Affinage

SLC39A3

Zinc transporter ZIP3 · UniProt Q9BRY0

Length
314 aa
Mass
33.6 kDa
Annotated
2026-06-10
26 papers in source corpus 12 papers cited in narrative 12 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

SLC39A3 (ZIP3) is an eight-transmembrane-domain zinc importer that mediates cellular zinc entry and redistribution across multiple specialized cell types, functioning largely as an ancillary, context-dependent component of zinc homeostasis rather than in primary dietary zinc acquisition (PMID:15964816, PMID:16652366). Genetic loss is phenotypically silent under zinc-replete conditions but, in combination with ZIP1, becomes essential for adaptation to dietary zinc deficiency during pregnancy, with expression concentrated in tissues consistent with zinc retention and redistribution (PMID:15964816, PMID:16652366). In the lactating mammary gland ZIP3 localizes to the luminal membrane and mediates reuptake of secreted zinc from the alveolar lumen, and its loss elevates milk zinc while disrupting mammary architecture and promoting apoptosis (PMID:15634741, PMID:19458277). In the hippocampus ZIP3 is positioned at mossy fiber terminals where it drives zinc influx into presynaptic granule cells, and its silencing slows neuronal zinc uptake and protects CA1/CA3 neurons from excitotoxic neurodegeneration after kainate-induced seizures (PMID:21209194, PMID:35169020). ZIP3 further sets free intracellular zinc in platelets, where its loss yields a poorly mobilizable zinc pool and selective hyperactivation through GPCR (thrombin) signaling with enhanced Ca2+/PKC/CaMKII/ERK1/2 responses (PMID:37359521), and supports the encephalitogenic survival of pathogenic Th17 cells via Golgi-localized regulation of cytosolic zinc (PMID:41547159). ZIP3 transcription is controlled by zinc status through direct promoter inputs from MTF-1 and the activator RREB1 (PMID:32858813), and concurrent RREB1 and ZIP3 downregulation accompanied by zinc loss is an early event in pancreatic carcinogenesis, where ZIP3-dependent zinc accumulation restrains proliferation (PMID:21613827, PMID:25050557, PMID:22427155).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 High

    Established that SLC39A3 encodes a functional zinc transporter and asked whether it is essential for organismal zinc homeostasis; the knockout revealed a dispensable, conditionally important role.

    Evidence ZIP3-knockout mouse with EGFP reporter, dietary zinc restriction during pregnancy, embryo morphology and metal measurements

    PMID:15964816

    Open questions at the time
    • Does not define which tissues drive the zinc-deficiency phenotype
    • No direct biophysical measurement of transport kinetics or substrate specificity
  2. 2006 High

    Resolved why single ZIP3 loss is mild by showing genetic redundancy with ZIP1, establishing both as a redundant system for zinc retention/redistribution rather than dietary acquisition.

    Evidence ZIP1/ZIP3 double-knockout mice with dietary zinc restriction and tissue expression mapping

    PMID:16652366

    Open questions at the time
    • Expression-pattern inference of function not validated by tissue-specific deletion
    • Mechanism of zinc redistribution not directly measured
  3. 2005 High

    Addressed the cell-autonomous transport role by showing ZIP3 is the dominant zinc importer in mammary epithelial cells and is required for their survival.

    Evidence siRNA silencing, 65Zn uptake assay, confocal localization and viability in HC11 cells

    PMID:15634741

    Open questions at the time
    • Cell-line model; localization dynamics not tied to a defined secretory trigger
    • Cause of cell death upon knockdown not mechanistically dissected
  4. 2009 High

    Determined the directional role of mammary ZIP3 in vivo, showing it performs luminal zinc reuptake rather than import from circulation, refining the earlier cell-based interpretation.

    Evidence ZIP3-null mice, immunolocalization, 65Zn transfer/retention, mammary histology and apoptosis assays

    PMID:19458277

    Open questions at the time
    • Molecular trigger for luminal targeting unresolved
    • Link between zinc reuptake and tissue remodeling not mechanistically established
  5. 2011 High

    Identified a neuronal role by showing ZIP1/ZIP3 mediate zinc entry into hippocampal neurons that contributes to excitotoxic neurodegeneration.

