Affinage

SLC26A3

Chloride anion exchanger · UniProt P40879

Length
764 aa
Mass
84.5 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC26A3 (DRA) is the principal apical Cl⁻/HCO₃⁻ exchanger in intestinal epithelial cells, driving electroneutral NaCl absorption in concert with Na⁺/H⁺ exchangers NHE2 and NHE3, and sustaining luminal HCO₃⁻ secretion required for mucus layer integrity and epithelial barrier function (PMID:17001077, PMID:24373192, PMID:19056765). Its STAS domain is essential for transport activity and for the separate function of activating CFTR; disease-causing mutations in this domain cause protein misfolding or mistrafficking, and a STAS missense variant that selectively abolishes CFTR activation is linked to male infertility (PMID:12651923, PMID:18216024, PMID:29079751). SLC26A3 surface expression and activity are regulated by clathrin-mediated endocytosis, lipid raft association, intracellular calcium signaling through the scaffold PDZK1, and CFTR-dependent cAMP stimulation, while transcription is repressed by TNF/NF-κB and induced by butyrate (via HDAC8 inhibition), HNF-4/YY1/GATA factors, and retinoic acid signaling (PMID:19447883, PMID:30659943, PMID:28823863, PMID:39440960, PMID:17761837). Loss-of-function mutations cause congenital chloride diarrhea, and DRA deficiency in mice additionally disrupts tight junction integrity through CUGBP1-mediated post-transcriptional down-regulation of occludin and E-cadherin, and triggers IL-33-driven mucosal immune dysregulation (PMID:8896562, PMID:33189700, PMID:36535508).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1995 High

    Establishing that DRA encodes an intestine-specific anion transporter resolved the molecular identity of a gene linked to congenital chloride diarrhea and demonstrated Na⁺-independent sulfate/oxalate transport.

    Evidence Xenopus oocyte expression with radiolabeled transport assays and Northern blot

    PMID:7744840

    Open questions at the time
    • Cl⁻/HCO₃⁻ exchange mode not yet demonstrated
    • no disease-causing mutations yet mapped
  2. 1996 High

    Identification of causative SLC26A3 mutations in congenital chloride diarrhea families established the gene–disease link and confirmed DRA as the intestinal Cl⁻/HCO₃⁻ exchanger responsible for chloride absorption.

    Evidence Genetic linkage and mutation analysis across multiple CLD pedigrees, mRNA in situ hybridization

    PMID:8896562

    Open questions at the time
    • molecular mechanism of transport not defined
    • animal model not yet available
  3. 2003 High

    Systematic reconstitution revealed that DRA operates as a Cl⁻/HCO₃⁻ (not sulfate) exchanger whose STAS domain is required for function, and that co-expression with CFTR confers cAMP sensitivity — establishing the functional transport mode and the CFTR regulatory connection.

    Evidence Xenopus oocyte expression with ion flux assays, truncation mutagenesis, CFTR co-expression

    PMID:12651923

    Open questions at the time
    • mechanism of CFTR-DRA coupling unknown
    • in vivo significance not tested
  4. 2006 High

    Slc26a3-knockout mice recapitulated congenital chloride diarrhea, proving DRA is the dominant apical Cl⁻/base exchanger in colon and revealing compensatory up-regulation of NHE3, ENaC, and H,K-ATPase.

    Evidence Gene-targeted KO mouse with ion transport assays, immunohistochemistry, Western blotting

    PMID:17001077

    Open questions at the time
    • HCO₃⁻ secretion contribution not yet quantified
    • mucus and barrier consequences unknown
  5. 2008 High

    Demonstrating that CLD-causing STAS domain mutations disrupt protein folding and trafficking defined two distinct molecular pathogenesis mechanisms — direct STAS dysfunction and late-stage mistrafficking — explaining genotype–phenotype variability.

    Evidence Heterologous mammalian expression with limited proteolysis, immunohistochemistry, transport assays of mutants

    PMID:18216024

    Open questions at the time
    • structural basis of STAS misfolding not resolved
    • no pharmacological rescue attempted
  6. 2008 High

    Functional coupling of DRA with NHE2/NHE3 was demonstrated in polarized epithelial cells, establishing the molecular basis of electroneutral NaCl absorption and showing regulation by cAMP, calcium, and clathrin-mediated endocytosis.

