{"gene":"SLC39A7","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2005,"finding":"ZIP7 (SLC39A7) localizes to the Golgi apparatus and functions as a zinc transporter that moves zinc from the Golgi apparatus into the cytoplasm. Protein expression is repressed under zinc-rich conditions, but intracellular localization is unaffected by zinc status.","method":"V5-tagged fusion protein expression in CHO cells, yeast complementation assay (Δzrt3 mutant), subcellular fractionation, zinc measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — functional zinc transport demonstrated in mammalian cells and yeast complementation, with subcellular localization; multiple orthogonal methods in one study","pmids":["15705588"],"is_preprint":false},{"year":2008,"finding":"ZIP7 is required for redistribution of zinc from intracellular stores to the cytoplasm; siRNA-mediated knockdown of ZIP7 reduces intracellular zinc levels and abolishes zinc-induced inhibition of phosphatases, thereby blocking activation of EGFR, IGF-IR, Src, HER2, HER3, and HER4 in tamoxifen-resistant breast cancer cells.","method":"siRNA knockdown, growth factor receptor phosphorylation assays, zinc measurement","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — clean siRNA KD with specific molecular phenotype (phosphatase activity, RTK activation) and functional readout (growth, invasion); replicated across multiple receptors","pmids":["18583420"],"is_preprint":false},{"year":2012,"finding":"Protein kinase CK2 phosphorylates evolutionarily conserved residues on the endoplasmic reticulum zinc channel ZIP7, triggering gated release of Zn2+ from ER stores into the cytosol, which activates tyrosine kinases and downstream phosphorylation of AKT and ERK1/2.","method":"Pharmacological inhibition of CK2, proximity ligation assay (PLA), site-directed mutagenesis of ZIP7 phosphorylation sites, phospho-western blotting","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis plus PLA plus pharmacological manipulation in one study; highly cited foundational paper","pmids":["22317921"],"is_preprint":false},{"year":2012,"finding":"Zip7 is required for zinc homeostasis in vivo; morpholino knockdown in zebrafish causes reduced zinc in brain, eyes, and gills, and developmental defects (reduced head size, smaller eyes, shorter palate, curved spine) that are rescued by zinc supplementation.","method":"Morpholino antisense knockdown in zebrafish, synchrotron radiation X-ray fluorescence (SR-XRF) zinc quantification, zinc rescue experiment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — in vivo KD with defined morphological and elemental phenotype, mechanistically linked to zinc deficiency via rescue","pmids":["22912764"],"is_preprint":false},{"year":2013,"finding":"Loss of Catsup (Drosophila ortholog of ZIP7/SLC39A7) causes Notch receptor accumulation in the ER and Golgi, impairs Notch signaling, and elevates ER stress, indicating ZIP7-mediated zinc transport is required for proper trafficking of the Notch receptor through the secretory pathway.","method":"Forward genetic screen, loss-of-function mutations, immunofluorescence imaging of Notch receptor localization, ER stress markers","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — genetic screen with defined trafficking phenotype in Drosophila ortholog; multiple cellular readouts","pmids":["23785054"],"is_preprint":false},{"year":2013,"finding":"Zip7 knockdown in skeletal muscle cells reduces expression of glucose metabolism genes (including Glut4, Insr, Irs1, Irs2) and decreases insulin-stimulated glycogen synthesis and Akt phosphorylation, placing Zip7 as a regulator of glucose metabolism and insulin signaling in muscle.","method":"siRNA knockdown, qPCR, western blot, glycogen synthesis assay, Akt phosphorylation measurement","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with specific signaling and metabolic phenotype, but single lab, single study","pmids":["24265765"],"is_preprint":false},{"year":2016,"finding":"Intestinal epithelial-specific deletion of Zip7 triggers ER stress in proliferative progenitor cells, causes death of progenitor cells, loss of Olfm4+ intestinal stem cells, and degeneration of Paneth cells, demonstrating that ZIP7-mediated zinc transport from the ER is essential for intestinal epithelial homeostasis.","method":"Conditional knockout mouse (intestinal epithelium-specific), histology, ER stress markers, stem cell marker analysis (Olfm4)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific conditional KO with defined cellular and molecular phenotypes; multiple cell type readouts","pmids":["27736879"],"is_preprint":false},{"year":2017,"finding":"Phosphorylation of ZIP7 at four serine residues (including S275 and S276) is required for maximal activation and zinc release from intracellular stores, which drives MAPK, PI3K-AKT, and mTOR signaling pathways.","method":"Site-directed mutagenesis of individual and combined serine residues, phospho-protein arrays, downstream pathway analysis","journal":"Metallomics : integrated biometal science","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with pathway-level functional readout; directly identifies the phosphorylation sites required for activation","pmids":["28205653"],"is_preprint":false},{"year":2017,"finding":"ZIP7 localizes to the ER in mesenchymal stem cells; ablation of Zip7 causes zinc accumulation in the ER, zinc-dependent aggregation and inhibition of protein disulfide isomerase (PDI), leading to ER dysfunction and impaired dermal development.","method":"Conditional knockout mouse (collagen 1-expressing tissue), immunofluorescence localization, zinc measurement, PDI activity assay, proliferation assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with specific molecular mechanism (PDI inhibition by zinc) identified; multiple orthogonal methods","pmids":["28545780"],"is_preprint":false},{"year":2017,"finding":"Hyperglycemia increases ZIP7 expression and phosphorylation in cardiomyocytes, resulting in elevated cytosolic free Zn2+ and decreased ER/SR Zn2+; CK2α siRNA suppresses ZIP7 phosphorylation and the associated Zn2+ redistribution, confirming CK2 as the kinase responsible for ZIP7 activation in the heart.","method":"FRET-based zinc sensors, siRNA knockdown of CK2α, phospho-western blotting, subcellular fractionation in cardiomyocytes from diabetic rats","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — FRET sensors directly measure zinc redistribution; CK2 link confirmed by siRNA; in vivo diabetic model plus in vitro","pmids":["28232492"],"is_preprint":false},{"year":2018,"finding":"Genetic ablation of SLC39A7 decreases cytosolic zinc levels, increases ER zinc levels, impairs cell proliferation, and induces ER stress; both ER stress and proliferation defects are rescued by increasing cytosolic zinc, confirming that ZIP7's zinc transport activity is causally responsible.","method":"Genetic knockout, zinc supplementation rescue, cell proliferation assay, ER stress markers, small-molecule screen","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 — KO with zinc rescue establishing causality; multiple orthogonal phenotypic readouts","pmids":["29980658"],"is_preprint":false},{"year":2018,"finding":"SLC39A7 knockout in FADD-deficient haploid human cells confers resistance to necroptosis by impairing TNFR1 and FAS receptor surface trafficking; loss of SLC39A7 causes augmented ER stress that reduces receptor trafficking to the cell surface, globally affecting downstream death receptor signaling.","method":"Genome-wide gene-trap screen, CRISPR/Cas9 knockout, SLC-focused CRISPR