Affinage

SLC26A3

Chloride anion exchanger · UniProt P40879

Length
764 aa
Mass
84.5 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC26A3 (DRA) is the principal apical anion exchanger of differentiated intestinal columnar epithelium, mediating electroneutral Cl- absorption coupled to base secretion and serving as the major route for transcellular oxalate absorption and luminal sulfate secretion (PMID:23886857, PMID:23660504, PMID:28526688). Originally identified as a Na+-independent, DIDS-sensitive sulfate/oxalate transporter, it functions as a bidirectional Cl-/Cl- and Cl-/HCO3- exchanger whose activity strictly requires an intact STAS domain, while the distal ~44 C-terminal residues are dispensable (PMID:7744840, PMID:12651923). In vivo, loss of SLC26A3 abolishes colonic Cl-/base exchange and HCO3- secretion, eliminates fluid absorption, raises colonocyte pH, and prevents formation of the firmly adherent mucus layer, while expanding the colonic crypt proliferative zone (PMID:17001077, PMID:24373192). Transport is organized at the apical surface in cholesterol-rich lipid raft domains where activity is highest and is regulated by PDZ-adaptor proteins: the C-terminal ETKF motif binds E3KARP, intracellular Ca2+ inhibits the exchanger through PDZK1, and SNX27 recycles internalized DRA from rab5-positive endosomes back to active raft domains (PMID:12369822, PMID:19447883, PMID:32116023, PMID:20884887). DRA is functionally coupled to apical NHE2/NHE3 for NaCl absorption and is acutely stimulated by cAMP through a CFTR-dependent but channel-activity-independent mechanism; reciprocally, DRA activates CFTR through a function separable from its own exchange activity (PMID:19056765, PMID:29079751, PMID:30659943). Transcription is repressed by TNF-driven NF-kB p65 binding to the DRA promoter and induced by HNF-4/YY1/GATA and by butyrate acting through HDAC8 inhibition (PMID:28823863, PMID:17761837, PMID:39440960). Loss-of-function mutations in SLC26A3 cause congenital chloride diarrhea, and the resulting epithelial dysfunction compromises barrier integrity via CUGBP1-mediated post-transcriptional suppression of tight-junction proteins and drives IL-33-dependent type 2 immune dysregulation (PMID:8896562, PMID:33189700, PMID:36535508); CLD mutations also abolish efferent-duct ion transport, causing male subfertility (PMID:16421216, PMID:16412765).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 High

    Established that DRA is a functional membrane anion transporter, defining the gene product's biochemical activity for the first time.

    Evidence Xenopus oocyte expression with radiolabeled sulfate/oxalate uptake and DIDS inhibition

    PMID:7744840

    Open questions at the time
    • Did not resolve Cl-/HCO3- exchange as the physiological mode
    • No structural basis for substrate selectivity
  2. 1996 High

    Linked SLC26A3 to a Mendelian disease, showing loss-of-function causes congenital chloride diarrhea and tying the transporter to colonic physiology.

    Evidence Genetic segregation of missense and frameshift mutations in CLD families plus mRNA in situ hybridization in colon

    PMID:8570216 PMID:8896562

    Open questions at the time
    • Did not establish the transport defect mechanistically
    • Tissue restriction not yet linked to function
  3. 2003 High

    Defined the physiological transport mode as Cl-/HCO3- exchange and mapped the STAS domain as essential for activity, while linking CLD mutants to loss of function.

    Evidence Xenopus oocyte reconstitution with STAS deletion, C-terminal truncations, CLD mutant analysis, and CFTR co-expression

    PMID:12651923

    Open questions at the time
    • Molecular basis of STAS requirement unresolved
    • cAMP/CFTR coupling mechanism not dissected
  4. 2002 Medium

    Identified the PDZ-based scaffolding and cytosolic carbonic anhydrase dependence that organize DRA at the apical membrane.

    Evidence In vitro PDZ-domain binding to E3KARP with PDZ-motif mutagenesis, immunofluorescence colocalization, and CAII mutant overexpression in HEK-293 cells

    PMID:12369822 PMID:12372813

    Open questions at the time
    • E3KARP binding shown in vitro without cellular trafficking consequence
    • DRA-CAII coupling indirect, no direct interaction
  5. 2006 High

    Demonstrated in vivo that SLC26A3 is the major apical Cl-/base exchanger required for colonic chloride absorption and that its loss also alters crypt proliferation and reproductive-tract ion transport.

    Evidence Slc26a3-knockout mouse with colonic Cl- flux assays and compensatory transporter immunoblotting; human CLD efferent-duct immunohistochemistry and semen analysis

    PMID:16412765 PMID:16421216 PMID:17001077

    Open questions at the time
    • Mechanism linking transport loss to crypt hyperproliferation unresolved
    • Reproductive phenotype based on patient immunolocalization, not mouse genetics
  6. 2009 High

    Showed DRA is functionally coupled to apical NHE2/NHE3 and acutely regulated by Ca2+ via PDZK1-dependent, clathrin-mediated endocytosis, defining short-term regulation of NaCl absorption.