    Evidence ²²Na⁺ and ³⁶Cl⁻ uptake assays in Caco-2BBE cells with inducible DRA, NHE isoform transfection, endocytosis inhibitors

    PMID:19056765

    Open questions at the time
    • relative contribution of NHE2 vs NHE3 in vivo not resolved
    • synaptotagmin I role not confirmed in vivo
  7. 2009 High

    Identification of PDZK1 as a required scaffold for calcium-dependent DRA inhibition revealed the signaling mechanism through which purinergic stimulation regulates intestinal Cl⁻/HCO₃⁻ exchange.

    Evidence DRA PDZ-motif mutants, PDZK1 co-transfection, intracellular pH assays in HEK and Caco-2 cells

    PMID:19447883

    Open questions at the time
    • identity of downstream calcium effector linking PDZK1 to DRA endocytosis unknown
    • other PDZ partners not excluded
  8. 2007 High

    Mapping the DRA promoter identified HNF-4, YY1, and GATA as activating transcription factors and butyrate as a transcriptional inducer, providing the first framework for how differentiation and dietary signals control DRA expression.

    Evidence Promoter deletion/reporter assays, transcription factor siRNA, transgenic mice with DRA promoter–reporter

    PMID:17761837

    Open questions at the time
    • chromatin-level regulation not addressed
    • HDAC involvement not yet identified
  9. 2011 High

    Quantifying HCO₃⁻ secretion in DRA-KO tissue established DRA as the primary mediator of luminal bicarbonate secretion in ileum and colon, and demonstrated that TNF selectively downregulates DRA among apical transporters.

    Evidence Ussing chamber HCO₃⁻ secretion, in vivo perfusion in DRA-KO and TNF-overexpressing mice

    PMID:21557395

    Open questions at the time
    • direct TNF-responsive promoter elements not mapped in this study
    • contribution of other SLC26 family members not excluded
  10. 2014 High

    Linking DRA loss to absent adherent mucus layer (MUC2) and elevated colonocyte pH that paralyzes NHE3 revealed how DRA deficiency disrupts two protective barriers — chemical (pH/mucus) and absorptive (Na⁺) — explaining colitis susceptibility.

    Evidence In vivo colon perfusion, fluorometric pHi measurement, MUC2 immunohistochemistry, DSS colitis in Slc26a3⁻/⁻ mice

    PMID:24373192

    Open questions at the time
    • mechanism of pH-dependent mucus defect not resolved
    • contribution of microbiome changes not fully dissected
  11. 2017 High

    ChIP-confirmed direct binding of NF-κB p65 to the DRA promoter established the molecular pathway (TNF→NF-κB→DRA repression) through which inflammation causes chloride malabsorption.

    Evidence Chromatin immunoprecipitation, luciferase reporters, p65 overexpression, mouse TNF injection, enteroids

    PMID:28823863

    Open questions at the time
    • epigenetic modifications at DRA locus during inflammation not characterized
    • relative contribution vs. post-transcriptional mechanisms not quantified
  12. 2017 Medium

    A STAS domain missense mutation (D688H) that preserves Cl⁻/HCO₃⁻ exchange but abolishes CFTR activation demonstrated that DRA's transport and CFTR-activating functions are separable, and linked impaired CFTR activation to male infertility.

    Evidence Exon sequencing of infertile men, functional transport assays, CFTR activation assays in heterologous cells

    PMID:29079751

    Open questions at the time
    • single kindred; broader population validation needed
    • structural basis of uncoupling not defined
    • epididymal physiology not directly measured
  13. 2018 Medium

    Demonstrating that Slc26a3-deficient mice have severe epididymal dysplasia and impaired sperm function confirmed in vivo that DRA is required for male reproductive tract anion homeostasis.

    Evidence Slc26a3⁻/⁻ mouse histology, sperm morphology/function, fertility assays

    PMID:30118583

    Open questions at the time
    • relative roles of DRA vs. CFTR in epididymal fluid not separated
    • human relevance beyond single variant not established
  14. 2019 High

    Demonstrating that cAMP stimulates DRA via a CFTR-dependent but channel-activity-independent mechanism in human colonoids resolved the long-standing question of how cAMP regulates intestinal chloride absorption.

