Affinage

SLC13A2

Solute carrier family 13 member 2 · UniProt Q13183

Length
592 aa
Mass
64.4 kDa
Annotated
2026-06-10
18 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC13A2 (NaDC-1) is an apical-membrane, sodium-coupled cotransporter of the renal proximal tubule that mediates electrogenic uptake of TCA-cycle dicarboxylates and tricarboxylates, providing a physiological route for citrate and succinate reabsorption (PMID:8596711, PMID:10886565, PMID:27927654). Transport is electrogenic and high-stoichiometry, with a Hill coefficient of ~2.9 for sodium indicating three Na+ co-transported per succinate, and shows pH-dependent citrate handling versus pH-insensitive succinate handling (PMID:8596711, PMID:14973148). Systematic mutagenesis localized cation- and substrate-binding determinants to acidic residues Asp-373 (TM8) and Glu-475 (TM9) and to Lys-84 and Arg-349, while His-106 and multiple cysteines are required not for catalysis but for surface expression and trafficking (PMID:9512488, PMID:10360950, PMID:10548552, PMID:10970779). Activity is acutely suppressed by PKC activation through endocytic removal and direct inhibition independent of consensus phosphorylation sites (PMID:10446305), and is chronically upregulated in metabolic acidosis via increased apical protein abundance through two parallel signaling arms: an endothelin-1/ETB-receptor pathway and a Pyk2/c-Src – Raf1-ERK1/2-p90RSK cascade (PMID:10886565, PMID:20703215, PMID:29678998). SLC13A2 is reciprocally regulated by SLC26A6, whose STAS domain binds the first intracellular loop of NaDC-1 to inhibit its transport and thereby couple citrate and oxalate handling (PMID:23833257). Beyond the kidney, SLC13A2-imported citrate fuels ACLY-dependent acetyl-CoA production for de novo cholesterol synthesis, driving hepatocyte proliferation during liver regeneration (PMID:39824985), and supports protein and histone acetylation that promotes PKM2 acetylation/degradation and tumor suppression in hepatocellular carcinoma (PMID:41950310).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    Established NaDC-1 as a sodium-coupled di/tricarboxylate cotransporter and defined its core transport mechanism, answering what substrates and ion stoichiometry the protein uses.

    Evidence Heterologous expression in COS-7 cells with radiolabeled succinate/citrate uptake and Hill-coefficient kinetic analysis

    PMID:8596711

    Open questions at the time
    • No structural model of the transport cycle
    • pH-sensitivity mechanism for citrate versus succinate not defined at the residue level
  2. 1998 High

    Distinguished residues needed for catalysis from those needed for surface delivery, showing His-106 governs trafficking rather than transport.

    Evidence Systematic mutagenesis of all 11 histidines with cell-surface biotinylation and succinate uptake in Xenopus oocytes

    PMID:9512488

    Open questions at the time
    • Trafficking machinery interacting with His-106 not identified
  3. 1999 High

    Mapped cation- and substrate-binding determinants to acidic transmembrane residues, building a topological picture of the binding site.

    Evidence Site-directed mutagenesis of acidic residues with two-electrode voltage clamp and uptake kinetics in oocytes

    PMID:10360950

    Open questions at the time
    • No high-resolution structure to confirm residue geometry
    • Reported anion-channel-like behavior of E475A not mechanistically resolved
  4. 1999 High

    Showed cysteines are collectively required for stability/trafficking rather than individually for transport, and identified pCMBS-accessible residues marking the aqueous transport pathway.

    Evidence Complete cysteine mutagenesis with pCMBS accessibility probing in oocytes

    PMID:10548552

    Open questions at the time
    • Conformational states sampled by accessible cysteines not defined
  5. 1999 High

    Defined PKC as an acute negative regulator acting through endocytosis plus direct inhibition, independent of canonical phosphorylation sites.

    Evidence PKC/PKA pharmacology, phosphosite mutagenesis, surface protein quantification and cytochalasin D treatment in oocytes

    PMID:10446305

    Open questions at the time
    • Molecular target of PKC if not direct phosphorylation of NaDC-1 unknown
    • Endocytic adaptors not identified
  6. 2000 Medium

    Identified additional substrate-handling residues (Lys-84, Arg-349) refining the succinate-binding site.