    Evidence 22Na+/36Cl- uptake coupling and endocytosis assays in Caco2BBE cells; pH-based assays with PDZ-motif deletion and PDZK1 co-transfection in HEK/Caco-2 cells

    PMID:19056765 PMID:19447883

    Open questions at the time
    • Synaptotagmin I role mechanistically incomplete
    • Physiological trigger for Ca2+ inhibition in vivo not defined
  7. 2011 High

    Mapped the N-glycosylation sites required for surface expression and proteolytic protection, defining post-translational control of DRA stability.

    Evidence Site-directed mutagenesis of N153/N161/N165, glycosidase treatment, surface expression and trypsin protection assays

    PMID:22159084

    Open questions at the time
    • Glycan structures not characterized
    • Link between glycosylation and disease mutations untested
  8. 2013 High

    Established DRA as the principal mediator of intestinal oxalate absorption and as a sulfate secretor, broadening its substrate physiology beyond Cl-.

    Evidence Unidirectional and net flux measurements across DRA-KO intestinal segments with urinary oxalate and sulfate correlates

    PMID:23660504 PMID:23886857 PMID:28526688

    Open questions at the time
    • Segment-specific contribution of paralogs not fully isolated
    • Directionality determinants of sulfate secretion unresolved
  9. 2014 High

    Showed that loss of SLC26A3 raises colonocyte pH, blocks NHE3-mediated fluid absorption, and eliminates the adherent mucus layer, connecting anion transport to mucosal barrier formation.

    Evidence In vivo perfusion and Ussing chamber HCO3- flux, fluorometric pHi, and MUC2 immunohistochemistry in Slc26a3-/- mice

    PMID:24373192

    Open questions at the time
    • Mechanism linking pH to mucus assembly not detailed
    • Causal chain to immune phenotype not yet established at this stage
  10. 2017 High

    Defined transcriptional repression of DRA by TNF/NF-kB and separated DRA's CFTR-activating function from its exchanger activity, refining how inflammation and CFTR coupling regulate transport.

    Evidence ChIP of p65 at mapped DRA promoter regions with reporter/siRNA/in vivo TNF; STAS-domain D688H mutant functional dissection of CFTR activation

    PMID:28823863 PMID:29079751

    Open questions at the time
    • Mechanism by which DRA activates CFTR unresolved
    • p65 cofactors at the promoter not identified
  11. 2019 High

    Resolved cAMP stimulation of DRA as CFTR-protein-dependent but channel-activity-independent and showed inflammation-associated adenosine induces DRA to buffer luminal pH.

    Evidence DRA-specific inhibitor, CFTR-KO and HEK293 co-expression rescue, colonoid monolayers; microarray plus loss/gain-of-function in colitis models and colonoids

    PMID:30659943 PMID:31792360

    Open questions at the time
    • Molecular intermediary of CFTR-protein-dependent cAMP stimulation unknown
    • In vivo relevance of adenosine-DRA axis in human disease incomplete
  12. 2020 Medium

    Connected DRA loss to barrier dysfunction via CUGBP1-mediated post-transcriptional suppression of tight-junction proteins and identified SNX27-dependent endosomal recycling to lipid rafts.

    Evidence RNP-IP and permeability assays in DRA-KO colon with cohousing controls; SNX27 co-IP, knockdown, and super-resolution imaging in Caco-2 cells

    PMID:32116023 PMID:33189700

    Open questions at the time
    • CUGBP1 activation upstream of DRA loss not mechanistically linked
    • SNX27 recycling shown in cell line only, not in vivo
  13. 2022 Medium

    Established that colonocyte DRA loss drives IL-33-dependent type 2 immune dysregulation, linking the transporter defect to mucosal immune homeostasis.

    Evidence NanoString/FACS immune profiling with in vivo IL-33 blockade in DRA-KO mice, ex vivo colonoids, and UC patient monolayers

    PMID:36535508

    Open questions at the time
    • Signal coupling transport loss to IL-33 release undefined
    • Causality versus dysbiosis only partially excluded
  14. 2024 Medium

    Clarified butyrate's induction of SLC26A3 as HDAC8 inhibition that blunts NF-kB and promotes histone acetylation at the locus, integrating metabolic and inflammatory transcriptional control.