    Evidence Human colonoid monolayers, CFTR inhibitor, DRA-specific inhibitor, HEK293 ± CFTR reconstitution

    PMID:30659943

    Open questions at the time
    • molecular intermediate between CFTR protein and DRA activation unknown
    • whether R-domain phosphorylation is sufficient not tested
  15. 2020 High

    Identifying CUGBP1-mediated post-transcriptional destabilization of occludin and E-cadherin mRNAs in DRA-KO colon established a non-canonical mechanism by which loss of an ion transporter disrupts epithelial barrier integrity.

    Evidence Ribonucleoprotein immunoprecipitation, FITC-dextran permeability, DRA knockdown in Caco-2, DRA-KO mice, cohousing

    PMID:33189700

    Open questions at the time
    • signal linking DRA loss to CUGBP1 activation not identified
    • whether intracellular pH change drives CUGBP1 not tested
  16. 2022 Medium

    Discovery that DRA loss triggers IL-33 release from colonocytes, driving type 2 immune dysregulation (ILC2, Th2 expansion), revealed an epithelial-immune signaling axis explaining the inflammatory predisposition of DRA-deficient intestine.

    Evidence NanoString immunology panel, FACS, IL-33 blockade in DRA-KO mice, UC biopsy-derived colonoids

    PMID:36535508

    Open questions at the time
    • upstream trigger for IL-33 release (pH change, ER stress, barrier breach) not defined
    • therapeutic potential of IL-33 blockade not tested long-term
  17. 2024 Medium

    Identification of HDAC8 as the specific deacetylase whose inhibition by butyrate upregulates SLC26A3 and restores barrier function connected the dietary short-chain fatty acid signal to a defined epigenetic target.

    Evidence Pan and class-specific HDAC inhibitors, HDAC8 activation/inhibition, histone acetylation assays, DSS colitis model

    PMID:39440960

    Open questions at the time
    • direct histone acetylation marks at SLC26A3 locus not mapped at nucleosome resolution
    • other HDAC-independent butyrate effects not excluded

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which DRA loss activates CUGBP1 and triggers IL-33 release, and the structural basis of STAS domain-mediated CFTR activation, remain unresolved.
  • no high-resolution structure of full-length DRA or DRA–CFTR complex
  • signal transduction from altered intracellular ion composition to CUGBP1 and IL-33 pathways undefined
  • pharmacological correctors for STAS-misfolding CLD mutations not developed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6
Localization
GO:0005886 plasma membrane 6
Pathway
R-HSA-382551 Transport of small molecules 7 R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3
Partners
CFTRKRT8NHE2NHE3PDZK1SLC26A6SLC9A3R1