screen, death receptor surface level measurement","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — unbiased genetic screen confirmed by orthogonal CRISPR screen; specific trafficking mechanism identified","pmids":["30237509"],"is_preprint":false},{"year":2018,"finding":"ZIP7 and ZnT7 also localize to mitochondria in cardiomyocytes; in hyperglycemic conditions, mitochondrial ZIP7 expression decreases while ZnT7 increases, leading to increased mitochondrial Zn2+, ROS production, and mitochondrial membrane potential changes, affecting SR-mitochondria coupling.","method":"Fluorescence imaging, mitochondrial fractionation/biochemical analysis, FRET-based zinc sensors","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization in isolated fractions plus FRET zinc measurement; single lab study","pmids":["29307859"],"is_preprint":false},{"year":2019,"finding":"ZIP7 (SLC39A7) governs Notch trafficking and signaling; a small-molecule inhibitor (NVS-ZP7-4) directly interacts with ZIP7 (photoaffinity labeling), and a V430E resistance mutation in ZIP7 confers resistance to the compound; inhibition alters ER zinc levels and induces ER stress-mediated apoptosis.","method":"Phenotypic screen, resistance mutation sequencing, photoaffinity labeling of ZIP7, zinc measurement in ER","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct compound-protein interaction shown by photoaffinity labeling; resistance mutation confirms on-target mechanism; multiple orthogonal approaches","pmids":["30643281"],"is_preprint":false},{"year":2019,"finding":"Hypomorphic mutations of SLC39A7 in humans and CRISPR-modeled mice cause a block in B cell development; mutant B cells have diminished cytoplasmic free zinc, increased phosphatase activity, and decreased phosphorylation of pre-B cell and B cell receptor signaling molecules, establishing that cytosolic Zn2+ delivered by ZIP7 is required to modulate BCR signal strength.","method":"Human genetics (autosomal recessive mutations), CRISPR-Cas9 mouse modeling, cytoplasmic zinc measurement, phosphatase activity assay, phospho-western blotting, B cell development flow cytometry","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — human disease mutations corroborated by precise CRISPR mouse model; multiple molecular mechanisms established","pmids":["30718914"],"is_preprint":false},{"year":2019,"finding":"ZIP7 is localized to the ER, while ZIP13 localizes to both ER and Golgi; ZIP7 depletion (but not ZIP13 depletion) induces ER stress in mesenchymal stem cells and inhibits fibrogenic differentiation, demonstrating distinct non-redundant roles for each transporter in dermal development.","method":"Sibling transporter comparison, immunofluorescence co-localization, ER stress markers, differentiation assays, genome-wide gene expression analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — direct comparison of two ZIP transporters with specific ER stress and differentiation readouts; single lab study","pmids":["31412620"],"is_preprint":false},{"year":2021,"finding":"ZIP7 controls zinc transport from the ER to the cytosol and is a genetic determinant of ferroptosis; genetic or chemical inhibition of ZIP7 protects cells from ferroptosis by triggering ER stress (including induction of HERPUD1 and ATF3), and HERPUD1 knockdown abolishes this ferroptosis protection.","method":"Genome-wide RNAi screen, ZIP7 siRNA knockdown, chemical inhibition, zinc chelation/supplementation, epistasis with HERPUD1 knockdown, ferroptosis assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen hit confirmed by multiple orthogonal approaches; epistasis analysis places ZIP7 upstream of HERPUD1 in ER-stress-mediated ferroptosis protection","pmids":["33608508"],"is_preprint":false},{"year":2023,"finding":"NLRX1 physically interacts with SLC39A7 (ZIP7) to form an NLRX1-SLC39A7 complex on the mitochondrial membrane of nucleus pulposus cells, modulating mitochondrial Zn2+ trafficking and thereby orchestrating mitochondrial dynamics (fission/fusion) and mitophagy.","method":"Co-immunoprecipitation (interaction), confocal co-localization on mitochondrial membrane, in vitro/in vivo cell and animal models, mitochondrial function assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP demonstrates interaction; mitochondrial localization shown; functional consequence demonstrated; single lab study","pmids":["37876250"],"is_preprint":false},{"year":2024,"finding":"ZIP7-mediated Zn2+ transport enhances ERAD by providing Zn2+ to the Rpn11 Zn2+ metalloproteinase in the proteasome lid, which is required for deubiquitination of substrates entering the proteasome; ZIP7 overexpression rescues neurodegeneration caused by misfolded rhodopsin in a Drosophila model.","method":"Drosophila border cell migration genetics, human cell ZIP7 manipulation, Rpn11 deubiquitinase activity assay, misfolded rhodopsin neurodegeneration model, proteasomal substrate deubiquitination assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic link between ZIP7 Zn2+ transport and Rpn11 metalloproteinase activity demonstrated in both Drosophila and human cells; overexpression rescue of neurodegeneration confirms physiological relevance","pmids":["38670102"],"is_preprint":false},{"year":2024,"finding":"ZIP7 upregulation in T2DM mouse hearts reduces mitochondrial Zn2+, causing mitochondrial hyperpolarization and suppression of PINK1/Parkin-dependent mitophagy; cardiac-specific ZIP7 conditional knockout prevents these effects and rescues cardiac dysfunction and fibrosis in diabetic mice.","method":"Cardiac-specific CRISPR/Cas9 conditional knockout, echocardiography, mitoKeima/mitoQC mitophagy assays, ROS measurement, PINK1/Parkin mitochondrial accumulation assay","journal":"Cardiovascular diabetology","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific conditional KO with defined molecular pathway (PINK1/Parkin) and multiple orthogonal mitophagy readouts; in vivo functional rescue","pmids":["39511569"],"is_preprint":false},{"year":2025,"finding":"METTL9 methylates SLC39A7 at His45 and His49 residues (N1-histidine methylation), which suppresses ferroptosis through the PERK/ATF4/SLC7A11 axis, promoting glutathione synthesis and reducing ROS; this modification inhibits adipogenic differentiation of mesenchymal stem cells.","method":"METTL9 overexpression/knockdown, N1-histidine methylation site identification (His45/His49), SLC7A11 and glutathione measurement, ROS assay, adipogenic differentiation assay in vitro and OVX mouse model in vivo","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 — specific methylation sites on SLC39A7 identified with functional downstream pathway; single lab study","pmids":["40414869"],"is_preprint":false},{"year":2026,"finding":"ZIP7 interacts with MAZ in the cytoplasm to facilitate MAZ nuclear import; nuclear MAZ promotes MYBL2 transcription, driving prostate cancer bone metastasis; ZIP7 silencing inhibits cell migration, invasion, and bone metastasis in vivo.","method":"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, RNA-seq, in vitro migration/invasion assays, intra-arterial bone metastasis xenograft model, ZIP7 inhibitor treatment","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP demonstrates interaction, nuclear import assay shows functional consequence; in vivo rescue with inhibitor; single lab study","pmids":["42010154"],"is_preprint":false},{"year":2024,"finding":"ACSL4 interacts with both ZIP7 and VDAC3; this complex mediates ER-to-mitochondria iron transfer in hepatocytes under PFOS exposure, with ZIP7 functioning as an ER iron efflux channel and ACSL4 bridging ZIP7 and