCC) family predominantly expressed in the digestive tract and trachea.

PubMed ID: 10437792

DOI: 10.1016/s0014-5793(99)00891-1

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

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: 15490240

Title: The CLCA gene locus as a modulator of the gastrointestinal basic defect in cystic fibrosis.

PubMed ID: 15490240

DOI: 10.1007/s00439-004-1190-y

PubMed ID: 16012037

Title: Expression and distribution of ion transport mRNAs in human nasal mucosa and nasal polyps.

PubMed ID: 16012037

DOI: 10.1080/00016480510028519

PubMed ID: 16740002

Title: Identification of N-linked glycoproteins in human saliva by glycoprotein capture and mass spectrometry.

PubMed ID: 16740002

DOI: 10.1021/pr050492k

PubMed ID: 18254958

Title: Transcriptomic dissection of tongue squamous cell carcinoma.

PubMed ID: 18254958

DOI: 10.1186/1471-2164-9-69

Sequence Information:

  • Length: 919
  • Mass: 101283
  • Checksum: 47C0DF125A319810
  • Sequence:
    • MGLFRGFVFL LVLCLLHQSN TSFIKLNNNG FEDIVIVIDP SVPEDEKIIE QIEDMVTTAS 
TYLFEATEKR FFFKNVSILI PENWKENPQY KRPKHENHKH ADVIVAPPTL PGRDEPYTKQ 
FTECGEKGEY IHFTPDLLLG KKQNEYGPPG KLFVHEWAHL RWGVFDEYNE DQPFYRAKSK 
KIEATRCSAG ISGRNRVYKC QGGSCLSRAC RIDSTTKLYG KDCQFFPDKV QTEKASIMFM 
QSIDSVVEFC NEKTHNQEAP SLQNIKCNFR STWEVISNSE DFKNTIPMVT PPPPPVFSLL 
KISQRIVCLV LDKSGSMGGK DRLNRMNQAA KHFLLQTVEN GSWVGMVHFD STATIVNKLI 
QIKSSDERNT LMAGLPTYPL GGTSICSGIK YAFQVIGELH SQLDGSEVLL LTDGEDNTAS 
SCIDEVKQSG AIVHFIALGR AADEAVIEMS KITGGSHFYV SDEAQNNGLI DAFGALTSGN 
TDLSQKSLQL ESKGLTLNSN AWMNDTVIID STVGKDTFFL ITWNSLPPSI SLWDPSGTIM 
ENFTVDATSK MAYLSIPGTA KVGTWAYNLQ AKANPETLTI TVTSRAANSS VPPITVNAKM 
NKDVNSFPSP MIVYAEILQG YVPVLGANVT AFIESQNGHT EVLELLDNGA GADSFKNDGV 
YSRYFTAYTE NGRYSLKVRA HGGANTARLK LRPPLNRAAY IPGWVVNGEI EANPPRPEID 
EDTQTTLEDF SRTASGGAFV VSQVPSLPLP DQYPPSQITD LDATVHEDKI ILTWTAPGDN 
FDVGKVQRYI IRISASILDL RDSFDDALQV NTTDLSPKEA NSKESFAFKP ENISEENATH 
IFIAIKSIDK SNLTSKVSNI AQVTLFIPQA NPDDIDPTPT PTPTPTPDKS HNSGVNISTL 
VLSVIGSVVI VNFILSTTI