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Mutations in SLC26A3 (DRA) cause congenital chloride diarrhea, establishing DRA as an intestinal anion transport molecule responsible for Cl-/HCO3- exchange in colonic epithelial cells; expression is restricted to highly differentiated colonic epithelial cells by mRNA in situ hybridization. Genetic linkage/mutation analysis, mRNA in situ hybridization Nature genetics High 8896562
1995 DRA encodes a Na+-independent transporter for sulfate and oxalate in intestinal epithelial cells, as demonstrated by expression in Xenopus oocytes; transport is DIDS-sensitive and expression is intestine-specific. Xenopus oocyte expression system, transport assays, Northern blot, RNase protection assay The Journal of biological chemistry High 7744840
2003 SLC26A3 expressed in Xenopus oocytes mediates bidirectional Cl-/Cl- and Cl-/HCO3- exchange; sulfate and butyrate transport are negligible. The STAS domain is required for function; truncation of up to 44 C-terminal amino acids leaves transport intact. Transport is inhibited by intracellular acidification, activated by NH4+, inhibited by niflumate and tenidap, and gains cAMP sensitivity when co-expressed with CFTR. Xenopus oocyte expression, ion flux assays, truncation mutagenesis, pharmacological inhibition, co-expression with CFTR The Journal of physiology High 12651923
2006 Slc26a3-null mice display high-chloride diarrhea, severely reduced apical Cl-/base exchange activity in colon, more acidic luminal pH, compensatory up-regulation of NHE3, colonic H,K-ATPase, and ENaC, and expanded colonic crypt proliferative zone; establishing SLC26A3 as the major apical Cl-/base exchanger in colon and a regulator of colonic crypt proliferation. Gene targeting/knockout mouse, ion transport assays, immunohistochemistry, Western blotting, plasma aldosterone measurement The Journal of biological chemistry High 17001077
2002 DRA (SLC26A3) physically and functionally interacts with carbonic anhydrase II (CAII): DRA-mediated bicarbonate transport requires cytosolic CAII activity (inhibited 53% by acetazolamide), but unlike AE1, DRA's C-terminal tail interacts only weakly with CAII and DRA transport is not stimulated by direct CAII interaction, distinguishing it from classical bicarbonate transport metabolons. Intracellular pH fluorometry in transfected HEK-293 cells, carbonic anhydrase inhibitors, dominant-negative CAII mutant overexpression, CAII-tail pull-down American journal of physiology. Cell physiology High 12372813
2008 Four CLD-causing missense/insertion mutations in the STAS domain of SLC26A3 (DeltaY526/7, I544N, I675/6ins, G702Tins) cause protein misfolding and/or mistrafficking, preventing functional transporter from reaching the plasma membrane; two molecular mechanisms are identified—direct STAS domain disruption and a later folding/trafficking block. Heterologous mammalian expression, immunohistochemistry, biochemical assays, ion transport assays, limited proteolysis, isolated STAS domain expression The Journal of biological chemistry High 18216024
2008 DRA (SLC26A3) activity is functionally coupled to apical Na+/H+ exchangers NHE2 and NHE3 in Caco2BBE cells to facilitate electroneutral NaCl absorption; coupled transport is inhibited by elevated cAMP and calcium and involves synaptotagmin I-dependent, clathrin-mediated endocytosis. 22Na+ and 36Cl- uptake assays, tetracycline-inducible DRA transgene, NHE isoform transfection, pharmacological inhibition, endocytosis assays American journal of physiology. Gastrointestinal and liver physiology High 19056765
2009 DRA-mediated Cl-/HCO3- exchange in polarized intestinal epithelial cells is inhibited by intracellular calcium, and this inhibition requires interaction of DRA with the PDZ scaffold protein PDZK1; the PDZ-binding motif of DRA (ETKF) is required for UTP/Ca2+-dependent inhibition but not for ionophore-induced inhibition at high calcium concentrations. HEK and Caco-2/BBE cell expression, intracellular pH assays, PDZK1 co-transfection, DRA C-terminal PDZ mutant (DRA-ETKFminus), calcium ionophore and UTP stimulation, fluorometric Ca2+ assessment The Journal of biological chemistry High 19447883