    Evidence Zip1/Zip3 double-knockout mice, FluoZin imaging, kainic acid seizure model with neurodegeneration scoring

    PMID:21209194

    Open questions at the time
    • Did not separate ZIP1 from ZIP3 contributions
    • Source of the transported zinc pool not defined
  6. 2022 High

    Pinpointed ZIP3 specifically to mossy fiber terminals and demonstrated it mediates presynaptic zinc reuptake, distinguishing its role from ZIP1.

    Evidence In vivo shRNA silencing, confocal localization, FluoZin-3 imaging in slices, kainate seizure model

    PMID:35169020

    Open questions at the time
    • Coupling of presynaptic zinc reuptake to neurotransmission not measured
    • Structural basis of zinc transport not addressed
  7. 2011 Medium

    Connected ZIP3 to disease by showing it is the basal-membrane zinc uptake transporter silenced in pancreatic adenocarcinoma alongside zinc loss.

    Evidence IHC, in situ RT-PCR and zinc staining on human pancreatic tissue

    PMID:21613827

    Open questions at the time
    • Correlative human-tissue data without functional reconstitution
    • Causality between ZIP3 loss and tumorigenesis not established
  8. 2012 Medium

    Identified RREB1 as a transcriptional driver of ZIP3 and showed their concurrent loss in early PanIN lesions.

    Evidence RREB1 knockdown in Panc1 cells, tissue microarray IHC, in situ zinc staining

    PMID:22427155

    Open questions at the time
    • IHC component is correlative
    • Direct RREB1 binding to ZIP3 promoter not shown here
  9. 2014 Medium

    Demonstrated functional consequence of the RREB1→ZIP3 axis, showing ZIP3-dependent zinc accumulation inhibits pancreatic cell proliferation.

    Evidence Panc1 zinc treatment, ZIP3 siRNA, proliferation assays, RREB1 knockdown/overexpression

    PMID:25050557

    Open questions at the time
    • Single-lab cell-line model
    • Mechanism by which zinc accumulation restrains proliferation not defined
  10. 2020 Medium

    Established the direct transcriptional logic of ZIP3 regulation by zinc status via MTF-1 and RREB1 promoter elements.

    Evidence Luciferase reporters, site-directed mutagenesis, EMSA with purified proteins in yellow catfish cells

    PMID:32858813

    Open questions at the time
    • Performed in teleost cells; mammalian conservation of elements not confirmed
    • Single lab
  11. 2023 High

    Revealed a hemostatic role by showing ZIP3 (with ZIP1) sets a mobilizable free zinc pool whose loss causes GPCR-selective platelet hyperactivation.

    Evidence ZIP1/ZIP3 double-knockout mice, ICP-MS, FluoZin3, aggregation, ex vivo and in vivo thrombosis, signaling phosphorylation analysis

    PMID:37359521

    Open questions at the time
    • ZIP1 and ZIP3 contributions not separated
    • Molecular link between zinc and selective GPCR signaling amplification not resolved
  12. 2026 High

    Identified a role in CNS autoimmunity, showing Golgi-localized ZIP3 maintains cytosolic zinc and survival selectively in pathogenic Th17 cells to drive EAE.

    Evidence In vivo shRNA screen, CRISPR deletion, genetically encoded cytosolic Zn2+ reporter, confocal localization, apoptosis/flow cytometry, in vivo EAE

