{"gene":"SLC39A7","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2004,"finding":"HKE4 (SLC39A7/ZIP7) localizes to intracellular membranes including the endoplasmic reticulum and increases intracellular free zinc in a time-, temperature-, and concentration-dependent manner, as measured by the zinc-specific fluorescent dye Newport Green. The protein contains a conserved HEXPHEXGD metalloprotease motif in transmembrane domain V and a consensus zinc-transport sequence in transmembrane domain IV.","method":"Transient expression in mammalian cells, fluorescent zinc dye (Newport Green), immunolocalization","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization and functional zinc transport assay in mammalian cells, single lab, two orthogonal methods","pmids":["14525538"],"is_preprint":false},{"year":2005,"finding":"Endogenous ZIP7 associates with the Golgi apparatus and transports zinc from the Golgi into the cytoplasm. In a yeast Δzrt3 mutant defective in vacuolar zinc release, ZIP7 expression decreased accumulated vacuolar zinc and increased nuclear/cytoplasmic labile zinc. ZIP7 protein expression is repressed under zinc-rich conditions but its intracellular localization is unaffected by zinc status.","method":"Subcellular fractionation, immunolocalization in CHO cells, yeast complementation assay (Δzrt3), V5-tagged overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization + functional yeast complementation + mammalian zinc transport assay, multiple orthogonal methods in one study","pmids":["15705588"],"is_preprint":false},{"year":2008,"finding":"ZIP7 knockdown (siRNA) in tamoxifen-resistant MCF7 (TamR) breast cancer cells reduces intracellular zinc levels and abolishes activation of EGFR, IGF-IR, Src, HER2, HER3, and HER4, demonstrating that ZIP7-mediated zinc redistribution from intracellular stores to the cytoplasm is required for zinc-induced phosphatase inhibition and downstream growth factor receptor activation.","method":"siRNA knockdown, western blot for receptor phosphorylation, intracellular zinc measurement","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with defined molecular phenotype (receptor phosphorylation), single lab, multiple receptors tested","pmids":["18583420"],"is_preprint":false},{"year":2012,"finding":"Protein kinase CK2 phosphorylates evolutionarily conserved residues in ZIP7 on the endoplasmic reticulum, triggering gated release of Zn2+ from ER stores into the cytosol, which activates tyrosine kinases and phosphorylation of AKT and ERK1/2. CK2 was identified as the responsible kinase by pharmacological inhibition, proximity ligation assay, and site-directed mutagenesis of the phosphorylation sites.","method":"Proximity ligation assay, pharmacological CK2 inhibition, site-directed mutagenesis, phospho-western blot, intracellular zinc imaging","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of phosphorylation sites + proximity ligation + pharmacological inhibition, multiple orthogonal methods establishing the CK2-ZIP7-zinc signaling axis","pmids":["22317921"],"is_preprint":false},{"year":2012,"finding":"Morpholino-mediated knockdown of zip7 in zebrafish causes morphological defects (reduced head size, smaller eyes, shorter palates, curved spinal cord) accompanied by reduced zinc concentrations in brain, eyes, and gills as measured by synchrotron radiation X-ray fluorescence, and these defects are partially rescued by zinc supplementation, establishing an in vivo requirement for Zip7 in developmental zinc homeostasis.","method":"Morpholino antisense knockdown in zebrafish, synchrotron radiation X-ray fluorescence (SR-XRF), zinc rescue experiment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with elemental analysis and zinc rescue, single lab, two orthogonal methods","pmids":["22912764"],"is_preprint":false},{"year":2013,"finding":"In Drosophila, loss of Catsup (the ZIP7 ortholog) causes Notch receptor to accumulate abnormally in the ER and Golgi, impairing Notch signaling, and elevates ER stress, linking ZIP7-dependent zinc homeostasis to secretory pathway protein trafficking and Notch receptor processing.","method":"Forward genetic screen, immunofluorescence localization of Notch in mutant epithelia, ER stress markers","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined trafficking phenotype in Drosophila ortholog, single lab","pmids":["23785054"],"is_preprint":false},{"year":2013,"finding":"siRNA knockdown of Zip7 in skeletal muscle cells downregulates expression of glucose metabolism genes (including Glut4, Insr, Irs1, Irs2) and reduces insulin-stimulated glycogen synthesis and AKT phosphorylation, placing ZIP7 upstream of insulin signaling and glucose uptake in skeletal muscle.","method":"siRNA knockdown, RT-PCR, western blot, glycogen synthesis assay, phospho-AKT immunoblot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple downstream readouts, single lab","pmids":["24265765"],"is_preprint":false},{"year":2014,"finding":"ZIP7 co-localizes with CLN6 (a disease-associated protein) at the ER/Golgi in neurons and astrocytes. Loss of Zip7 accompanies aberrant