    Evidence Site-directed mutagenesis with transport kinetics in oocytes

    PMID:10970779

    Open questions at the time
    • Single-lab kinetic inference without structural confirmation
    • Distinct effects on succinate versus citrate not mechanistically explained
  7. 2000 Medium

    Demonstrated physiological regulation in vivo, showing metabolic acidosis raises apical NaDC-1 mRNA and protein in proximal tubule while alkali has no effect.

    Evidence Rat acidosis model with immunohistochemistry, brush-border immunoblot and mRNA quantification

    PMID:10886565

    Open questions at the time
    • Signaling pathway linking acidosis to expression not yet defined
    • Segment-specific regulation mechanism unclear
  8. 2004 Medium

    Showed acid stimulation can occur post-transcriptionally, indicating regulation acts on protein activity/trafficking and not only transcription.

    Evidence OKP cell acidification with Na-dependent citrate uptake, GFP-tagged constructs, and oocyte characterization of the opossum ortholog

    PMID:14973148

    Open questions at the time
    • Post-transcriptional mechanism (stability vs trafficking) not resolved
    • Reconciliation with transcriptional induction in vivo incomplete
  9. 2010 High

    Identified the ETB receptor as a required upstream node for acid stimulation, defining a receptor-level entry point to the regulatory cascade.

    Evidence ETB antagonism and ETA/ETB chimeras in OKP cells plus ETB-knockout mice with brush-border activity assays

    PMID:20703215

    Open questions at the time
    • Downstream effectors linking ETB to transporter at this stage unknown
    • Source of acid-induced ET-1 not defined
  10. 2013 High

    Defined SLC26A6 as a direct physical and reciprocal functional regulator, coupling citrate and oxalate handling at the membrane.

    Evidence STAS-domain/intracellular-loop interaction mapping, oocyte co-expression, and Slc26a6-null mice with succinate uptake and citraturia readouts

    PMID:23833257

    Open questions at the time
    • Structural basis of STAS-loop binding not resolved
    • Whether interaction is constitutive or regulated is unclear
  11. 2018 High

    Resolved the intracellular signaling cascade for acid stimulation as a Pyk2/c-Src and Raf1-ERK1/2-p90RSK pathway distinct from ETB signaling.

    Evidence Pyk2/c-Src inhibition in OKP cells, Pyk2-knockout mice, NH4Cl loading and brush-border activity assays with pathway phospho-immunoblots

    PMID:29678998

    Open questions at the time
    • How parallel ETB and Pyk2 arms converge on the transporter unknown
    • Terminal step modifying NaDC-1 trafficking not identified
  12. 2025 High

    Extended SLC13A2 function beyond the kidney, showing citrate import feeds ACLY-dependent acetyl-CoA and cholesterol synthesis to drive liver regeneration.

    Evidence Partial hepatectomy with liver-specific AAV overexpression/knockout, metabolic flux analysis, and ACLY/HMGCR inhibitor rescue in mice

    PMID:39824985

    Open questions at the time
    • Whether the same citrate-acetyl-CoA axis operates in renal cells untested
    • Regulation of hepatic SLC13A2 expression not defined
  13. 2026 Medium

    Connected SLC13A2 citrate import to acetylation-driven PKM2 degradation and histone acetylation, establishing a tumor-suppressive role in hepatocellular carcinoma.