    Evidence HDAC inhibitor panel, histone acetylation assays, and Slc26a3 expression in Caco-2BBe and DSS colitis mice

    PMID:39440960

    Open questions at the time
    • Direct HDAC8 occupancy at the locus not shown
    • Interplay with HNF-4/YY1/GATA regulation not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of STAS-domain-dependent transport, the molecular mechanism by which DRA activates CFTR, and the signal coupling epithelial DRA loss to IL-33 release remain unresolved.
  • No high-resolution structure of human SLC26A3
  • Mechanism of CFTR activation separable from exchange activity unknown
  • Sensor linking transport loss to immune signaling undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0060090 molecular adaptor activity 3 GO:0140104 molecular carrier activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2
Pathway
R-HSA-382551 Transport of small molecules 5 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 2
Partners
CFTRNHE3PDZK1SLC9A3R1SNX27ZO-1

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 SLC26A3 (DRA) encodes a Na+-independent transporter for sulfate and oxalate, as demonstrated by functional expression in Xenopus oocytes; transport was sensitive to the anion exchange inhibitor DIDS. Xenopus oocyte expression system with radiolabeled ion uptake assays The Journal of biological chemistry High 7744840
1996 Mutations in SLC26A3 (DRA) cause congenital chloride diarrhea (CLD); two missense mutations (deltaV317, H124L) and one frameshift (344delT) segregate with CLD in Finnish and Polish patients. DRA expression by mRNA in situ hybridization is preferentially in differentiated colonic epithelial cells. Genetic mapping, mutation screening, mRNA in situ hybridization Nature genetics High 8896562
1996 SLC26A3 (DRA) protein is a membrane glycoprotein expressed specifically in intestinal columnar epithelial cells, particularly at the brush border, with expression limited to duodenum, ileum, cecum, and distal colon but absent from esophagus and stomach. Immunohistochemistry, Northern blot, in situ hybridization Oncogene Medium 8570216
2003 SLC26A3 expressed in Xenopus oocytes mediates bidirectional Cl-/Cl- and Cl-/HCO3- exchange; transport of oxalate was low and sulfate/butyrate transport was undetectable. Deletion of the STAS domain abolished transport function, but truncation of up to 44 C-terminal amino acids left function intact. Two CLD missense disease mutants were nonfunctional. cAMP-insensitive Cl-/HCO3- exchange gained modest cAMP sensitivity when co-expressed with CFTR. Xenopus oocyte expression, C-terminal truncation mutants, disease mutant functional analysis, co-expression with CFTR The Journal of physiology High 12651923
2002 The C-terminal PDZ-binding motif (ETKF) of DRA binds to the second PDZ domain of the adapter protein E3KARP (NHE3 kinase A regulatory protein) in vitro, with affinity comparable to CFTR. The C-terminal phenylalanine is critical and can only be substituted by leucine. DRA, NHE3, and E3KARP colocalize in the apical compartment of human proximal colon by immunofluorescence. In vitro PDZ-domain binding assay, site-directed mutagenesis of PDZ motif, immunofluorescence colocalization Biochemistry Medium 12369822
2002 DRA-mediated HCO3- transport activity in HEK-293 cells is inhibited ~53% by the carbonic anhydrase inhibitor acetazolamide (membrane-permeant), but not by a membrane-impermeant CA inhibitor. Unlike AE1, DRA's C-terminal tail interacts only weakly with CAII; overexpression of a functionally inactive CAII mutant (V143Y) had no effect on DRA transport (vs. 61% inhibition of AE1), indicating DRA requires cytosolic CAII but not through direct interaction. Intracellular pH-based anion exchange assay in transfected HEK-293 cells, CAII mutant overexpression, pharmacological inhibition American journal of physiology. Cell physiology Medium 12372813
2006 Slc26a3-knockout mice exhibit chloride-losing diarrhea with high chloride content, volume depletion, growth retardation, distended colonic loops, and massively expanded colonic crypt proliferative zone. Apical membrane Cl-/base exchange activity was sharply reduced in null mouse colon. Adaptive up-regulation of NHE3, H,K-ATPase, and ENaC occurred in response. SLC26A3 is the major apical Cl-/base exchanger essential for colonic chloride absorption and also regulates colonic crypt proliferation. Gene targeting/knockout mouse, functional Cl- flux assays in colon, immunoblotting of compensatory transporters, plasma aldosterone measurement The Journal of biological chemistry High 17001077
2006 SLC26A3 is expressed in the male reproductive tract (elongating spermatids, efferent ducts, epididymis, seminal vesicle) and co-localizes with CFTR and NHE3 at apical membranes of efferent duct non-ciliated cells. In CLD patients (V317del), SLC26A3 and CFTR expression was absent in efferent ducts but normal in testis, suggesting a primary role for SLC26A3 in male reproductive tract ion transport. Immunohistochemistry in human testis, efferent ducts, epididymis, seminal vesicle from controls and CLD patients Molecular human reproduction Medium 16421216
2006 Men with CLD (SLC26A3 mutations) exhibit constant oligoasthenoteratozoospermia with normal spermatogenesis, high chloride and low pH in seminal plasma, and spermatoceles, establishing that disruption of SLC26A3-mediated Cl-/HCO3- exchange in the male reproductive tract causes male subfertility. Prospective clinical and laboratory study in 8 adult male CLD patients; semen analysis, seminal plasma electrolytes, pH measurement Fertility and sterility Medium 16412765