    PMID:41547159

    Open questions at the time
    • How Golgi zinc handling protects against apoptosis not mechanistically defined
    • Selectivity for pTh17 over non-polarized CD4+ cells unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biophysical transport mechanism, substrate selectivity, and structural basis of ZIP3-mediated zinc transport remain undefined, as does how a single transporter is selectively deployed across such diverse cell types and subcellular sites.
  • No purified-protein transport reconstitution or structure in the corpus
  • Determinants of plasma membrane versus Golgi localization not established
  • Mechanism coupling intracellular zinc to downstream signaling outputs unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-109582 Hemostasis 1 R-HSA-168256 Immune System 1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Mouse ZIP3 (SLC39A3) encodes an eight-transmembrane-domain protein that functions as a zinc transporter; ZIP3-null mice exhibit increased sensitivity to embryonic malformation under zinc-deficient dietary conditions during pregnancy, but show no phenotypic abnormalities under zinc-replete conditions, indicating an ancillary role in zinc homeostasis. Knockout mouse generation (replacement of ZIP3 ORF with EGFP), dietary zinc restriction challenge, embryo morphology scoring, metal level measurements, zinc-responsive gene expression analysis Molecular and cellular biology High 15964816
2006 ZIP1 and ZIP3 together are essential for adaptation to dietary zinc deficiency during pregnancy; double-knockout of ZIP1 and ZIP3 results in 91% of embryos developing abnormally under zinc-limited conditions, while single knockouts show partial defects. Expression is predominantly in intestinal stromal cells, nephric-tubular epithelial cells, pancreatic ductal epithelial cells, and hepatocytes surrounding the central vein, suggesting these transporters function in zinc redistribution/retention rather than dietary acquisition. ZIP1/ZIP3 double-knockout mouse generation, dietary zinc restriction during pregnancy, embryo morphology scoring, tissue expression pattern analysis Genesis (New York, N.Y. : 2000) High 16652366
2005 ZIP3 (SLC39A3) is localized to the cell surface of mammary epithelial cells under basal conditions and transiently relocalizes to an intracellular compartment in cells with a secretory phenotype. Gene silencing of ZIP3 decreased 65Zn uptake into mammary epithelial cells (particularly in secretory phenotype cells) and resulted in cell death, establishing ZIP3 as the primary zinc importer in this cell type. Confocal microscopy for localization, siRNA gene silencing, 65Zn radiotracer transport assay, cell viability assessment in HC11 mammary epithelial cell model American journal of physiology. Cell physiology High 15634741
2009 In the lactating mammary gland, ZIP3 (SLC39A3) is primarily localized to the luminal membrane of secretory mammary cells. ZIP3-null mice show higher zinc concentration in secreted milk, indicating that ZIP3 functions in reuptake of zinc from the alveolar lumen back into the mammary cell rather than in import of zinc from maternal circulation. ZIP3-null mammary glands also show altered tissue architecture, increased apoptosis, and reduced gland weight. ZIP3-null mouse model, immunolocalization, 65Zn transfer/retention studies, mammary tissue histology, apoptosis assays American journal of physiology. Regulatory, integrative and comparative physiology High 19458277
2011 SLC39A3 (ZIP1 and ZIP3) are predominantly expressed in the hippocampus. In ZIP1,3-deficient mice, passive zinc uptake into CA1 neurons (isolated by NMDA receptor and voltage-gated calcium channel blockade) was slowed, and CA1 neurodegeneration following kainic acid-induced seizures was greatly attenuated, establishing these transporters as mediators of zinc entry contributing to excitotoxic neurodegeneration. Zip1/Zip3 double-knockout mice, intracellular fluorescent zinc dye (FluoZin) imaging, NMDA/Ca-channel pharmacological isolation, in vivo kainic acid seizure model with histological neurodegeneration scoring The Journal of neuroscience : the official journal of the Society for Neuroscience High 21209194
2011 ZIP3 transporter and RREB1 transcription factor are consistently downregulated in pancreatic adenocarcinoma compared to normal ductal/acinar epithelium, where ZIP3 is identified as the basal membrane zinc uptake transporter. ZIP3 gene expression is silenced in adenocarcinoma, accompanied by major zinc loss. RREB1 downregulation co-occurs with ZIP3 loss. Immunohistochemistry for ZIP3 protein, in situ RT-PCR for ZIP3 mRNA, in situ Dithizone/Zinquin zinc staining on human tissue sections Cancer biology & therapy Medium 21613827