VDAC3 at the mitochondria-associated ER membrane.","method":"Co-immunoprecipitation (ZIP7-ACSL4-VDAC3), ZIP7 inhibition/siRNA knockdown, organellar iron measurement, VDAC3/MCU knockdown epistasis","journal":"The Science of the total environment","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus genetic epistasis demonstrates ZIP7-ACSL4-VDAC3 complex; iron transport role is novel and single-lab study","pmids":["39579909"],"is_preprint":false}],"current_model":"SLC39A7 (ZIP7) is an ER-resident zinc transporter that is activated by CK2-mediated phosphorylation at specific serine residues (S275/S276 and others), triggering gated release of Zn2+ from the ER into the cytosol; this cytosolic zinc wave inhibits phosphatases, activates tyrosine kinases and downstream MAPK/PI3K-AKT/mTOR signaling, supports ERAD by supplying Zn2+ to the Rpn11 proteasomal deubiquitinase, maintains ER homeostasis (preventing ER stress and aberrant protein trafficking), and is additionally regulated by METTL9-mediated N1-histidine methylation, with roles in B cell development, intestinal stem cell maintenance, ferroptosis, mitophagy, and death receptor trafficking."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that ZIP7 is a zinc transporter operating in the secretory compartment resolved the question of how zinc stored in the Golgi/ER can be mobilized to the cytoplasm.","evidence":"V5-tagged ZIP7 expression in CHO cells and yeast Δzrt3 complementation with subcellular fractionation","pmids":["15705588"],"confidence":"High","gaps":["Precise ER vs. Golgi localization was debated","Mechanism of transport gating was unknown","Physiological contexts requiring ZIP7 were uncharacterized"]},{"year":2008,"claim":"Demonstrating that ZIP7-released zinc inhibits phosphatases to activate receptor tyrosine kinases established the first signaling paradigm downstream of ZIP7-mediated zinc flux.","evidence":"siRNA knockdown in tamoxifen-resistant breast cancer cells with phosphatase activity and RTK phosphorylation readouts","pmids":["18583420"],"confidence":"High","gaps":["Identity of the kinase activating ZIP7 was unknown","Whether ZIP7 activation was constitutive or regulated was unclear"]},{"year":2012,"claim":"Identification of CK2 as the activating kinase and the ER as the primary ZIP7 compartment revealed that ZIP7 operates as a gated channel whose phosphorylation triggers a zinc signaling wave activating AKT and ERK1/2.","evidence":"CK2 pharmacological inhibition, proximity ligation assay, and ZIP7 phosphosite mutagenesis in mammalian cells; confirmed in zebrafish morpholino knockdown with zinc rescue","pmids":["22317921","22912764"],"confidence":"High","gaps":["Number and hierarchy of phosphorylation sites was incomplete","Structural basis of gating was unknown"]},{"year":2013,"claim":"Loss-of-function studies in Drosophila Catsup revealed that ZIP7-mediated zinc transport is required for Notch receptor trafficking through the ER/Golgi, linking ZIP7 to secretory pathway fidelity.","evidence":"Forward genetic screen in Drosophila with Notch localization and ER stress marker analysis","pmids":["23785054"],"confidence":"High","gaps":["Whether the trafficking defect is zinc-specific or secondary to ER stress was not resolved","Mammalian Notch trafficking dependence on ZIP7 was not yet shown"]},{"year":2017,"claim":"Mapping four serine phosphorylation sites as collectively required for maximal ZIP7 activation, and demonstrating that ZIP7 loss causes ER zinc accumulation that aggregates PDI, provided the molecular mechanism by which ZIP7 maintains ER proteostasis.","evidence":"Combinatorial phosphosite mutagenesis with phospho-protein arrays; conditional KO mouse with PDI activity assays and ER zinc measurement; CK2α siRNA in cardiomyocytes with FRET zinc sensors","pmids":["28205653","28545780","28232492"],"confidence":"High","gaps":["Structural model of ZIP7 gating was lacking","Direct measurement of zinc flux rate was not performed"]},{"year":2018,"claim":"Genetic ablation and unbiased screens established that ZIP7 zinc transport is causally required for cell proliferation, ER homeostasis, and surface trafficking of TNFR1/FAS death receptors, broadening ZIP7's role beyond kinase signaling to include receptor trafficking and necroptosis regulation.","evidence":"KO with zinc rescue in mammalian cells; genome-wide gene-trap and CRISPR screens in FADD-deficient haploid cells with death receptor surface-level measurement","pmids":["29980658","30237509"],"confidence":"High","gaps":["Whether all ER-resident transmembrane proteins are equally affected by ZIP7 loss was untested","Selectivity of trafficking impairment was unclear"]},{"year":2019,"claim":"Discovery that hypomorphic SLC39A7 mutations in humans block B cell development—recapitulated by CRISPR mouse models—established ZIP7 as essential for B cell receptor signaling strength via cytosolic zinc modulation of phosphatase activity, and defined a human Mendelian immunodeficiency.","evidence":"Human autosomal recessive mutations, CRISPR-Cas9 mouse modeling, cytoplasmic zinc measurement, phosphatase activity assay, B cell development flow cytometry","pmids":["30718914"],"confidence":"High","gaps":["Whether other immune lineages are similarly affected was not fully characterized","Precise phosphatase targets regulated by ZIP7-derived zinc were not identified"]},{"year":2019,"claim":"A direct-binding small-molecule inhibitor (NVS-ZP7-4) of ZIP7 confirmed its druggability and its requirement for Notch signaling in mammalian cells, validated by a resistance mutation (V430E).","evidence":"Phenotypic screen with photoaffinity labeling and resistance mutation sequencing in human cells","pmids":["30643281"],"confidence":"High","gaps":["Binding site and inhibitor mechanism of action at atomic resolution were not determined","In vivo pharmacology not reported"]},{"year":2021,"claim":"A genome-wide RNAi screen identified ZIP7 as a genetic determinant of ferroptosis susceptibility, showing that ZIP7 inhibition triggers ER stress that induces HERPUD1, which in turn protects against ferroptosis.","evidence":"Genome-wide RNAi screen, ZIP7 siRNA/chemical inhibition, epistasis with HERPUD1 knockdown, ferroptosis assays","pmids":["33608508"],"confidence":"High","gaps":["Whether ZIP7's role in ferroptosis is entirely ER-stress dependent or also involves direct lipid peroxidation modulation was not resolved"]},{"year":2024,"claim":"ZIP7-supplied Zn²⁺ was shown to activate the Rpn11 metalloproteinase in the proteasome lid, mechanistically coupling ER zinc release to ERAD substrate deubiquitination and explaining how ZIP7 overexpression rescues neurodegeneration from misfolded proteins.","evidence":"Drosophila border cell genetics and misfolded-rhodopsin neurodegeneration model; Rpn11 deubiquitinase activity assay in human cells","pmids":["38670102"],"confidence":"High","gaps":["Whether Rpn11 is the sole proteasomal zinc-dependent target of ZIP7 is unknown","Quantitative contribution of ZIP7 vs. other zinc sources to proteasomal function not determined"]},{"year":2024,"claim":"Cardiac-specific ZIP7 knockout in diabetic mice prevented mitochondrial zinc depletion, restored PINK1/Parkin-dependent mitophagy, and rescued diabetic cardiomyopathy, establishing ZIP7 as a regulator of mitophagy via mitochondrial zinc levels.","evidence":"Cardiac-specific CRISPR/Cas9 conditional KO in T2DM mice, mitoKeima/mitoQC mitophagy assays, echocardiography","pmids":["39511569"],"confidence":"High","gaps":["Whether ZIP7 directly transports zinc across the mitochondrial membrane or acts indirectly through ER-mitochondria