2008 DRA-mediated Cl-/base exchange in Caco2BBE cells is functionally coupled to apical NHE2 and NHE3; DRA activity was largely dependent on apical NHE activity, and coupled transport was inhibited by increased cellular cAMP and calcium through synaptotagmin I-dependent, clathrin-mediated endocytosis. 22Na+ and 36Cl- uptake in Caco2BBE cells with inducible DRA transgene, pharmacological inhibitors, endocytosis assays American journal of physiology. Gastrointestinal and liver physiology Medium 19056765
2009 DRA is inhibited by elevated intracellular calcium [Ca2+]i. In Caco-2 cells, Ca2+-dependent inhibition via natural agonist UTP required the PDZ-binding motif of DRA and interaction with the PDZ adaptor PDZK1. In HEK cells lacking PDZK1, additional transfection of PDZK1 was required for UTP-mediated inhibition of DRA. Intracellular pH measurements in HEK and Caco-2 cells expressing wild-type or PDZ-motif-deleted DRA, calcium ionophores, PDZK1 co-transfection, UTP stimulation The Journal of biological chemistry High 19447883
2011 SLC26A3 is N-glycosylated at residues N153, N161, and N165 in the large second extracellular loop. Deglycosylation reduces cell surface expression of SLC26A3 and increases susceptibility to tryptic proteolysis; transport activity is reduced but not abolished when glycosylation is absent. Glycosidase treatment, site-directed mutagenesis of N-glycosylation consensus sites (N→Q substitutions), cell surface expression assay, trypsin digestion protection assay, immunoblotting American journal of physiology. Cell physiology High 22159084
2012 SLC26A3, SLC26A6, and SLC9A3R1 (NHERF1) are expressed in mouse sperm, localize to the midpiece, and interact with each other and with CFTR as shown by immunoprecipitation. SLC26A3 and CFTR are functionally involved in the db-cAMP-induced increase in intracellular Cl- during sperm capacitation, and SLC26A3 inhibitors interfere with membrane potential changes during capacitation. RT-PCR, immunocytochemistry, Western blot, co-immunoprecipitation, pharmacological inhibition of sperm capacitation assays Biology of reproduction Medium 21976599
2013 DRA (Slc26a3) mediates the predominant apical uptake of oxalate and Cl- absorbed in small and large intestine of mice; DRA-KO mice show net anion secretion and a 66% reduction in urinary oxalate excretion without changes in urinary creatinine, establishing DRA as the principal mediator of transcellular intestinal oxalate absorption. Unidirectional and net ion flux measurements across short-circuited intestinal segments from wild-type and DRA-KO mice; urine collection and analysis American journal of physiology. Gastrointestinal and liver physiology High 23886857
2013 DRA (Slc26a3) mediates sulfate secretion and Cl- absorption in the mouse cecum; DRA-KO mice reversed cecal SO4 secretion to net absorption (60% reduction in serosal-to-mucosal SO4 flux) and abolished net Cl- absorption, demonstrating DRA mediates DIDS-sensitive HCO3-/SO4 exchange in addition to being the principal DIDS-resistant Cl-/HCO3- exchanger. Transepithelial 35SO4 and 36Cl- flux measurements in isolated short-circuited cecum from WT and DRA-KO mice, pharmacological inhibition (DIDS, bumetanide), ion substitution experiments American journal of physiology. Gastrointestinal and liver physiology High 23660504
2014 Slc26a3 deletion results in severely reduced colonic HCO3- secretory rate, loss of colonic fluid absorption, and absence of a firmly adherent mucus layer; the high colonocyte pH in KO mice prevented NHE3-mediated fluid absorption in vivo despite increased NHE3 expression. Single-pass in vivo perfusion and Ussing chamber HCO3- flux measurements, fluorometric pHi assay, MUC2 immunohistochemistry in Slc26a3-/- mice Acta physiologica High 24373192
2017 TNF activates NF-κB, which reduces SLC26A3 expression by direct binding of the p65 subunit to the DRA promoter at regions -935 to -629 and -375 to -84. Knockdown of IκBα, expression of p65 or p50 transgenes, and chromatin immunoprecipitation confirmed direct p65-promoter interaction as the mechanism of DRA transcriptional repression. NF-κB luciferase reporter assay, chromatin immunoprecipitation (ChIP) of p65 at DRA promoter, IκBα siRNA knockdown, 125I uptake transport assay, enteroid/mouse in vivo TNF injection model Gastroenterology High 28823863
2017 DRA (Slc26a3) contributes to sulfate efflux at the apical membrane of the distal ileum; DRA-KO mice showed enhanced net sulfate absorption (increased mucosal-to-serosal flux, reduced serosal-to-mucosal flux), elevated plasma sulfate (61% higher), and 2.2-fold increased urinary sulfate, demonstrating DRA secretes sulfate into the intestinal lumen. Transepithelial 35SO4 and 36Cl- fluxes in short-circuited distal ileum from WT and DRA-KO mice; urine and plasma sulfate measurements American journal of physiology. Gastrointestinal and liver physiology High 28526688
2017 A missense mutation in the STAS domain of SLC26A3 (p.Asp688His) retains normal Cl-/HCO3- exchange activity but suppresses CFTR-dependent anion transport despite unaffected STAS domain binding and expression, revealing that SLC26A3 activates CFTR through a mechanism separable from its own anion exchange activity. Exon sequencing, functional anion transport assays, CFTR activation assays with wild-type and D688H mutant SLC26A3 Scientific reports Medium 29079751