    Evidence Liver-specific AAV knockout/overexpression in mouse HCC models with metabolic flux, PKM2 acetylation/degradation and histone acetylation assays

    PMID:41950310

    Open questions at the time
    • Not independently replicated
    • Acetyltransferase mediating PKM2 acetylation not identified
    • Relevance to human HCC outcomes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the parallel acidosis-sensing pathways (ETB and Pyk2/Raf-ERK-RSK) ultimately converge to modify NaDC-1 protein trafficking, and whether the hepatic citrate-acetyl-CoA functions generalize to kidney, remain open.
  • No identified terminal modification or adaptor that increases apical NaDC-1 abundance
  • No structural model linking residue-level binding data to the transport cycle
  • Cross-tissue unification of transport and metabolic roles incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0140104 molecular carrier activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-382551 Transport of small molecules 2
Partners
SLC26A6

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 NaDC-1 expressed in COS-7 cells mediates sodium-dependent transport of succinate and citrate; transport kinetics show a Hill coefficient of ~2.9 for sodium activation, indicating three Na+ ions are co-transported per succinate; citrate transport is stimulated by acidic pH while succinate transport is pH-insensitive; lithium inhibits succinate transport. Heterologous expression in COS-7 mammalian cells, radiolabeled uptake assays, kinetic analysis Pflugers Archiv : European journal of physiology High 8596711
1998 His-106 in NaDC-1 is required for normal cell-surface membrane expression rather than for catalytic function; mutagenesis of His-153 and His-569 confers insensitivity to DEPC inhibition, implicating these residues in DEPC binding but not transport activity; no other histidine residue is individually essential for transport. Site-directed mutagenesis of all 11 histidine residues, expression in Xenopus oocytes, radiolabeled succinate uptake, cell-surface biotinylation The Biochemical journal High 9512488
1999 Asp-373 (TM8) substitutions alter sodium affinity and cation selectivity, implicating its carbonyl oxygen in cation-binding site topology; Glu-475 (TM9) substitutions dramatically reduce transport and alter substrate/sodium affinity; E475A produces voltage-dependent substrate-induced currents with current reversal at −30 mV, suggesting a role in cation binding and possible anion channel activity; mutations at both Asp-373 and Glu-475 also affect succinate Km, indicating these residues contribute to the substrate-binding site. Site-directed mutagenesis of acidic residues, two-electrode voltage clamp and radiolabeled uptake in Xenopus oocytes, kinetic analysis Biochemistry High 10360950
1999 None of the 11 individual cysteine residues are essential for NaDC-1 transport activity, but impermeant cysteine reagent pCMBS inhibits transport; Cys-227 (TM5) and Cys-476 (TM9) are the pCMBS-accessible residues; cumulative cysteine mutagenesis progressively reduces transport activity and expression, indicating multiple cysteines collectively support protein stability or trafficking to the plasma membrane. Site-directed mutagenesis of all 11 cysteine residues, pCMBS inhibition assays, expression in Xenopus oocytes, radiolabeled uptake The Biochemical journal High 10548552
1999 Protein kinase C (PKC) activation by PMA or DAG inhibits NaDC-1 succinate transport by up to 95% in Xenopus oocytes; inhibition is dose-dependent and prevented by staurosporine; consensus PKC phosphorylation sites on NaDC-1 are not required for this inhibition; PMA causes ~30% reduction in plasma membrane NaDC-1 protein; cytochalasin D (microfilament disruptor/endocytosis inhibitor) partially prevents PMA inhibition, indicating the mechanism involves endocytosis plus direct activity inhibition. PKA activation has no effect. PKC/PKA pharmacological activation in Xenopus oocytes expressing NaDC-1, site-directed mutagenesis of consensus phosphorylation sites, surface protein quantification, cytochalasin D treatment Biochimica et biophysica acta High 10446305
2000 Lys-84 (cytoplasmic end of TM3) mutation to Ala increases the Km for succinate ~6-fold (from 0.3 mM to 1.8 mM) without affecting surface expression, implicating Lys-84 in substrate binding. Arg-349 (extracellular end of TM7) mutation alters succinate handling (inhibition at high succinate concentrations) with normal sodium and citrate kinetics; both residues affect succinate handling but are not essential for surface targeting. Site-directed mutagenesis, expression in Xenopus oocytes, radiolabeled uptake, transport kinetics The Biochemical journal Medium 10970779
