Details for: CLCA1

Gene ID: 1179

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: CLCA1

Ensembl ID: ENSG00000016490

Description: chloride channel accessory 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • goblet cell CL0000160
    CSI 28.9
    rCSI 27.31%
    PRS 99.69
  • intestine goblet cell CL0019031
    CSI 24.39
    rCSI 21.65%
    PRS 99.55
  • small intestine goblet cell CL1000495
    CSI 17.59
    rCSI 38.52%
    PRS 99.81
  • colon goblet cell CL0009039
    CSI 12.16
    rCSI 28.9%
    PRS 99.72
  • paneth cell CL0000510
    CSI 10.68
    rCSI 15.77%
    PRS 99.92
  • enteroendocrine cell CL0000164
    CSI 10.57
    rCSI 14.44%
    PRS 99.29
  • transit amplifying cell of colon CL0009011
    CSI 8.06
    rCSI 9.47%
    PRS 99.84
  • colonocyte CL1000347
    CSI 7.7
    rCSI 11.04%
    PRS 99.65
  • brush cell CL0002204
    CSI 6.89
    rCSI 13.63%
    PRS 99.65
  • paneth cell of epithelium of small intestine CL1000343
    CSI 3.83
    rCSI 10.73%
    PRS 99.82
  • type L enteroendocrine cell CL0002279
    CSI 2.76
    rCSI 5.18%
    PRS 99.7
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.87
    rCSI 5.03%
    PRS 99.87