2018 DRA colocalizes and directly binds tight junction proteins (ZO-1) as shown by co-immunoprecipitation in polarized Caco-2BBe cells; knockdown or overexpression of DRA alters tight junction protein expression and epithelial permeability. TNF-α downregulates DRA via NF-κB activation, subsequently compromising barrier integrity. Co-immunoprecipitation, immunofluorescence, siRNA knockdown, DRA overexpression, TEER and permeability assays, DSS colitis mouse model with adenoviral DRA delivery Laboratory investigation Medium 29330471
2019 cAMP (forskolin) acutely stimulates DRA activity in human colonoids and Caco-2 cells by a CFTR-dependent mechanism that does not require CFTR channel activity (not blocked by CFTRinh-172). In HEK293 cells lacking CFTR, cAMP had no effect on DRA; co-expression of CFTR restored cAMP stimulation of DRA. DRA-specific inhibitor (DRAinh-A250), CFTR-knockout cell model, colonoid monolayers, Caco-2 cells, HEK293/DRA±CFTR co-expression, anion exchange transport assay Cellular and molecular gastroenterology and hepatology High 30659943
2019 Adenosine (Ado) generated during neutrophil transepithelial migration induces SLC26A3 expression in intestinal epithelial cells, and SLC26A3 promotes an adaptive phenotype that buffers local pH during active inflammation; loss-of-function of SLC26A3 abrogated pH buffering during PMN-induced acidification. Unbiased gene expression microarray, loss- and gain-of-function approaches, murine and human colonoids, chronic colitis mouse models, pH measurement assays Mucosal immunology Medium 31792360
2020 DRA deficiency increases colonic paracellular permeability with decreased ZO-1, occludin, and E-cadherin; increased binding of RNA-binding protein CUGBP1 to occludin and E-cadherin transcripts in DRA-KO mouse colon suggests posttranscriptional downregulation of barrier proteins. Dysbiosis plays only a partial role (cohousing studies). FITC-dextran flux assay, immunoblotting, immunofluorescence, immunohistochemistry, ribonucleoprotein immunoprecipitation (RNP-IP), gut microbiome analysis, cohousing, DRA-KO mouse colonoids, Caco-2 shRNA knockdown Gastroenterology Medium 33189700
2020 SNX27 interacts with DRA via its PDZ domain in rab5-positive early endosomes at the apical pole of differentiated intestinal Caco-2 cells. SNX27 knockdown reduces DRA activity by 50% without decreasing surface expression, indicating SNX27 mediates direct recycling of DRA to lipid raft domains where it is most active. Co-immunoprecipitation, SNX27 knockdown, super-resolution microscopy, DRA activity assay, methyl-β-cyclodextrin (lipid raft disruption), co-localization with rab5 endosome marker American journal of physiology. Gastrointestinal and liver physiology Medium 32116023
2007 The DRA promoter contains functional binding sites for HNF-4 (required for basal activity), YY1, and GATA transcription factors. Sodium butyrate induces DRA promoter activity in LS174T cells via YY1 and GATA binding. IFN-γ reduces DRA promoter activity in Caco-2 cells. A single transcription initiation site was identified by primer extension. Reporter gene assays (3765-bp DRA promoter fragment), primer extension, EMSA, transcription factor binding site mutagenesis, transgenic mouse with DRA promoter-HGH reporter American journal of physiology. Gastrointestinal and liver physiology Medium 17761837
2010 DRA (SLC26A3) is predominantly expressed in the detergent-insoluble, low-density (lipid raft) fractions of colonic apical membranes. NPY stimulates DRA Cl-/HCO3- exchange activity via ERK1/2 MAP kinase pathway by enhancing DRA association with lipid rafts, without changing total DRA surface expression. Cholesterol depletion by MβCD decreases DRA lipid raft association and reduces Cl-/HCO3- exchange activity. Detergent-resistant membrane fractionation, cell surface biotinylation, 36Cl- uptake assay, cholesterol depletion (MβCD), ERK1/2 inhibitor, NPY receptor agonists American journal of physiology. Gastrointestinal and liver physiology Medium 20884887
2015 DRA recycling to the apical membrane involves clathrin-mediated endocytosis and microtubule-dependent exocytosis under basal conditions. EPEC infection reduces DRA surface expression via increased endocytosis and decreased exocytosis through virulence genes espG1 and espG2, via a clathrin-independent internalization mechanism. Cell surface biotinylation for endocytosis/exocytosis rates, pharmacological inhibitors (chlorpromazine, dynasore, nocodazole), EPEC infection with virulence gene mutants, confocal microscopy, 125I uptake transport assay, colchicine-treated mouse colon American journal of physiology. Cell physiology Medium 26447204
2022 Loss of DRA in colonocytes triggers release of IL-33 (>8-fold induction), which drives type 2 immune dysregulation (increased ILC2, Th2, Th17, and GATA3+ iTregs) via epithelial-immune cell crosstalk. In vivo IL-33 blocking established that T2 immune dysregulation in DRA-KO mice is IL-33-dependent. NanoString Immunology Panel, FACS, immunoblotting, qRT-PCR, IL-33 blocking antibody in DRA-KO mice, ex vivo colonoid studies, cohousing/antibiotics to rule out microbiota, UC patient colonoid-derived monolayers Cellular and molecular gastroenterology and hepatology Medium 36535508
2024 Butyrate increases SLC26A3 expression by inhibiting HDAC8, which blunts NF-κB pathway activity and promotes histone acetylation at the Slc26a3 locus in intestinal epithelial cells. Pan-HDAC inhibitor and class-specific inhibitor experiments identified HDAC8 as the primary target; HDAC8 activation counteracted butyrate's protective effect in DSS colitis. DSS colitis mouse model, Caco-2BBe cells, HDAC inhibitor panel (pan-HDAC and class-specific), histone acetylation assay, NF-κB pathway analysis, Slc26a3 expression by qPCR and Western blot Journal of agricultural and food chemistry Medium 39440960