2011 Loss of DRA (Slc26a3) dramatically impairs HCO3- secretion in the murine ileocolonic mucosa; in TNF-overexpressing mice, DRA mRNA and protein are strongly downregulated while CFTR, NHE3, NBC, and ENaC are unchanged, indicating that DRA is the primary mediator of luminal Cl--dependent HCO3- secretion in the ileum and colon. Ussing chamber HCO3- secretion assays, in vivo single-pass perfusion, mRNA expression, immunohistochemistry in TNF(+/ΔARE) and DRA-KO mice Inflammatory bowel diseases High 21557395
2014 Slc26a3-/- mice show severely reduced colonic HCO3- secretion and fluid absorption; elevated colonocyte intracellular pH in KO mice prevents NHE3-mediated Na+/H+ exchange despite increased NHE3 expression; KO mice lack a firm adherent mucus layer (MUC2) and are highly susceptible to DSS-induced colitis. In vivo colon perfusion, Ussing chamber assays, fluorometric pHi measurement, immunohistochemistry (MUC2), DSS colitis model, Slc26a3-/- mice Acta physiologica (Oxford, England) High 24373192
2012 SLC26A3, SLC26A6, and the scaffolding factor SLC9A3R1 are expressed in mouse sperm midpiece and interact with each other and with CFTR (demonstrated by immunoprecipitation); SLC26A3 and CFTR are involved in intracellular Cl- increase in noncapacitated sperm; SLC26A3 inhibitors interfere with membrane potential changes during sperm capacitation. RT-PCR, immunocytochemistry, Western blot, co-immunoprecipitation, intracellular Cl- imaging, pharmacological inhibition of SLC26A3 Biology of reproduction High 21976599
2019 cAMP (via forskolin) acutely stimulates DRA (SLC26A3) Cl-/HCO3- exchange activity in human colonoids and Caco-2 cells via a CFTR-dependent mechanism that does not require CFTR channel activity; in HEK293 cells lacking CFTR, cAMP has no effect on DRA, but co-expression of CFTR restores cAMP stimulation of DRA. Human colonoid monolayers, Caco-2 cells, HEK293/DRA cells ± CFTR transfection, DRA-specific inhibitor (DRAinh-A250), DRA KO cell model, cAMP stimulation (forskolin), CFTR inhibitor (CFTRinh-172) Cellular and molecular gastroenterology and hepatology High 30659943
2017 TNF activates NF-κB (p65 subunit), which directly binds the DRA/SLC26A3 promoter (at regions -935 to -629 and -375 to -84) and reduces DRA mRNA and protein expression in intestinal epithelial cells and mouse intestinal epithelia, establishing a TNF→NF-κB→DRA transcriptional repression pathway. qRT-PCR, immunofluorescence, immunoblot, chromatin immunoprecipitation (ChIP), luciferase reporter assays, p65/p50 transgene expression, IkBa siRNA knockdown, mouse TNF injection, crypt-derived enteroids Gastroenterology High 28823863
1998 Intestinal inflammation reduces DRA mRNA expression five- to sevenfold in the surface epithelium of the colon; IL-1β reduces DRA mRNA expression in vitro by inhibiting gene transcription; loss of DRA transporter gene expression in surface epithelium is a mechanism contributing to inflammatory diarrhea. In situ hybridization, immunohistochemistry, in vitro cytokine treatment (IL-1β), transgenic colitis rat model, IL-10 KO mouse, human UC samples The American journal of physiology High 9843783
2007 DRA promoter activity is regulated by HNF-4, YY1, and GATA transcription factors; sodium butyrate induces DRA promoter activity via YY1 and GATA binding sites; IFN-γ reduces DRA promoter activity; a single transcriptional initiation site was identified; the promoter drives tissue-specific expression in villus epithelial cells and upper crypt/surface colonocytes in vivo. Promoter cloning and deletion analysis, primer extension, luciferase reporter assays, transcription factor siRNA, transgenic mice with DRA promoter-driven HGH transgene American journal of physiology. Gastrointestinal and liver physiology High 17761837
2020 DRA-KO mice exhibit increased colonic paracellular permeability with decreased tight junction proteins ZO-1, occludin, and E-cadherin; increased binding of RNA-binding protein CUGBP1 to occludin and E-cadherin mRNAs in DRA-KO colon indicates posttranscriptional mechanisms of barrier dysfunction; gut dysbiosis plays only a partial role. FITC-dextran flux, immunoblotting, immunofluorescence, immunohistochemistry, ribonucleoprotein immunoprecipitation (RIP), gut microbiome analysis, DRA-KO mice, Caco-2 DRA knockdown, cohousing experiments Gastroenterology High 33189700