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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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
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    • 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 **Overall**, [CLCA1](/details-gene/1179), or Chloride Channel Accessory 1, is a protein-coding gene located on chromosome 1p22.3. While historically named for its association with calcium-activated chloride channels, current evidence suggests it functions as a secreted, self-cleaving metalloprotease rather than an ion channel itself ([Link](https://doi.org/10.1074/jbc.m112.410282); [Link](https://doi.org/10.1074/jbc.m504654200)). Its expression is remarkably specific and abundant in secretory epithelial cells, particularly intestinal [goblet cell](/details-cell/CL0000160)s, where it is a defining marker. The gene is implicated in regulating mucus production and ion transport, and its dysregulation has been linked to inflammatory airway diseases like asthma and to the progression of colorectal cancer. ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [CLCA1](/details-gene/1179) demonstrates a highly specialized role within the secretory lineages of the gastrointestinal tract. The gene shows its highest significance in [goblet cell](/details-cell/CL0000160)s (CSI: 28.90), including those specific to the [intestine](/details-cell/CL0019031), [small intestine](/details-cell/CL1000495), and [colon](/details-cell/CL0009039). This strong and consistent signal underscores its central function in mucus-producing cells responsible for forming the protective epithelial barrier. Beyond goblet cells, [CLCA1](/details-gene/1179) is also significantly expressed in other specialized intestinal epithelial cells such as [paneth cell](/details-cell/CL0000510)s and [enteroendocrine cell](/details-cell/CL0000164)s. Its presence in progenitor populations, including [transit amplifying cell of colon](/details-cell/CL0009011) and [intestinal crypt stem cell of small intestine](/details-cell/CL0009017), suggests it may also play a role in the differentiation and functional maturation of these secretory cell types. This highly restricted expression pattern within the gut epithelium indicates a primary function related to secretion, ion homeostasis, and mucosal defense. ## Pathways and Molecular Function The functional annotations for [CLCA1](/details-gene/1179) are consistent with its role as a regulator of mucosal physiology. Its involvement in [Chloride transmembrane transport](/details-go/GO:1902476) and [Calcium ion transport](/details-go/GO:0006816), as well as general pathways like [Ion channel transport](/details-pathway/R-HSA-983712), highlights its connection to the movement of ions and water across epithelial surfaces, a process critical for hydrating mucus. Notably, research has refined the understanding of its molecular function. While initially believed to be a channel, subsequent studies have demonstrated that [CLCA1](/details-gene/1179) is a secreted protein that undergoes autoproteolytic cleavage via an intrinsic [Metalloendopeptidase activity](/details-go/GO:0004222) domain ([Link](https://doi.org/10.1074/jbc.m112.410282)). This processing event appears to be crucial for its function, which is likely to involve the activation or regulation of other membrane proteins, such as actual chloride channels, from the extracellular space. Its annotation to the [Extracellular region](/details-go/GO:0005576) supports this model of action as a secreted signaling or regulatory molecule. This dual function as a protease and channel regulator is critical to its biological role in mucus production and release. ## Research Directions The context-specific dysregulation of [CLCA1](/details-gene/1179) provides a foundation for several compelling research avenues. Published literature indicates that while it is a marker of healthy, differentiated secretory cells in the gut, its expression is significantly increased in the airways of asthma patients ([Link](https://doi.org/10.1164/ajrccm.165.8.2107068); [Link](https://doi.org/10.1067/mai.2002.121555)) and is downregulated in human colorectal cancer ([Link](https://doi.org/10.1089/10445490152122442)). This opposing regulation in different pathological contexts suggests it plays a complex, tissue-specific role in disease. Based on this evidence, several testable hypotheses can be proposed: 1. **In Airway Disease:** The upregulation of [CLCA1](/details-gene/1179) in asthma is a key driver of mucus hypersecretion. Inflammatory stimuli, such as histamine or IL-9, induce its expression and secretion from bronchial epithelial cells, where its proteolytic activity directly or indirectly triggers the release of MUC5AC-containing mucins, contributing to airway obstruction. 2. **In Colorectal Cancer:** The loss of [CLCA1](/details-gene/1179) expression serves as a tumor-promoting event. As a protein characteristic of terminally differentiated goblet cells, its downregulation may be an early indicator of failed differentiation and disrupted epithelial homeostasis, creating a microenvironment permissive for tumorigenesis. A key experiment to test the first hypothesis would be to investigate the direct causal link between [CLCA1](/details-gene/1179) and mucus production. To test the role of [CLCA1](/details-gene/1179) in driving mucus hypersecretion, a CRISPR-Cas9 knockout of the gene could be performed in primary human bronchial epithelial cells grown at an air-liquid interface. Control and knockout cultures could be stimulated with IL-13, a known inducer of mucus production. The impact on MUC5AC expression and secretion would be quantified by qPCR, immunofluorescence, and ELISA. This would determine if [CLCA1](/details-gene/1179) is necessary for pathological mucus production in the airway. Given its role as a secreted protease implicated in asthma pathophysiology, [CLCA1](/details-gene/1179) represents a promising candidate for therapeutic **inhibition**. Its extracellular location makes it highly accessible to biologics, such as monoclonal antibodies, or to inhaled small molecule inhibitors designed to block its proteolytic active site. Such a therapy could potentially reduce mucus plugging in severe asthma and other muco-obstructive lung diseases. Conversely, if its tumor suppressor role in colorectal cancer is confirmed, strategies for its therapeutic **activation** or re-expression could be explored, although this remains a more challenging therapeutic approach.

Genular Protein ID: 880919068

Symbol: CLCA1_HUMAN

Name: Calcium-activated chloride channel regulator 1

UniProtKB Accession Codes:

A8K7I4 B2RAV5 O95151 Q5TDF4 Q9UNF6 Q9UPC6

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 DNASU 1 DisGeNET 1 EMBL 7 Ensembl 2 GO 12 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 MassIVE 1 NCBI Taxonomy 1 NCBIfam 2 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 SASBDB 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: 9828122

Title: Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl- channel proteins.

PubMed ID: 9828122

DOI: 10.1006/geno.1998.5562

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: 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: 23112050

Title: Self-cleavage of human CLCA1 protein by a novel internal metalloprotease domain controls calcium-activated chloride channel activation.