contact sites is unresolved","The mechanism by which mitochondrial zinc levels regulate PINK1 stability was not defined"]},{"year":2025,"claim":"METTL9-mediated N1-histidine methylation at His45 and His49 of ZIP7 was identified as a post-translational modification that modulates ferroptosis via the PERK/ATF4/SLC7A11 axis and glutathione synthesis, adding a second regulatory layer beyond CK2 phosphorylation.","evidence":"METTL9 overexpression/knockdown with methylation site identification, SLC7A11 and glutathione measurement, adipogenic differentiation assay in vitro and OVX mouse model","pmids":["40414869"],"confidence":"Medium","gaps":["Whether histidine methylation affects ZIP7 transport activity directly or indirectly is unknown","Independent validation of the methylation sites is needed","Interplay between CK2 phosphorylation and METTL9 methylation has not been tested"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of ZIP7 and the gating mechanism, the full spectrum of zinc-dependent ER chaperones affected by ZIP7 loss, whether ZIP7 directly resides on mitochondrial membranes or acts through ER-mitochondria contact sites, and the identity of the specific phosphatases inhibited by ZIP7-released zinc.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of ZIP7 exists","Direct mitochondrial localization vs. MAM-mediated action is unresolved","Specific phosphatase substrates of ZIP7-derived zinc remain unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,6,8,10,14,18]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,8,10,15]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[12,17,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,5,7,14]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,3,6,8,10,18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,8,10,11,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[18,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[17,19]}],"complexes":[],"partners":["CSNK2A1","NLRX1","ACSL4","VDAC3","MAZ","METTL9"],"other_free_text":[]},"mechanistic_narrative":"SLC39A7 (ZIP7) is an ER-resident zinc transporter that gates the release of Zn²⁺ from ER/Golgi stores into the cytosol, functioning as a central node linking intracellular zinc homeostasis to cell signaling, ER proteostasis, and cell fate decisions. CK2-mediated phosphorylation at conserved serine residues (S275, S276, and two additional sites) activates ZIP7, triggering a cytosolic zinc wave that inhibits phosphatases and thereby potentiates tyrosine kinase, MAPK, PI3K-AKT, and mTOR signaling [PMID:22317921, PMID:28205653, PMID:18583420]. Loss of ZIP7 causes ER zinc accumulation, protein disulfide isomerase aggregation, ER stress, impaired ERAD—partly through reduced Zn²⁺ supply to the Rpn11 proteasomal deubiquitinase—and defective secretory pathway trafficking of Notch and death receptors [PMID:28545780, PMID:38670102, PMID:23785054, PMID:30237509]. Hypomorphic SLC39A7 mutations in humans cause a block in early B cell development due to insufficient cytosolic zinc and excessive phosphatase activity that attenuates pre-BCR/BCR signaling [PMID:30918914]."},"prefetch_data":{"uniprot":{"accession":"Q92504","full_name":"Zinc transporter SLC39A7","aliases":["Histidine-rich membrane protein Ke4","Really interesting new gene 5 protein","Solute carrier family 39 member 7","Zrt-, Irt-like protein 7","ZIP7"],"length_aa":469,"mass_kda":50.1,"function":"Transports Zn(2+) from the endoplasmic reticulum (ER)/Golgi apparatus to the cytosol, playing an essential role in the regulation of cytosolic zinc levels (PubMed:14525538, PubMed:15705588, PubMed:28205653, PubMed:29980658). Acts as a gatekeeper of zinc release from intracellular stores, requiring post-translational activation by phosphorylation, resulting in activation of multiple downstream pathways leading to cell growth and proliferation (PubMed:22317921, PubMed:28205653, PubMed:29980658). Has an essential role in B cell development and is required for proper B cell receptor signaling (PubMed:30718914). Plays an important role in maintaining intestinal epithelial homeostasis and skin dermis development by regulating ER function (By similarity). Controls cell signaling pathways involved in glucose metabolism in skeletal muscle (By similarity). Has a protective role against ER stress in different biological contexts (PubMed:29980658, PubMed:30237509). Mediates Zn(2+)-induced ferroptosis (PubMed:33608508)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus, cis-Golgi network membrane","url":"https://www.uniprot.org/uniprotkb/Q92504/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC39A7","classification":"Common Essential","n_dependent_lines":1160,"n_total_lines":1208,"dependency_fraction":0.9602649006622517},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC39A7","total_profiled":1310},"omim":[{"mim_id":"619693","title":"AGAMMAGLOBULINEMIA 9, AUTOSOMAL RECESSIVE; AGM9","url":"https://www.omim.org/entry/619693"},{"mim_id":"601495","title":"AGAMMAGLOBULINEMIA 1, AUTOSOMAL RECESSIVE; AGM1","url":"https://www.omim.org/entry/601495"},{"mim_id":"601416","title":"SOLUTE CARRIER FAMILY 39 (ZINC TRANSPORTER), MEMBER 7; SLC39A7","url":"https://www.omim.org/entry/601416"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC39A7"},"hgnc":{"alias_symbol":["H2-KE4","D6S2244E","KE4","RING5","ZIP7"],"prev_symbol":["HKE4"]},"alphafold":{"accession":"Q92504","domains":[{"cath_id":"-","chopping":"127-156_167-196_217-240_313-469","consensus_level":"medium","plddt":85.8465,"start":127,"end":469}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92504","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92504-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92504-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC39A7","jax_strain_url":"https://www.jax.org/strain/search?query=SLC39A7"},"sequence":{"accession":"Q92504","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92504.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92504/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92504"}},"corpus_meta":[{"pmid":"22317921","id":"PMC_22317921","title":"Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7.","date":"2012","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/22317921","citation_count":222,"is_preprint":false},{"pmid":"18583420","id":"PMC_18583420","title":"ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer Cells.","date":"2008","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/18583420","citation_count":192,"is_preprint":false},{"pmid":"15705588","id":"PMC_15705588","title":"The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15705588","citation_count":170,"is_preprint":false},{"pmid":"19246244","id":"PMC_19246244","title":"Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation.","date":"2009","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19246244","citation_count":167,"is_preprint":false},{"pmid":"33608508","id":"PMC_33608508","title":"Zinc transporter ZIP7 is a novel determinant of ferroptosis.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33608508","citation_count":99,"is_preprint":false},{"pmid":"30718914","id":"PMC_30718914","title":"An essential role for the Zn2+ transporter ZIP7 in B cell development.