2000 Chronic metabolic acidosis increases NaDC-1 mRNA abundance (detectable at 3 hours, correlating with acidosis severity) and apical membrane NaDC-1 protein abundance (maximal in S2 segment, time-dependent) in rat kidney proximal tubule; alkali feeding has no effect on NaDC-1 mRNA or protein. NaDC-1 localizes to the apical membrane of the proximal tubule. Rat metabolic acidosis model, immunohistochemistry, immunoblot of brush border membrane vesicles, mRNA quantification Kidney international Medium 10886565
2004 In OKP cells (proximal tubule model), media acidification increases Na-dependent citrate uptake post-transcriptionally (NaDC-1 mRNA abundance is unchanged); the opossum NaDC-1 ortholog shows ≥3 Na:1 citrate stoichiometry, dicarboxylate/tricarboxylate selectivity, pH-dependent citrate transport, and pH-independent succinate transport when expressed in Xenopus oocytes. cDNA cloning, Xenopus oocyte expression, radiolabeled citrate uptake, GFP-tagged construct transfection in OKP cells, mRNA quantification under pH variation American journal of physiology. Cell physiology Medium 14973148
2010 Acid-induced stimulation of NaDC-1 activity requires a functional endothelin B (ETB) receptor: pharmacological ETB blockade (BQ788) abolishes acid and ET-1 stimulation of NaDC-1 in OKP cells; ETB knockout mice show no increase in brush border NaDC-1 activity upon acid feeding. Using ETА/ETB chimeric constructs, ET-1 stimulation of NaDC-1 requires the receptor C-terminal tail (from either ETA or ETB) and is greatest with the ETB transmembrane domain plus a C-terminal tail. Pharmacological ETB antagonism in OKP cells, ETB knockout mouse model, brush border membrane vesicle NaDC-1 activity assay, ETА/ETB chimeric receptor constructs Kidney international High 20703215
2013 SLC26A6 physically and functionally interacts with NaDC-1: the STAS domain of SLC26A6 and the first intracellular loop of NaDC-1 mediate their physical interaction (biochemical pull-down/co-expression) and functional cross-regulation. NaDC-1 enhances SLC26A6 transport activity, while SLC26A6 inhibits NaDC-1 transport activity in an activity-dependent manner. Slc26a6-null mice show increased renal/intestinal sodium-dependent succinate uptake and hypocitraturia, consistent with loss of SLC26A6-mediated NaDC-1 inhibition. Co-expression in Xenopus oocytes, Slc26a6-knockout mouse model, biochemical domain interaction analysis (STAS domain and NaDC-1 intracellular loop), transport assays Journal of the American Society of Nephrology : JASN High 23833257
2016 In normal human kidney, NaDC-1 (SLC13A2) protein localizes exclusively to the apical (luminal) membrane throughout the entire proximal tubule (including proximal convoluted and proximal straight tubule), co-localizing with NBCe1; NaDC-1 is not detectable in other renal cell types or in renal tumors (clear cell RCC, papillary RCC, oncocytoma, chromophobe carcinoma). Immunoblot (~61 kDa band), immunohistochemistry, colocalization with NBCe1 in human kidney tissue sections American journal of physiology. Renal physiology Medium 27927654
2018 Acid stimulation of NaDC-1 activity requires Pyk2/c-Src and a Raf1-ERK1/2-p90RSK signaling cascade; these pathways are distinct from and not downstream of ET-1/ETB signaling. Pyk2-null mice fail to show NH4Cl-induced increase in brush border NaDC-1 activity; ERK1/2 phosphorylation by acid is Pyk2-independent; Raf1 and p90RSK inhibition blocks acid but not ET-1 stimulation of NaDC-1. Pyk2 and c-Src inhibition in OKP cells, Pyk2-knockout mice, NH4Cl loading, brush border vesicle NaDC-1 activity assay, immunoblot for pathway phosphorylation, [14C]-citrate uptake Journal of the American Society of Nephrology : JASN High 29678998
2025 SLC13A2 promotes liver regeneration by importing citrate into hepatocytes, which serves as substrate for ACLY-dependent acetyl-CoA generation and de novo cholesterol biosynthesis via increased SREBP2 cleavage and upregulation of LDLR and HMGCR; ACLY inhibition or HMGCR inhibition (lovastatin) abrogates SLC13A2-mediated regeneration. Liver-specific overexpression promotes, and liver-specific depletion attenuates, liver regeneration after partial hepatectomy in mice. Partial hepatectomy mouse model, liver-specific SLC13A2 overexpression/knockout (AAV), metabolic flux analysis, ACLY inhibitor, lovastatin treatment, SREBP2 cleavage assay, cholesterol synthesis measurement The EMBO journal High 39824985
2026 In hepatocellular carcinoma, SLC13A2-imported citrate generates acetyl-CoA that acetylates pyruvate kinase M2 (PKM2), triggering its degradation; reduced PKM2 activity limits pyruvate supply, impairing amino acid synthesis and nucleotide metabolism. SLC13A2-imported citrate also increases intracellular protein acetylation (including histone acetylation), altering transcriptional regulation and contributing to tumor suppression. AAV-mediated liver-specific SLC13A2 knockout promotes, while overexpression ameliorates, HCC progression. AAV-mediated liver-specific knockout/overexpression in mouse HCC models, metabolic flux analysis, PKM2 acetylation and degradation assays, histone acetylation analysis, acetyl-CoA measurement Science advances Medium 41950310