PubMed ID: 23112050

DOI: 10.1074/jbc.m112.410282

PubMed ID: 11445004

Title: Expression of the Ca2+-activated chloride channel genes CLCA1 and CLCA2 is downregulated in human colorectal cancer.

PubMed ID: 11445004

DOI: 10.1089/10445490152122442

PubMed ID: 11956057

Title: Increased expression of the human Ca2+-activated Cl- channel 1 (CaCC1) gene in the asthmatic airway.

PubMed ID: 11956057

DOI: 10.1164/ajrccm.165.8.2107068

PubMed ID: 11842292

Title: A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma.

PubMed ID: 11842292

DOI: 10.1067/mai.2002.121555

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: 15696080

Title: Niflumic acid and MSI-2216 reduce TNF-alpha-induced mucin expression in human airway mucosa.

PubMed ID: 15696080

DOI: 10.1016/j.jaci.2004.09.039

PubMed ID: 15919655

Title: hCLCA1 and mCLCA3 are secreted non-integral membrane proteins and therefore are not ion channels.

PubMed ID: 15919655

DOI: 10.1074/jbc.m504654200

PubMed ID: 16151054

Title: Differential regulation of MUC5AC/Muc5ac and hCLCA-1/mGob-5 expression in airway epithelium.

PubMed ID: 16151054

DOI: 10.1165/rcmb.2004-0220rc

PubMed ID: 17622767

Title: Histamine induces MUC5AC expression via a hCLCA1 pathway.

PubMed ID: 17622767

DOI: 10.1159/000104419

Sequence Information:

  • Length: 914
  • Mass: 100226
  • Checksum: 8D8999E855822711
  • Sequence:
    • MGPFKSSVFI LILHLLEGAL SNSLIQLNNN GYEGIVVAID PNVPEDETLI QQIKDMVTQA 
SLYLLEATGK RFYFKNVAIL IPETWKTKAD YVRPKLETYK NADVLVAEST PPGNDEPYTE 
QMGNCGEKGE RIHLTPDFIA GKKLAEYGPQ GRAFVHEWAH LRWGVFDEYN NDEKFYLSNG 
RIQAVRCSAG ITGTNVVKKC QGGSCYTKRC TFNKVTGLYE KGCEFVLQSR QTEKASIMFA 
QHVDSIVEFC TEQNHNKEAP NKQNQKCNLR STWEVIRDSE DFKKTTPMTT QPPNPTFSLL 
QIGQRIVCLV LDKSGSMATG NRLNRLNQAG QLFLLQTVEL GSWVGMVTFD SAAHVQNELI 
QINSGSDRDT LAKRLPAAAS GGTSICSGLR SAFTVIRKKY PTDGSEIVLL TDGEDNTISG 
CFNEVKQSGA IIHTVALGPS AAQELEELSK MTGGLQTYAS DQVQNNGLID AFGALSSGNG 
AVSQRSIQLE SKGLTLQNSQ WMNGTVIVDS TVGKDTLFLI TWTMQPPQIL LWDPSGQKQG 
GFVVDKNTKM AYLQIPGIAK VGTWKYSLQA SSQTLTLTVT SRASNATLPP ITVTSKTNKD 
TSKFPSPLVV YANIRQGASP ILRASVTALI ESVNGKTVTL ELLDNGAGAD ATKDDGVYSR 
YFTTYDTNGR YSVKVRALGG VNAARRRVIP QQSGALYIPG WIENDEIQWN PPRPEINKDD 
VQHKQVCFSR TSSGGSFVAS DVPNAPIPDL FPPGQITDLK AEIHGGSLIN LTWTAPGDDY 
DHGTAHKYII RISTSILDLR DKFNESLQVN TTALIPKEAN SEEVFLFKPE NITFENGTDL 
FIAIQAVDKV DLKSEISNIA RVSLFIPPQT PPETPSPDET SAPCPNIHIN STIPGIHILK 
IMWKWIGELQ LSIA