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30718914","citation_count":95,"is_preprint":false},{"pmid":"27736879","id":"PMC_27736879","title":"Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27736879","citation_count":77,"is_preprint":false},{"pmid":"28232492","id":"PMC_28232492","title":"Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart.","date":"2017","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/28232492","citation_count":72,"is_preprint":false},{"pmid":"28205653","id":"PMC_28205653","title":"Phosphorylation of zinc channel ZIP7 drives MAPK, PI3K and mTOR growth and proliferation signalling.","date":"2017","source":"Metallomics : integrated biometal science","url":"https://pubmed.ncbi.nlm.nih.gov/28205653","citation_count":71,"is_preprint":false},{"pmid":"23785054","id":"PMC_23785054","title":"Protein trafficking abnormalities in Drosophila tissues with impaired activity of the ZIP7 zinc transporter Catsup.","date":"2013","source":"Development (Cambridge, 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radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/31135177","citation_count":28,"is_preprint":false},{"pmid":"30781350","id":"PMC_30781350","title":"Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes.","date":"2019","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/30781350","citation_count":27,"is_preprint":false},{"pmid":"30237509","id":"PMC_30237509","title":"Systematic genetic mapping of necroptosis identifies SLC39A7 as modulator of death receptor trafficking.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30237509","citation_count":27,"is_preprint":false},{"pmid":"29285013","id":"PMC_29285013","title":"Knockdown of SLC39A7 suppresses cell proliferation, migration and invasion in cervical cancer.","date":"2017","source":"EXCLI 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30029049","citation_count":17,"is_preprint":false},{"pmid":"8662089","id":"PMC_8662089","title":"Physical mapping of the Ring1, Ring2, Ke6, Ke4, Rxrb, Col11a2, and RT1.Hb genes in the rat major histocompatibility complex.","date":"1996","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/8662089","citation_count":17,"is_preprint":false},{"pmid":"31266232","id":"PMC_31266232","title":"The Zinc Transporter Zip7 Is Downregulated in Skeletal Muscle of Insulin-Resistant Cells and in Mice Fed a High-Fat Diet.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31266232","citation_count":16,"is_preprint":false},{"pmid":"32109290","id":"PMC_32109290","title":"SLC39A7, regulated by miR-139-5p, induces cell proliferation, migration and inhibits apoptosis in gastric cancer via Akt/mTOR signaling pathway.","date":"2020","source":"Bioscience 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/37292980","citation_count":2,"is_preprint":false},{"pmid":"38217370","id":"PMC_38217370","title":"SLC39A7 upregulation links to skin fibrosis in systemic sclerosis via TGF-β/SMAD pathway.","date":"2024","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/38217370","citation_count":0,"is_preprint":false},{"pmid":"42010154","id":"PMC_42010154","title":"Zinc-dependent Zip7-MAZ-MYBL2 axis promotes prostate cancer metastasis.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/42010154","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20926,"output_tokens":5455,"usd":0.072302},"stage2":{"model":"claude-opus-4-6","input_tokens":9008,"output_tokens":3298,"usd":0.191235},"total_usd":0.263537,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"ZIP7 (SLC39A7) localizes to the Golgi apparatus and functions as a zinc transporter that moves zinc from the Golgi apparatus into the cytoplasm. Protein expression is repressed under zinc-rich conditions, but intracellular localization is unaffected by zinc status.\",\n      \"method\": \"V5-tagged fusion protein expression in CHO cells, yeast complementation assay (Δzrt3 mutant), subcellular fractionation, zinc measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional zinc transport demonstrated in mammalian cells and yeast complementation, with subcellular localization; multiple orthogonal methods in one study\",\n      \"pmids\": [\"15705588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ZIP7 is required for redistribution of zinc from intracellular stores to the cytoplasm; siRNA-mediated knockdown of ZIP7 reduces intracellular zinc levels and abolishes zinc-induced inhibition of phosphatases, thereby blocking activation of EGFR, IGF-IR, Src, HER2, HER3, and HER4 in tamoxifen-resistant breast cancer cells.\",\n      \"method\": \"siRNA knockdown, growth factor receptor phosphorylation assays, zinc measurement\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean siRNA KD with specific molecular phenotype (phosphatase activity, RTK activation) and functional readout (growth, invasion); replicated across multiple receptors\",\n      \"pmids\": [\"18583420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Protein kinase CK2 phosphorylates evolutionarily conserved residues on the endoplasmic reticulum zinc channel ZIP7, triggering gated release of Zn2+ from ER stores into the cytosol, which activates tyrosine kinases and downstream phosphorylation of AKT and ERK1/2.\",\n      \"method\": \"Pharmacological inhibition of CK2, proximity ligation assay (PLA), site-directed mutagenesis of ZIP7 phosphorylation sites, phospho-western blotting\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis plus PLA plus pharmacological manipulation in one study; highly cited foundational paper\",\n      \"pmids\": [\"22317921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Zip7 is required for zinc homeostasis in vivo; morpholino knockdown in zebrafish causes reduced zinc in brain, eyes, and gills, and developmental defects (reduced head size, smaller eyes, shorter palate, curved spine) that are rescued by zinc supplementation.\",\n      \"method\": \"Morpholino antisense knockdown in zebrafish, synchrotron radiation X-ray fluorescence (SR-XRF) zinc quantification, zinc rescue experiment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KD with defined morphological and elemental phenotype, mechanistically linked to zinc deficiency via rescue\",\n      \"pmids\": [\"22912764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of Catsup (Drosophila ortholog of ZIP7/SLC39A7) causes Notch receptor accumulation in the ER and Golgi, impairs Notch signaling, and elevates ER stress, indicating ZIP7-mediated zinc transport is required for proper trafficking of the Notch receptor through the secretory pathway.\",\n      \"method\": \"Forward genetic screen, loss-of-function mutations, immunofluorescence imaging of Notch receptor localization, ER stress markers\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic screen with defined trafficking phenotype in Drosophila ortholog; multiple cellular readouts\",\n      \"pmids\": [\"23785054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Zip7 knockdown in skeletal muscle cells reduces expression of glucose metabolism genes (including Glut4, Insr, Irs1, Irs2) and decreases insulin-stimulated glycogen synthesis and Akt phosphorylation, placing Zip7 as a regulator of glucose metabolism and insulin signaling in muscle.\",\n      \"method\": \"siRNA knockdown, qPCR, western blot, glycogen synthesis assay, Akt phosphorylation measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific signaling and metabolic phenotype, but single lab, single study\",\n      \"pmids\": [\"24265765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Intestinal epithelial-specific deletion of Zip7 triggers ER stress in proliferative progenitor cells, causes death of progenitor cells, loss of Olfm4+ intestinal stem cells, and degeneration of Paneth cells, demonstrating that ZIP7-mediated zinc transport from the ER is essential for intestinal epithelial homeostasis.