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
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 Down regulated in Adenoma (dra) gene encodes an intestine-specific membrane sulfate transport protein. The Journal of biological chemistry 126 7744840
2020 A Novel Role of SLC26A3 in the Maintenance of Intestinal Epithelial Barrier Integrity. Gastroenterology 120 33189700
2002 SLC26A3 mutations in congenital chloride diarrhea. Human mutation 116 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 79 9573151
2002 The down regulated in adenoma (dra) gene product binds to the second PDZ domain of the NHE3 kinase A regulatory protein (E3KARP), potentially linking intestinal Cl-/HCO3- exchange to Na+/H+ exchange. Biochemistry 77 12369822
1996 The down-regulated in adenoma (DRA) gene encodes an intestine-specific membrane glycoprotein. Oncogene 76 8570216
2010 Segregation of Na/H exchanger-3 and Cl/HCO3 exchanger SLC26A3 (DRA) in rodent cecum and colon. American journal of physiology. Gastrointestinal and liver physiology 74 20466943
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
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) 71 24373192
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 69 21976599
1992 In vivo footprint analysis of the HLA-DRA gene promoter: cell-specific interaction at the octamer site and up-regulation of X box binding by interferon gamma. Proceedings of the National Academy of Sciences of the United States of America 68 1502171
2004 Genetic polymorphisms of ADH2, ADH3, CYP4502E1 Dra-I and Pst-I, and ALDH2 in Spanish men: lack of association with alcoholism and alcoholic liver disease. Journal of hepatology 66 15519646
2014 HLA-DRA variants predict penicillin allergy in genome-wide fine-mapping genotyping. The Journal of allergy and clinical immunology 65 25224099
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
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
2013 Transcellular oxalate and Cl- absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate. American journal of physiology. Gastrointestinal and liver physiology 59 23886857
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 55 19056765
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
1997 Nature and origin of polymorphism in feline MHC class II DRA and DRB genes. Journal of immunology (Baltimore, Md. : 1950) 50 9058818
2009 Lactobacillus acidophilus stimulates the expression of SLC26A3 via a transcriptional mechanism. American journal of physiology. Gastrointestinal and liver physiology 49 20044511
2002 Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis. American journal of physiology. Gastrointestinal and liver physiology 49 12181169
2000 Regulation of DRA and AE1 in rat colon by dietary Na depletion. American journal of physiology. Gastrointestinal and liver physiology 48 11052990
2019 cAMP Stimulates SLC26A3 Activity in Human Colon by a CFTR-Dependent Mechanism That Does Not Require CFTR Activity. Cellular and molecular gastroenterology and hepatology 47 30659943
2018 SLC26A3 (DRA) prevents TNF-alpha-induced barrier dysfunction and dextran sulfate sodium-induced acute colitis. Laboratory investigation; a journal of technical methods and pathology 46 29330471
2024 Butyrate Inhibits the HDAC8/NF-κB Pathway to Enhance Slc26a3 Expression and Improve the Intestinal Epithelial Barrier to Relieve Colitis. Journal of agricultural and food chemistry 40 39440960
2016 Lactobacillus acidophilus counteracts inhibition of NHE3 and DRA expression and alleviates diarrheal phenotype in mice infected with Citrobacter rodentium. American journal of physiology. Gastrointestinal and liver physiology 40 27634011
2011 Role of N-glycosylation in cell surface expression and protection against proteolysis of the intestinal anion exchanger SLC26A3. American journal of physiology. Cell physiology 40 22159084
2007 Molecular cloning and promoter analysis of downregulated in adenoma (DRA). American journal of physiology. Gastrointestinal and liver physiology 40 17761837
1996 A Wzz (Cld) protein determines the chain length of K lipopolysaccharide in Escherichia coli O8 and O9 strains. Journal of bacteriology 39 8606163
1991 Transcriptional regulation of the HLA-DRA gene. Critical reviews in immunology 39 1930684
2017 Activation of Nuclear Factor-κB by Tumor Necrosis Factor in Intestinal Epithelial Cells and Mouse Intestinal Epithelia Reduces Expression of the Chloride Transporter SLC26A3. Gastroenterology 37 28823863