2014 ZIP3 is required for zinc accumulation in pancreatic cells and for zinc-mediated inhibition of cell proliferation. RREB1 functions as a positive transcriptional regulator of ZIP3 expression in pancreatic cells. Exposure of Panc1 cells to physiological zinc concentrations increases zinc uptake and accumulation via ZIP3, inhibiting cell proliferation. Panc1 cell zinc treatment assays, ZIP3 siRNA knockdown, cell proliferation assays, RREB1 knockdown/overexpression with ZIP3 expression readout Cancer biology & therapy Medium 25050557
2012 RREB1 regulates ZIP3 expression in pancreatic cells; knockdown of RREB1 reduces ZIP3 expression in Panc1 cells, and both RREB1 and ZIP3 are downregulated concurrently in pancreatic intraepithelial neoplasia (PanIN) lesions, indicating this regulatory relationship is an early event in pancreatic carcinogenesis. RREB1 knockdown in Panc1 cells with ZIP3 expression readout, immunohistochemistry on pancreatic tissue microarrays including PanIN lesions, in situ zinc staining Journal of gastrointestinal cancer Medium 22427155
2022 In adult mouse hippocampus, ZIP3 (SLC39A3) is primarily localized to the stratum lucidum (mossy fiber terminals of dentate gyrus granule cells), distinct from ZIP1 which localizes to CA3 stratum pyramidale. ZIP3 silencing in vivo reduced zinc influx into dentate gyrus granule cells. In vivo silencing of ZIP3 (but not ZIP1) protected CA3 neurons from neurodegeneration following kainate-induced seizures, establishing ZIP3 as the transporter responsible for zinc re-uptake at the mossy fiber synapse into presynaptic granule cells. In vivo ZIP3 shRNA silencing, confocal immunofluorescence localization in brain sections, FluoZin-3 zinc uptake imaging in acute hippocampal slices, in vivo kainate seizure model with CA3 neurodegeneration scoring, ZIP1/ZIP3 siRNA in cultured hippocampal neurons The Journal of neuroscience : the official journal of the Society for Neuroscience High 35169020
2020 MTF-1 (metal-responsive transcription factor-1) and RREB1 directly bind functional response elements in the ZIP3 promoter to regulate its transcription. Low zinc increases MTF-1 binding to its site at -1327/-1343 bp on the ZIP3 promoter, while high zinc increases RREB1-mediated transcriptional activation via the -248/-267 bp RREB1 binding site. These are direct regulatory inputs on ZIP3 expression in response to zinc status. Luciferase reporter assays with ZIP3 promoter deletion constructs, site-directed mutagenesis of binding sites, electrophoretic mobility shift assay (EMSA) with purified proteins, zinc concentration-dependent transcription assays in yellow catfish cells International journal of molecular sciences Medium 32858813
2023 Loss of ZIP1 and ZIP3 in platelets results in increased free (FluoZin3-stainable) intracellular zinc that is released less efficiently upon thrombin stimulation. ZIP1/3-deficient platelets show hyperactivation in response to GPCR agonists (thrombin) but not ITAM-coupled receptor agonists, resulting in enhanced aggregation, larger thrombus volume ex vivo, and faster in vivo thrombus formation. Augmented GPCR responses are accompanied by enhanced Ca2+, PKC, CaMKII, and ERK1/2 signaling. ZIP1/ZIP3 double-knockout mice, ICP-MS for total platelet zinc, FluoZin3 fluorescence for free zinc, platelet aggregation assays, ex vivo flow chamber thrombus formation, in vivo thrombosis model, Ca2+ signaling assays, PKC/CaMKII/ERK1/2 phosphorylation analysis Frontiers in immunology High 37359521
2026 ZIP3 (SLC39A3) is required for the encephalitogenic function of pathogenic Th17 (pTh17) cells in EAE. When ectopically expressed, ZIP3 localizes predominantly to the Golgi apparatus. Deletion of Slc39a3 decreases cytosolic zinc levels selectively in pTh17 cells (not non-polarized CD4+ T cells), increases susceptibility to apoptosis, and reduces CD69 expression, without affecting proliferation or cytokine production. In vivo, Slc39a3 deletion in pTh17 cells reduces CNS leukocyte infiltration and EAE severity. shRNA screen in vivo, CRISPR/Cas9 deletion of Slc39a3, genetically encoded cytosolic Zn2+ reporter, confocal microscopy for subcellular localization (Golgi), apoptosis assays, CD69/proliferation/cytokine flow cytometry, in vivo EAE model with histological CNS inflammation scoring Journal of trace elements in medicine and biology High 41547159