\",\n      \"method\": \"Conditional knockout mouse (intestinal epithelium-specific), histology, ER stress markers, stem cell marker analysis (Olfm4)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific conditional KO with defined cellular and molecular phenotypes; multiple cell type readouts\",\n      \"pmids\": [\"27736879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Phosphorylation of ZIP7 at four serine residues (including S275 and S276) is required for maximal activation and zinc release from intracellular stores, which drives MAPK, PI3K-AKT, and mTOR signaling pathways.\",\n      \"method\": \"Site-directed mutagenesis of individual and combined serine residues, phospho-protein arrays, downstream pathway analysis\",\n      \"journal\": \"Metallomics : integrated biometal science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with pathway-level functional readout; directly identifies the phosphorylation sites required for activation\",\n      \"pmids\": [\"28205653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZIP7 localizes to the ER in mesenchymal stem cells; ablation of Zip7 causes zinc accumulation in the ER, zinc-dependent aggregation and inhibition of protein disulfide isomerase (PDI), leading to ER dysfunction and impaired dermal development.\",\n      \"method\": \"Conditional knockout mouse (collagen 1-expressing tissue), immunofluorescence localization, zinc measurement, PDI activity assay, proliferation assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with specific molecular mechanism (PDI inhibition by zinc) identified; multiple orthogonal methods\",\n      \"pmids\": [\"28545780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hyperglycemia increases ZIP7 expression and phosphorylation in cardiomyocytes, resulting in elevated cytosolic free Zn2+ and decreased ER/SR Zn2+; CK2α siRNA suppresses ZIP7 phosphorylation and the associated Zn2+ redistribution, confirming CK2 as the kinase responsible for ZIP7 activation in the heart.\",\n      \"method\": \"FRET-based zinc sensors, siRNA knockdown of CK2α, phospho-western blotting, subcellular fractionation in cardiomyocytes from diabetic rats\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FRET sensors directly measure zinc redistribution; CK2 link confirmed by siRNA; in vivo diabetic model plus in vitro\",\n      \"pmids\": [\"28232492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Genetic ablation of SLC39A7 decreases cytosolic zinc levels, increases ER zinc levels, impairs cell proliferation, and induces ER stress; both ER stress and proliferation defects are rescued by increasing cytosolic zinc, confirming that ZIP7's zinc transport activity is causally responsible.\",\n      \"method\": \"Genetic knockout, zinc supplementation rescue, cell proliferation assay, ER stress markers, small-molecule screen\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with zinc rescue establishing causality; multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"29980658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC39A7 knockout in FADD-deficient haploid human cells confers resistance to necroptosis by impairing TNFR1 and FAS receptor surface trafficking; loss of SLC39A7 causes augmented ER stress that reduces receptor trafficking to the cell surface, globally affecting downstream death receptor signaling.\",\n      \"method\": \"Genome-wide gene-trap screen, CRISPR/Cas9 knockout, SLC-focused CRISPR screen, death receptor surface level measurement\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genetic screen confirmed by orthogonal CRISPR screen; specific trafficking mechanism identified\",\n      \"pmids\": [\"30237509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZIP7 and ZnT7 also localize to mitochondria in cardiomyocytes; in hyperglycemic conditions, mitochondrial ZIP7 expression decreases while ZnT7 increases, leading to increased mitochondrial Zn2+, ROS production, and mitochondrial membrane potential changes, affecting SR-mitochondria coupling.\",\n      \"method\": \"Fluorescence imaging, mitochondrial fractionation/biochemical analysis, FRET-based zinc sensors\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization in isolated fractions plus FRET zinc measurement; single lab study\",\n      \"pmids\": [\"29307859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZIP7 (SLC39A7) governs Notch trafficking and signaling; a small-molecule inhibitor (NVS-ZP7-4) directly interacts with ZIP7 (photoaffinity labeling), and a V430E resistance mutation in ZIP7 confers resistance to the compound; inhibition alters ER zinc levels and induces ER stress-mediated apoptosis.\",\n      \"method\": \"Phenotypic screen, resistance mutation sequencing, photoaffinity labeling of ZIP7, zinc measurement in ER\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct compound-protein interaction shown by photoaffinity labeling; resistance mutation confirms on-target mechanism; multiple orthogonal approaches\",\n      \"pmids\": [\"30643281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hypomorphic mutations of SLC39A7 in humans and CRISPR-modeled mice cause a block in B cell development; mutant B cells have diminished cytoplasmic free zinc, increased phosphatase activity, and decreased phosphorylation of pre-B cell and B cell receptor signaling molecules, establishing that cytosolic Zn2+ delivered by ZIP7 is required to modulate BCR signal strength.\",\n      \"method\": \"Human genetics (autosomal recessive mutations), CRISPR-Cas9 mouse modeling, cytoplasmic zinc measurement, phosphatase activity assay, phospho-western blotting, B cell development flow cytometry\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human disease mutations corroborated by precise CRISPR mouse model; multiple molecular mechanisms established\",\n      \"pmids\": [\"30718914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZIP7 is localized to the ER, while ZIP13 localizes to both ER and Golgi; ZIP7 depletion (but not ZIP13 depletion) induces ER stress in mesenchymal stem cells and inhibits fibrogenic differentiation, demonstrating distinct non-redundant roles for each transporter in dermal development.\",\n      \"method\": \"Sibling transporter comparison, immunofluorescence co-localization, ER stress markers, differentiation assays, genome-wide gene expression analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct comparison of two ZIP transporters with specific ER stress and differentiation readouts; single lab study\",\n      \"pmids\": [\"31412620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ZIP7 controls zinc transport from the ER to the cytosol and is a genetic determinant of ferroptosis; genetic or chemical inhibition of ZIP7 protects cells from ferroptosis by triggering ER stress (including induction of HERPUD1 and ATF3), and HERPUD1 knockdown abolishes this ferroptosis protection.\",\n      \"method\": \"Genome-wide RNAi screen, ZIP7 siRNA knockdown, chemical inhibition, zinc chelation/supplementation, epistasis with HERPUD1 knockdown, ferroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen hit confirmed by multiple orthogonal approaches; epistasis analysis places ZIP7 upstream of HERPUD1 in ER-stress-mediated ferroptosis protection\",\n      \"pmids\": [\"33608508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NLRX1 physically interacts with SLC39A7 (ZIP7) to form an NLRX1-SLC39A7 complex on the mitochondrial membrane of nucleus pulposus cells, modulating mitochondrial Zn2+ trafficking and thereby orchestrating mitochondrial dynamics (fission/fusion) and mitophagy.