2014 Probiotic Bifidobacterium species stimulate human SLC26A3 gene function and expression in intestinal epithelial cells. American journal of physiology. Cell physiology 37 25143346
2020 Slc26a3 deletion alters pH-microclimate, mucin biosynthesis, microbiome composition and increases the TNFα expression in murine colon. Acta physiologica (Oxford, England) 36 32415725
2006 Disruption of the SLC26A3-mediated anion transport is associated with male subfertility. Fertility and sterility 35 16412765
2006 Direct role of NF-kappaB activation in Toll-like receptor-triggered HLA-DRA expression. European journal of immunology 35 16619292
2021 Slc26a3 (DRA) in the Gut: Expression, Function, Regulation, Role in Infectious Diarrhea and Inflammatory Bowel Disease. Inflammatory bowel diseases 34 32989468
1998 Expression and crystallization of the complex of HLA-DR2 (DRA, DRB1*1501) and an immunodominant peptide of human myelin basic protein. Proceedings of the National Academy of Sciences of the United States of America 32 9751750
1986 Effect of combined lipase deficiency (cld/cld) on hepatic and lipoprotein lipase activities in liver and plasma of newborn mice. Biochimica et biophysica acta 30 3955063
2022 HLA class II molecule HLA-DRA identifies immuno-hot tumors and predicts the therapeutic response to anti-PD-1 immunotherapy in NSCLC. BMC cancer 29 35794593
2014 Lactobacillus acidophilus attenuates downregulation of DRA function and expression in inflammatory models. American journal of physiology. Gastrointestinal and liver physiology 29 25059823
2019 Insights into the polymorphism in HLA-DRA and its evolutionary relationship with HLA haplotypes. HLA 28 31617688
2009 Polymorphism and selection in the major histocompatibility complex DRA and DQA genes in the family Equidae. Immunogenetics 28 19557406
1998 Genomic structure of the human congenital chloride diarrhea (CLD) gene. Gene 27 9729124
2018 Protostemonine attenuates alternatively activated macrophage and DRA-induced asthmatic inflammation. Biochemical pharmacology 26 29991449
2009 Intestinal anion exchanger down-regulated in adenoma (DRA) is inhibited by intracellular calcium. The Journal of biological chemistry 26 19447883
2011 LPA stimulates intestinal DRA gene transcription via LPA2 receptor, PI3K/AKT, and c-Fos-dependent pathway. American journal of physiology. Gastrointestinal and liver physiology 25 22159277
1992 B-cell factor 1 is required for optimal expression of the DRA promoter in B cells. Molecular and cellular biology 25 1569956
2018 Slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse. Molecular reproduction and development 24 30118583
2017 A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR. Scientific reports 24 29079751
2001 Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea. Human mutation 24 11524734
1999 cld and lec23 are disparate mutations that affect maturation of lipoprotein lipase in the endoplasmic reticulum. Journal of lipid research 24 10553008
1990 Lipoprotein lipase mRNA in neonatal and adult mouse tissues: comparison of normal and combined lipase deficiency (cld) mice assessed by in situ hybridization. Journal of lipid research 24 2079607
2023 Increased intestinal permeability and downregulation of absorptive ion transporters Nhe3, Dra, and Sglt1 contribute to diarrhea during Clostridioides difficile infection. Gut microbes 22 37350393
2019 Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3. Mucosal immunology 22 31792360
2015 Slc26a3/Dra and Slc26a6 in Murine Ameloblasts. Journal of dental research 22 26394631
2004 Oct-1 maintains an intermediate, stable state of HLA-DRA promoter repression in Rb-defective cells: an Oct-1-containing repressosome that prevents NF-Y binding to the HLA-DRA promoter. The Journal of biological chemistry 22 15105429
2022 Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer. Cellular oncology (Dordrecht, Netherlands) 21 35543859
2015 All-trans-retinoic Acid Increases SLC26A3 DRA (Down-regulated in Adenoma) Expression in Intestinal Epithelial Cells via HNF-1β. The Journal of biological chemistry 20 25887398
1996 Brefeldin A enables synthesis of active lipoprotein lipase in cld/cld and castanospermine-treated mouse brown adipocytes via translocation of Golgi components to endoplasmic reticulum. The Biochemical journal 20 8694753
1992 Activation of the HLA-DRA gene in primary human T lymphocytes: novel usage of TATA and the X and Y promoter elements. Molecular and cellular biology 20 1448091