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Zip3 provides a link between recombination enzymes and synaptonemal complex proteins. Cell 246 10943844
2004 Targeted gene knockout reveals a role in meiotic recombination for ZHP-3, a Zip3-related protein in Caenorhabditis elegans. Molecular and cellular biology 97 15340062
2006 Mouse ZIP1 and ZIP3 genes together are essential for adaptation to dietary zinc deficiency during pregnancy. Genesis (New York, N.Y. : 2000) 87 16652366
2013 Differential association of the conserved SUMO ligase Zip3 with meiotic double-strand break sites reveals regional variations in the outcome of meiotic recombination. PLoS genetics 77 23593021
2005 Bioinformatic analyses implicate the collaborating meiotic crossover/chiasma proteins Zip2, Zip3, and Spo22/Zip4 in ubiquitin labeling. Proceedings of the National Academy of Sciences of the United States of America 69 16314568
2005 Zip3 plays a major role in zinc uptake into mammary epithelial cells and is regulated by prolactin. American journal of physiology. Cell physiology 67 15634741
2005 Generation and characterization of mice lacking the zinc uptake transporter ZIP3. Molecular and cellular biology 67 15964816
2011 Knockout of Zn transporters Zip-1 and Zip-3 attenuates seizure-induced CA1 neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 63 21209194
2019 Mitochondrial UPR repression during Pseudomonas aeruginosa infection requires the bZIP protein ZIP-3. Proceedings of the National Academy of Sciences of the United States of America 62 30850535
2011 Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma. Cancer biology & therapy 52 21613827
2009 Fpr3 and Zip3 ensure that initiation of meiotic recombination precedes chromosome synapsis in budding yeast. Current biology : CB 52 19765989
2002 ZIP3, a new splice variant of the PKC-zeta-interacting protein family, binds to GABAC receptors, PKC-zeta, and Kv beta 2. The Journal of biological chemistry 48 12431995
2014 The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma. Cancer biology & therapy 37 25050557
2012 Evidence for changes in RREB-1, ZIP3, and Zinc in the early development of pancreatic adenocarcinoma. Journal of gastrointestinal cancer 31 22427155
2009 Zip3 (Slc39a3) functions in zinc reuptake from the alveolar lumen in lactating mammary gland. American journal of physiology. Regulatory, integrative and comparative physiology 26 19458277
2022 The ZIP3 Zinc Transporter Is Localized to Mossy Fiber Terminals and Is Required for Kainate-Induced Degeneration of CA3 Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 18 35169020
2017 A Zip3-like protein plays a role in crossover formation in the SC-less meiosis of the protist Tetrahymena. Molecular biology of the cell 15 28100637
2020 Participation of Zip3, a ZIP domain-containing protein, in stress response and virulence in Cryptococcus gattii. Fungal genetics and biology : FG & B 13 32738289
2020 Functional Analysis of Two Zinc (Zn) Transporters (ZIP3 and ZIP8) Promoters and Their Distinct Response to MTF1 and RREB1 in the Regulation of Zn Metabolism. International journal of molecular sciences 11 32858813
2011 Spartin recruits PKC-ζ via the PKC-ζ-interacting proteins ZIP1 and ZIP3 to lipid droplets. Journal of neurochemistry 10 21707618
2025 Wheat ZIP3-2A encodes a metal transporter for Cd influx. Plant physiology and biochemistry : PPB 4 40215733
2011 PKCζ-interacting protein ZIP3 is generated by intronic polyadenylation, and is expressed in the brain and retina of the rat. The Biochemical journal 4 20979579
2023 Loss of zinc transporters ZIP1 and ZIP3 augments platelet reactivity in response to thrombin and accelerates thrombus formation in vivo. Frontiers in immunology 3 37359521
2025 Crossover formation and coordinated assembly of synaptonemal complex relies on a direct interaction between Zip1 and Zip3. bioRxiv : the preprint server for biology 1 41332580
2026 ZIP3 is essential for the encephalitogenic function of pTh17 cells by regulating intracellular zinc levels. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 0 41547159
2026 Crossover formation and coordinated assembly of synaptonemal complex relies on a direct interaction between Zip1 and Zip3. Genetics 0 41894234

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