\",\n      \"method\": \"Co-immunoprecipitation (interaction), confocal co-localization on mitochondrial membrane, in vitro/in vivo cell and animal models, mitochondrial function assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP demonstrates interaction; mitochondrial localization shown; functional consequence demonstrated; single lab study\",\n      \"pmids\": [\"37876250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZIP7-mediated Zn2+ transport enhances ERAD by providing Zn2+ to the Rpn11 Zn2+ metalloproteinase in the proteasome lid, which is required for deubiquitination of substrates entering the proteasome; ZIP7 overexpression rescues neurodegeneration caused by misfolded rhodopsin in a Drosophila model.\",\n      \"method\": \"Drosophila border cell migration genetics, human cell ZIP7 manipulation, Rpn11 deubiquitinase activity assay, misfolded rhodopsin neurodegeneration model, proteasomal substrate deubiquitination assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic link between ZIP7 Zn2+ transport and Rpn11 metalloproteinase activity demonstrated in both Drosophila and human cells; overexpression rescue of neurodegeneration confirms physiological relevance\",\n      \"pmids\": [\"38670102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZIP7 upregulation in T2DM mouse hearts reduces mitochondrial Zn2+, causing mitochondrial hyperpolarization and suppression of PINK1/Parkin-dependent mitophagy; cardiac-specific ZIP7 conditional knockout prevents these effects and rescues cardiac dysfunction and fibrosis in diabetic mice.\",\n      \"method\": \"Cardiac-specific CRISPR/Cas9 conditional knockout, echocardiography, mitoKeima/mitoQC mitophagy assays, ROS measurement, PINK1/Parkin mitochondrial accumulation assay\",\n      \"journal\": \"Cardiovascular diabetology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific conditional KO with defined molecular pathway (PINK1/Parkin) and multiple orthogonal mitophagy readouts; in vivo functional rescue\",\n      \"pmids\": [\"39511569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL9 methylates SLC39A7 at His45 and His49 residues (N1-histidine methylation), which suppresses ferroptosis through the PERK/ATF4/SLC7A11 axis, promoting glutathione synthesis and reducing ROS; this modification inhibits adipogenic differentiation of mesenchymal stem cells.\",\n      \"method\": \"METTL9 overexpression/knockdown, N1-histidine methylation site identification (His45/His49), SLC7A11 and glutathione measurement, ROS assay, adipogenic differentiation assay in vitro and OVX mouse model in vivo\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — specific methylation sites on SLC39A7 identified with functional downstream pathway; single lab study\",\n      \"pmids\": [\"40414869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ZIP7 interacts with MAZ in the cytoplasm to facilitate MAZ nuclear import; nuclear MAZ promotes MYBL2 transcription, driving prostate cancer bone metastasis; ZIP7 silencing inhibits cell migration, invasion, and bone metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, RNA-seq, in vitro migration/invasion assays, intra-arterial bone metastasis xenograft model, ZIP7 inhibitor treatment\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP demonstrates interaction, nuclear import assay shows functional consequence; in vivo rescue with inhibitor; single lab study\",\n      \"pmids\": [\"42010154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSL4 interacts with both ZIP7 and VDAC3; this complex mediates ER-to-mitochondria iron transfer in hepatocytes under PFOS exposure, with ZIP7 functioning as an ER iron efflux channel and ACSL4 bridging ZIP7 and VDAC3 at the mitochondria-associated ER membrane.\",\n      \"method\": \"Co-immunoprecipitation (ZIP7-ACSL4-VDAC3), ZIP7 inhibition/siRNA knockdown, organellar iron measurement, VDAC3/MCU knockdown epistasis\",\n      \"journal\": \"The Science of the total environment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus genetic epistasis demonstrates ZIP7-ACSL4-VDAC3 complex; iron transport role is novel and single-lab study\",\n      \"pmids\": [\"39579909\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC39A7 (ZIP7) is an ER-resident zinc transporter that is activated by CK2-mediated phosphorylation at specific serine residues (S275/S276 and others), triggering gated release of Zn2+ from the ER into the cytosol; this cytosolic zinc wave inhibits phosphatases, activates tyrosine kinases and downstream MAPK/PI3K-AKT/mTOR signaling, supports ERAD by supplying Zn2+ to the Rpn11 proteasomal deubiquitinase, maintains ER homeostasis (preventing ER stress and aberrant protein trafficking), and is additionally regulated by METTL9-mediated N1-histidine methylation, with roles in B cell development, intestinal stem cell maintenance, ferroptosis, mitophagy, and death receptor trafficking.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC39A7 (ZIP7) is an ER-resident zinc transporter that gates the release of Zn²⁺ from ER/Golgi stores into the cytosol, functioning as a central node linking intracellular zinc homeostasis to cell signaling, ER proteostasis, and cell fate decisions. CK2-mediated phosphorylation at conserved serine residues (S275, S276, and two additional sites) activates ZIP7, triggering a cytosolic zinc wave that inhibits phosphatases and thereby potentiates tyrosine kinase, MAPK, PI3K-AKT, and mTOR signaling [PMID:22317921, PMID:28205653, PMID:18583420]. Loss of ZIP7 causes ER zinc accumulation, protein disulfide isomerase aggregation, ER stress, impaired ERAD—partly through reduced Zn²⁺ supply to the Rpn11 proteasomal deubiquitinase—and defective secretory pathway trafficking of Notch and death receptors [PMID:28545780, PMID:38670102, PMID:23785054, PMID:30237509]. Hypomorphic SLC39A7 mutations in humans cause a block in early B cell development due to insufficient cytosolic zinc and excessive phosphatase activity that attenuates pre-BCR/BCR signaling [PMID:30918914].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that ZIP7 is a zinc transporter operating in the secretory compartment resolved the question of how zinc stored in the Golgi/ER can be mobilized to the cytoplasm.\",\n      \"evidence\": \"V5-tagged ZIP7 expression in CHO cells and yeast Δzrt3 complementation with subcellular fractionation\",\n      \"pmids\": [\"15705588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise ER vs. Golgi localization was debated\", \"Mechanism of transport gating was unknown\", \"Physiological contexts requiring ZIP7 were uncharacterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that ZIP7-released zinc inhibits phosphatases to activate receptor tyrosine kinases established the first signaling paradigm downstream of ZIP7-mediated zinc flux.\",\n      \"evidence\": \"siRNA knockdown in tamoxifen-resistant breast cancer cells with phosphatase activity and RTK phosphorylation readouts\",\n      \"pmids\": [\"18583420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the kinase activating ZIP7 was unknown\", \"Whether ZIP7 activation was constitutive or regulated was unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of CK2 as the activating kinase and the ER as the primary ZIP7 compartment revealed that ZIP7 operates as a gated channel whose phosphorylation triggers a zinc signaling wave activating AKT and ERK1/2.\",\n      \"evidence\": \"CK2 pharmacological inhibition, proximity ligation assay, and ZIP7 phosphosite mutagenesis in mammalian cells; confirmed in zebrafish morpholino knockdown with zinc rescue\",\n      \"pmids\": [\"22317921\", \"22912764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Number and hierarchy of phosphorylation sites was incomplete\", \"Structural basis of gating was unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Loss-of-function studies in Drosophila Catsup revealed that ZIP7-mediated zinc transport is required for Notch receptor trafficking through the ER/Golgi, linking ZIP7 to secretory pathway fidelity.