2009 DRA (Slc26a3) mediates apical Cl-/HCO3- exchange activity in intestinal villus cells; during chronic inflammation, cyclooxygenase pathway metabolites (prostaglandins, not leukotrienes) inhibit DRA-mediated Cl-/HCO3- exchange by decreasing the affinity of the transporter for Cl- without altering DRA brush-border membrane expression. Brush-border membrane vesicle Cl-/HCO3- exchange kinetics, cyclooxygenase inhibitor (piroxicam), lipoxygenase inhibition, arachidonic acid inhibitor, DRA protein expression in chronically inflamed rabbit ileum Biochimica et biophysica acta Medium 22963933
2009 Lactobacillus acidophilus stimulates SLC26A3 expression and promoter activity via transcriptional mechanisms in Caco-2 cells and in mouse colon; long-term treatment increases DRA mRNA and protein. Cl-/OH- exchange activity assay, DRA mRNA quantification, DRA promoter-luciferase reporter assay, Western blot, immunofluorescence, in vivo mouse gavage American journal of physiology. Gastrointestinal and liver physiology Medium 20044511
2013 miR-494 represses SLC26A3 (DRA) expression at the translational level by binding to a conserved site in the DRA 3'-UTR; mutation of the miR-494 seed sequence in DRA 3'-UTR abrogates repression. Dual luciferase reporter with DRA 3'-UTR, miR-494 mimic transfection, site-directed mutagenesis of 3'-UTR seed sequence, Western blot, qRT-PCR in Caco-2 and T-84 cells American journal of physiology. Gastrointestinal and liver physiology Medium 24177028
2010 Neuropeptide Y (NPY) stimulates SLC26A3-mediated Cl-/HCO3- exchange activity via ERK1/2 MAP kinase pathway; NPY enhances DRA association with lipid rafts (detergent-insoluble, low-density fractions) in colonic apical membranes without altering total DRA surface expression; cholesterol depletion by MβCD disrupts lipid raft association and reduces DRA exchange activity. 36Cl- uptake assay, cell surface biotinylation, sucrose gradient fractionation, cholesterol depletion (MβCD), ERK1/2 inhibition, NPY receptor agonists in Caco-2 cells American journal of physiology. Gastrointestinal and liver physiology Medium 20884887
2015 DRA membrane recycling involves clathrin-mediated endocytosis and intact microtubules for exocytosis under basal conditions; enteropathogenic E. coli (EPEC) reduces DRA apical surface expression by increasing endocytosis and decreasing exocytosis via virulence genes espG1 and espG2, involving clathrin-independent internalization. Cell surface biotinylation, endocytosis/exocytosis assays, clathrin inhibitor (chlorpromazine), dynamin inhibitor (dynasore), microtubule disruption (nocodazole, colchicine), EPEC virulence gene mutants, confocal microscopy, 125I- uptake American journal of physiology. Cell physiology Medium 26447204
2013 DRA (Slc26a3) in the mouse cecum mediates both Cl- absorption and sulfate (SO4²-) secretion; in DRA-KO mice, net SO4²- secretion is reversed to absorption and net Cl- absorption is abolished; DRA contributes to SO4²- secretion via DIDS-sensitive HCO3-/SO4²- exchange in addition to its role as the principal DIDS-resistant Cl-/HCO3- exchanger. 35SO4²- and 36Cl- transepithelial flux measurements in Ussing chambers, DRA-KO vs. WT mice, DIDS, bumetanide, ion substitutions American journal of physiology. Gastrointestinal and liver physiology High 23660504
2017 A heterozygous missense mutation p.Asp688His in the STAS domain of SLC26A3 is associated with male infertility; the mutant protein retains normal Cl-/HCO3- exchange activity but suppresses CFTR-dependent anion transport despite unaffected STAS domain binding to CFTR, revealing that SLC26A3 STAS domain activates CFTR and that this activation can be uncoupled from anion exchange activity. SLC26A3 exon sequencing in infertile vs. control men, functional transport assays in heterologous expression, CFTR activation assays, domain binding assays Scientific reports Medium 29079751