1986 Effect of the combined lipase deficiency mutation (cld/cld) on ultrastructure of tissues in mice. Diaphragm, heart, brown adipose tissue, lung, and liver. Laboratory investigation; a journal of technical methods and pathology 20 3747449
2013 Translational repression of SLC26A3 by miR-494 in intestinal epithelial cells. American journal of physiology. Gastrointestinal and liver physiology 19 24177028
2010 Study of cynomolgus monkey (Macaca fascicularis) DRA polymorphism in four populations. Immunogenetics 19 20094710
2000 Catabolite repression of dra-nupC-pdp operon expression in Bacillus subtilis. Microbiology (Reading, England) 19 11065368
1993 Current concepts in DRA gene regulation. Immunologic research 19 8515184
2022 CD74 and HLA-DRA in Cervical Carcinogenesis: Potential Targets for Antitumour Therapy. Medicina (Kaunas, Lithuania) 18 35208514
2022 Loss of SLC26A3 Results in Colonic Mucosal Immune Dysregulation via Epithelial-Immune Cell Crosstalk. Cellular and molecular gastroenterology and hepatology 18 36535508
2017 Loss of the anion exchanger DRA (Slc26a3), or PAT1 (Slc26a6), alters sulfate transport by the distal ileum and overall sulfate homeostasis. American journal of physiology. Gastrointestinal and liver physiology 18 28526688
2015 Mechanisms of DRA recycling in intestinal epithelial cells: effect of enteropathogenic E. coli. American journal of physiology. Cell physiology 18 26447204
2010 Stimulation of apical Cl⁻/HCO₃⁻(OH⁻) exchanger, SLC26A3 by neuropeptide Y is lipid raft dependent. American journal of physiology. Gastrointestinal and liver physiology 18 20884887
1991 Description of a polymorphism in the regulatory region of the HLA-DRA gene. Human immunology 18 1685491
2013 Sulfate secretion and chloride absorption are mediated by the anion exchanger DRA (Slc26a3) in the mouse cecum. American journal of physiology. Gastrointestinal and liver physiology 17 23660504
2009 Regulation of the intestinal anion exchanger DRA (downregulated in adenoma). Annals of the New York Academy of Sciences 17 19538314
1998 Intestinal cancer in patients with a germline mutation in the down-regulated in adenoma (DRA) gene. Oncogene 17 9482116
1998 Combined lipase deficiency (cld/cld) in mice affects differently post-translational processing of lipoprotein lipase, hepatic lipase and pancreatic lipase. Chemistry and physics of lipids 17 9720257
2012 Multiple histone methyl and acetyltransferase complex components bind the HLA-DRA gene. PloS one 16 22701520
1993 The regulatory gene, hXBP-1, and its target, HLA-DRA, utilize both common and distinct regulatory elements and protein complexes. The Journal of biological chemistry 16 8349596
2016 Effect of Genetic Diversity in Swine Leukocyte Antigen-DRA Gene on Piglet Diarrhea. Genes 15 27429004
1999 HLA-DMB gene and HLA-DRA promoter region polymorphisms in Australian multiple sclerosis patients. Human immunology 15 10527398
2023 Small molecule inhibitors of intestinal epithelial anion exchanger SLC26A3 (DRA) with a luminal, extracellular site of action. European journal of medicinal chemistry 13 36724632
2022 Upregulation of antimicrobial peptide expression in slc26a3-/- mice with colonic dysbiosis and barrier defect. Gut microbes 13 35230892
2022 Vitamin D receptor involves in the protection of intestinal epithelial barrier function via up-regulating SLC26A3. The Journal of steroid biochemistry and molecular biology 13 36462760
2018 Effect of Ovar-DRA and Ovar-DRB1 genotype in small ruminants with haemonchosis. Parasite immunology 13 29719931
2016 HLA-DRA/HLA-DRB5 polymorphism affects risk of sporadic ALS and survival in a southwest Chinese cohort. Journal of the neurological sciences 13 28131168
1993 T-cell repertoire in a strain of transgenic C57BL/6 mice with the HLA-DRA gene on the X-chromosome. Immunogenetics 13 8420827
2022 CD55-deficiency in Jews of Bukharan descent is caused by the Cromer blood type Dr(a-) variant. Human genetics 12 35314883
2020 SNX27 regulates DRA activity and mediates its direct recycling by PDZ-interaction in early endosomes at the apical pole of Caco2 cells. American journal of physiology. Gastrointestinal and liver physiology 12 32116023
2001 Differential effect of combined lipase deficiency (cld/cld) on human hepatic lipase and lipoprotein lipase secretion. Journal of lipid research 12 11714855

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