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney. Kidney international 90 10886565
2013 SLC26A6 and NaDC-1 transporters interact to regulate oxalate and citrate homeostasis. Journal of the American Society of Nephrology : JASN 60 23833257
1998 Mutational analysis of histidine residues in the rabbit Na+/dicarboxylate co-transporter NaDC-1. The Biochemical journal 34 9512488
1999 Cysteine residues in the Na+/dicarboxylate co-transporter, NaDC-1. The Biochemical journal 29 10548552
1999 Protein kinase C-mediated regulation of the renal Na(+)/dicarboxylate cotransporter, NaDC-1. Biochimica et biophysica acta 28 10446305
1999 Acidic residues involved in cation and substrate interactions in the Na+/dicarboxylate cotransporter, NaDC-1. Biochemistry 26 10360950
2010 Acid regulation of NaDC-1 requires a functional endothelin B receptor. Kidney international 21 20703215
2016 Expression of sodium-dependent dicarboxylate transporter 1 (NaDC1/SLC13A2) in normal and neoplastic human kidney. American journal of physiology. Renal physiology 18 27927654
2018 Acid Stimulation of the Citrate Transporter NaDC-1 Requires Pyk2 and ERK1/2 Signaling Pathways. Journal of the American Society of Nephrology : JASN 17 29678998
2004 OKP cells express the Na-dicarboxylate cotransporter NaDC-1. American journal of physiology. Cell physiology 16 14973148
2000 Role of cationic amino acids in the Na+/dicarboxylate co-transporter NaDC-1. The Biochemical journal 14 10970779
2016 Evidence for epistatic interaction between VDR and SLC13A2 genes in the pathogenesis of hypocitraturia in recurrent calcium oxalate stone formers. Journal of nephrology 12 27639591
1996 Expression of the renal Na+/dicarboxylate cotransporter, NaDC-1, in COS-7 cells. Pflugers Archiv : European journal of physiology 12 8596711
2025 SLC13A2 promotes hepatocyte metabolic remodeling and liver regeneration by enhancing de novo cholesterol biosynthesis. The EMBO journal 6 39824985
2021 SLC26A6 and NADC‑1: Future direction of nephrolithiasis and calculus‑related hypertension research (Review). Molecular medicine reports 5 34458928
2018 rs11567842 SNP in SLC13A2 gene associates with hypocitraturia in Thai patients with nephrolithiasis. Genes & genomics 5 30155711
2026 SLC13A2-transported citrate remodels transcriptional regulation through protein acetylation to suppress tumor growth. Science advances 0 41950310
2025 Investigation of rs11568476 Polymorphism in the SLC13A2 Gene in Turkish Patients with Hypocitraturia and Calcium-Containing Kidney Stones. Biomedicines 0 40868238

Missed literature

Know a paper Affinage missed for SLC13A2? Flag it for the maintainers and the community.

No submissions yet.