2018 DRA (SLC26A3) colocalizes and directly binds tight junction proteins in polarized Caco-2BBe cells (demonstrated by co-immunoprecipitation); knockdown or overexpression of DRA alters tight junction protein levels and epithelial permeability; TNF-α downregulates DRA via NF-κB activation, impairing barrier integrity, while DRA overexpression partially reverses TNF-α-induced damage. Immunofluorescence, co-immunoprecipitation, DRA knockdown/overexpression, transepithelial resistance, TNF-α treatment, NF-κB activation assay, DSS colitis mouse model, adenovirus-mediated DRA delivery Laboratory investigation Medium 29330471
2019 Neutrophil transepithelial migration generates adenosine that induces SLC26A3 expression in intestinal epithelial cells via an adenosine signaling pathway; induced SLC26A3 promotes pH buffering/acid-adaptive response during acute intestinal inflammation, as demonstrated by loss- and gain-of-function and colonoid studies. Neutrophil transepithelial migration model, microarray gene expression profiling, murine and human colonoids, loss- and gain-of-function, chronic DSS colitis model, pH measurement Mucosal immunology Medium 31792360
2022 Loss of DRA (SLC26A3) in colonocytes triggers release of IL-33, which drives type 2 mucosal immune dysregulation (increased ILC2, Th2, CD4+ Th2, RORγt+ Th17, FOXP3+ Tregs) via epithelial-immune cell crosstalk; in vivo IL-33 blocking confirmed the DRA→IL-33 signaling axis. NanoString Immunology Panel, FACS, immunoblotting, immunofluorescence, qRT-PCR, IL-33 blockade in DRA-KO mice, cohousing, antibiotics treatment, colonoid-derived monolayers from UC biopsies Cellular and molecular gastroenterology and hepatology Medium 36535508
2015 ATRA increases SLC26A3 (DRA) expression via the RAR-β receptor subtype and downstream HNF-1β transcription factor; RAR-β knockdown attenuates ATRA-induced DRA expression and HNF-1β siRNA inhibits ATRA-induced DRA induction. qRT-PCR, Western blot, DRA promoter-luciferase assay, RAR agonist/antagonist treatment, RAR-β siRNA, HNF-1β siRNA in Caco-2 cells The Journal of biological chemistry Medium 25887398
2024 Butyrate increases SLC26A3 expression and improves intestinal epithelial barrier function by inhibiting HDAC8, blunting the NF-κB pathway, and promoting histone acetylation at the SLC26A3 locus; pan-HDAC inhibitors and class-specific inhibitors identified HDAC8 as the primary target; HDAC8 activation counteracted the protective butyrate effect in DSS colitis. DSS colitis mouse model, Caco-2BBe cells, HDAC inhibitors (pan and class-specific), HDAC8-specific inhibition/activation, Western blot, qRT-PCR, histone acetylation assays Journal of agricultural and food chemistry Medium 39440960
2016 Keratin 8 (K8) is required for normal DRA protein levels in the colon; K8 knockout mice show near-complete loss of DRA protein in cecum and colon with a 3-4-fold reduction in DRA mRNA; K8 knockdown in Caco-2 cells similarly decreases DRA levels, indicating K8 modulates DRA in an inflammation-independent manner. K8-/- and K8+/- mouse analysis, immunofluorescence, Western blot, qRT-PCR, K8 siRNA knockdown in Caco-2 cells American journal of physiology. Gastrointestinal and liver physiology Medium 27125276
2018 Slc26a3 deficiency in mice is associated with severe epididymis dysplasia, abnormal cytoarchitecture, and impaired sperm quantitative, morphological, and functional parameters, compromising male fertility; phenotype is reminiscent of CFTR deficiency in the male genital tract. Slc26a3-/- mice, histological and morphological analysis of epididymis and sperm, fertility assays Molecular reproduction and development Medium 30118583
2000 DRA protein is expressed at apical membranes of both surface and crypt cells in rat colon; dietary Na depletion does not alter DRA mRNA abundance but reduces AE1 mRNA, indicating DRA encodes aldosterone-insensitive Cl-/OH- exchange while AE1 encodes aldosterone-regulated Cl-/HCO3- exchange in surface cells. RT-PCR, in situ hybridization, immunolocalization, dietary Na depletion rat model American journal of physiology. Gastrointestinal and liver physiology Medium 11052990