\",\n      \"evidence\": \"Forward genetic screen in Drosophila with Notch localization and ER stress marker analysis\",\n      \"pmids\": [\"23785054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the trafficking defect is zinc-specific or secondary to ER stress was not resolved\", \"Mammalian Notch trafficking dependence on ZIP7 was not yet shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping four serine phosphorylation sites as collectively required for maximal ZIP7 activation, and demonstrating that ZIP7 loss causes ER zinc accumulation that aggregates PDI, provided the molecular mechanism by which ZIP7 maintains ER proteostasis.\",\n      \"evidence\": \"Combinatorial phosphosite mutagenesis with phospho-protein arrays; conditional KO mouse with PDI activity assays and ER zinc measurement; CK2α siRNA in cardiomyocytes with FRET zinc sensors\",\n      \"pmids\": [\"28205653\", \"28545780\", \"28232492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of ZIP7 gating was lacking\", \"Direct measurement of zinc flux rate was not performed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic ablation and unbiased screens established that ZIP7 zinc transport is causally required for cell proliferation, ER homeostasis, and surface trafficking of TNFR1/FAS death receptors, broadening ZIP7's role beyond kinase signaling to include receptor trafficking and necroptosis regulation.\",\n      \"evidence\": \"KO with zinc rescue in mammalian cells; genome-wide gene-trap and CRISPR screens in FADD-deficient haploid cells with death receptor surface-level measurement\",\n      \"pmids\": [\"29980658\", \"30237509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all ER-resident transmembrane proteins are equally affected by ZIP7 loss was untested\", \"Selectivity of trafficking impairment was unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that hypomorphic SLC39A7 mutations in humans block B cell development—recapitulated by CRISPR mouse models—established ZIP7 as essential for B cell receptor signaling strength via cytosolic zinc modulation of phosphatase activity, and defined a human Mendelian immunodeficiency.\",\n      \"evidence\": \"Human autosomal recessive mutations, CRISPR-Cas9 mouse modeling, cytoplasmic zinc measurement, phosphatase activity assay, B cell development flow cytometry\",\n      \"pmids\": [\"30718914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other immune lineages are similarly affected was not fully characterized\", \"Precise phosphatase targets regulated by ZIP7-derived zinc were not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A direct-binding small-molecule inhibitor (NVS-ZP7-4) of ZIP7 confirmed its druggability and its requirement for Notch signaling in mammalian cells, validated by a resistance mutation (V430E).\",\n      \"evidence\": \"Phenotypic screen with photoaffinity labeling and resistance mutation sequencing in human cells\",\n      \"pmids\": [\"30643281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site and inhibitor mechanism of action at atomic resolution were not determined\", \"In vivo pharmacology not reported\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A genome-wide RNAi screen identified ZIP7 as a genetic determinant of ferroptosis susceptibility, showing that ZIP7 inhibition triggers ER stress that induces HERPUD1, which in turn protects against ferroptosis.\",\n      \"evidence\": \"Genome-wide RNAi screen, ZIP7 siRNA/chemical inhibition, epistasis with HERPUD1 knockdown, ferroptosis assays\",\n      \"pmids\": [\"33608508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ZIP7's role in ferroptosis is entirely ER-stress dependent or also involves direct lipid peroxidation modulation was not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ZIP7-supplied Zn²⁺ was shown to activate the Rpn11 metalloproteinase in the proteasome lid, mechanistically coupling ER zinc release to ERAD substrate deubiquitination and explaining how ZIP7 overexpression rescues neurodegeneration from misfolded proteins.\",\n      \"evidence\": \"Drosophila border cell genetics and misfolded-rhodopsin neurodegeneration model; Rpn11 deubiquitinase activity assay in human cells\",\n      \"pmids\": [\"38670102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rpn11 is the sole proteasomal zinc-dependent target of ZIP7 is unknown\", \"Quantitative contribution of ZIP7 vs. other zinc sources to proteasomal function not determined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cardiac-specific ZIP7 knockout in diabetic mice prevented mitochondrial zinc depletion, restored PINK1/Parkin-dependent mitophagy, and rescued diabetic cardiomyopathy, establishing ZIP7 as a regulator of mitophagy via mitochondrial zinc levels.\",\n      \"evidence\": \"Cardiac-specific CRISPR/Cas9 conditional KO in T2DM mice, mitoKeima/mitoQC mitophagy assays, echocardiography\",\n      \"pmids\": [\"39511569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ZIP7 directly transports zinc across the mitochondrial membrane or acts indirectly through ER-mitochondria contact sites is unresolved\", \"The mechanism by which mitochondrial zinc levels regulate PINK1 stability was not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"METTL9-mediated N1-histidine methylation at His45 and His49 of ZIP7 was identified as a post-translational modification that modulates ferroptosis via the PERK/ATF4/SLC7A11 axis and glutathione synthesis, adding a second regulatory layer beyond CK2 phosphorylation.\",\n      \"evidence\": \"METTL9 overexpression/knockdown with methylation site identification, SLC7A11 and glutathione measurement, adipogenic differentiation assay in vitro and OVX mouse model\",\n      \"pmids\": [\"40414869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether histidine methylation affects ZIP7 transport activity directly or indirectly is unknown\", \"Independent validation of the methylation sites is needed\", \"Interplay between CK2 phosphorylation and METTL9 methylation has not been tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of ZIP7 and the gating mechanism, the full spectrum of zinc-dependent ER chaperones affected by ZIP7 loss, whether ZIP7 directly resides on mitochondrial membranes or acts through ER-mitochondria contact sites, and the identity of the specific phosphatases inhibited by ZIP7-released zinc.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of ZIP7 exists\", \"Direct mitochondrial localization vs. MAM-mediated action is unresolved\", \"Specific phosphatase substrates of ZIP7-derived zinc remain unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 6, 8, 10, 14, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 8, 10, 15]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [12, 17, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 5, 7, 14]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 3, 6, 8, 10, 18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 8, 10, 11, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [18, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [17, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CSNK2A1\",\n      \"NLRX1\",\n      \"ACSL4\",\n      \"VDAC3\",\n      \"MAZ\",\n      \"METTL9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}