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nature genetics 328 8896562
1998 Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein. The Journal of experimental medicine 236 9782128
2006 slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon. The Journal of biological chemistry 184 17001077
2003 Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes. The Journal of physiology 132 12651923
1995 The transcriptional regulatory protein, YB-1, promotes single-stranded regions in the DRA promoter. The Journal of biological chemistry 128 7876087
1995 The Down regulated in Adenoma (dra) gene encodes an intestine-specific membrane sulfate transport protein. The Journal of biological chemistry 126 7744840
1990 Mutational analysis of the DRA promoter: cis-acting sequences and trans-acting factors. Molecular and cellular biology 124 2105459
2020 A Novel Role of SLC26A3 in the Maintenance of Intestinal Epithelial Barrier Integrity. Gastroenterology 114 33189700
2002 SLC26A3 mutations in congenital chloride diarrhea. Human mutation 114 12442266
1983 Combined lipase deficiency (cld): a lethal mutation on chromosome 17 of the mouse. Science (New York, N.Y.) 105 6857276
2011 Update on SLC26A3 mutations in congenital chloride diarrhea. Human mutation 95 21394828
1998 Intestinal inflammation reduces expression of DRA, a transporter responsible for congenital chloride diarrhea. The American journal of physiology 87 9843783
2006 Expression of SLC26A3, CFTR and NHE3 in the human male reproductive tract: role in male subfertility caused by congenital chloride diarrhoea. Molecular human reproduction 81 16421216
1998 The wzz (cld) protein in Escherichia coli: amino acid sequence variation determines O-antigen chain length specificity. Journal of bacteriology 78 9573151
1996 The down-regulated in adenoma (DRA) gene encodes an intestine-specific membrane glycoprotein. Oncogene 76 8570216
1991 Two B cell factors bind the HLA-DRA X box region and recognize different subsets of HLA class II promoters. Nucleic acids research 73 1956787
2011 Loss of downregulated in adenoma (DRA) impairs mucosal HCO3(-) secretion in murine ileocolonic inflammation. Inflammatory bowel diseases 72 21557395
2002 The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II. American journal of physiology. Cell physiology 72 12372813
2014 Slc26a3 deficiency is associated with loss of colonic HCO3 (-) secretion, absence of a firm mucus layer and barrier impairment in mice. Acta physiologica (Oxford, England) 70 24373192
2008 Cl- is required for HCO3- entry necessary for sperm capacitation in guinea pig: involvement of a Cl-/HCO3- exchanger (SLC26A3) and CFTR. Biology of reproduction 68 18784352
2012 Participation of the Cl-/HCO(3)- exchangers SLC26A3 and SLC26A6, the Cl- channel CFTR, and the regulatory factor SLC9A3R1 in mouse sperm capacitation. Biology of reproduction 67 21976599
1996 Dra-nupC-pdp operon of Bacillus subtilis: nucleotide sequence, induction by deoxyribonucleosides, and transcriptional regulation by the deoR-encoded DeoR repressor protein. Journal of bacteriology 65 8550462
1992 Single base pair substitutions within the HLA-DRA gene promoter separate the functions of the X1 and X2 boxes. Journal of immunology (Baltimore, Md. : 1950) 64 1560213
2009 Decreased expression of colonic Slc26a3 and carbonic anhydrase iv as a cause of fatal infectious diarrhea in mice. Infection and immunity 61 19546193
1990 NF-X2 that binds to the DRA X2-box is activator protein 1. Expression cloning of c-Jun. Journal of immunology (Baltimore, Md. : 1950) 61 1700011
1985 Combined lipase deficiency (cld/cld) in mice. Demonstration that an inactive form of lipoprotein lipase is synthesized. The Journal of biological chemistry 61 3972797
1990 Synthesis of inactive nonsecretable high mannose-type lipoprotein lipase by cultured brown adipocytes of combined lipase-deficient cld/cld mice. The Journal of biological chemistry 59 2104849
2004 Metabolic primers for detection of (Per)chlorate-reducing bacteria in the environment and phylogenetic analysis of cld gene sequences. Applied and environmental microbiology 56 15345454
2008 Functional coupling of the downregulated in adenoma Cl-/base exchanger DRA and the apical Na+/H+ exchangers NHE2 and NHE3. American journal of physiology. Gastrointestinal and liver physiology 54 19056765
2008 Congenital chloride-losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3. The Journal of biological chemistry 53 18216024
2012 SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer. Breast cancer research and treatment 52 23203637
1993 Isolation, characterization and evolution of ovine major histocompatibility complex class II DRA and DQA genes. Animal genetics 52 7902039
2016 CRISPR library designer (CLD): software for multispecies design of single guide RNA libraries. Genome biology 51 27013184
1997 Nature and origin of polymorphism in feline MHC class II DRA and DRB genes. Journal of immunology (Baltimore, Md. : 1950) 50 9058818
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