biometal accumulation in CLN6-variant NCL, and treatment with ZnII(atsm) upregulates Zip7, promotes zinc redistribution, and restores zinc-dependent functions in Cln6-deficient mouse neurons and astrocytes.","method":"Immunofluorescence co-localization, metal analysis, pharmacological rescue (ZnII(atsm)) in primary mouse neurons","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization with disease protein + pharmacological rescue, single lab, two orthogonal methods","pmids":["24581221"],"is_preprint":false},{"year":2016,"finding":"Intestinal epithelium-specific knockout of Zip7 in mice triggers ER stress in proliferative progenitor cells, causes cell death of progenitors, loss of Olfm4+ intestinal stem cells, and degeneration of Paneth cells, establishing ZIP7 as essential for intestinal epithelial homeostasis through maintenance of ER function.","method":"Conditional knockout mouse (intestinal epithelium-specific), histology, immunofluorescence, ER stress markers","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse with defined cellular phenotypes and ER stress mechanism, multiple cell types and markers assessed","pmids":["27736879"],"is_preprint":false},{"year":2017,"finding":"Site-directed mutagenesis of ZIP7 phosphorylation sites (S275, S276, and two additional predicted sites) demonstrates that all four residues are required for maximal ZIP7 activation and zinc release from intracellular stores. Phospho-protein arrays identify MAPK, mTOR, and PI3K-AKT as major downstream pathways activated by ZIP7-mediated zinc release.","method":"Site-directed mutagenesis, phospho-protein arrays, intracellular zinc imaging","journal":"Metallomics : integrated biometal science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific phosphorylation residues with functional readout (zinc release + pathway arrays), single lab but multiple sites tested","pmids":["28205653"],"is_preprint":false},{"year":2017,"finding":"ZIP7 ablation in collagen 1-expressing mesenchymal stem cells causes dermal dysplasia in mice. Loss of ZIP7 causes zinc accumulation in the ER, leading to zinc-dependent aggregation and inhibition of protein disulfide isomerase (PDI), resulting in ER dysfunction and impaired cell proliferation.","method":"Conditional knockout mouse (mesenchymal), subcellular zinc measurement, PDI aggregation/activity assay, histology","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with in vitro mechanistic follow-up (PDI inhibition assay), multiple orthogonal methods establishing ER zinc-PDI axis","pmids":["28545780"],"is_preprint":false},{"year":2017,"finding":"In hyperglycemic cardiomyocytes, ZIP7 is phosphorylated (CK2α-dependent) and redistributes cytosolic free Zn2+ from the ER to the cytosol as shown by FRET-based Zn2+ sensors. siRNA silencing of CK2α suppresses this redistribution. ZIP7 and ZnT7 are also localized to the sarco(endo)plasmic reticulum in cardiomyocytes by fractionation.","method":"FRET-based Zn2+ sensors, siRNA knockdown of CK2α, subcellular fractionation, phospho-western blot","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1 / Moderate — FRET sensors + siRNA epistasis + fractionation, multiple orthogonal methods in one study, single lab","pmids":["28232492"],"is_preprint":false},{"year":2018,"finding":"Genetic ablation of SLC39A7 decreases cytosolic zinc, increases ER zinc levels, impairs cell proliferation, and induces ER stress. Increasing cytosolic zinc rescues both the ER stress and impaired proliferation, confirming impaired zinc transport as the causal mechanism.","method":"Genetic ablation (KO), intracellular zinc measurement, ER stress markers, proliferation assay, zinc supplementation rescue","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple phenotypes and zinc-rescue epistasis confirming mechanism, multiple orthogonal methods","pmids":["29980658"],"is_preprint":false},{"year":2018,"finding":"ZIP7 and ZnT7 are localized to both the sarco(endo)plasmic reticulum and mitochondria in cardiomyocytes, as confirmed by fluorescence imaging and biochemical fractionation. In hyperglycemic cells, ZIP7 is decreased and ZnT7 is increased in mitochondrial fractions, associated with elevated mitochondrial Zn2+, increased ROS, and altered S(E)R-mitochondria coupling proteins.","method":"Fluorescence microscopy, subcellular fractionation, western blot of mitochondrial fractions, ROS measurement","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual localization confirmed by fractionation + fluorescence, functional correlations, single lab","pmids":["29307859"],"is_preprint":false},{"year":2018,"finding":"Zinc promotes myoblast proliferation and differentiation via ZIP7-mediated activation of the PI3K/AKT pathway. siRNA depletion of ZIP7 reduces PI3K/AKT signaling and significantly reduces multinucleated myofibre and myotube formation.","method":"siRNA knockdown, western blot for pAKT, multinucleation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with defined signaling and differentiation phenotypes, single lab","pmids":["30206294"],"is_preprint":false},{"year":2018,"finding":"Loss-of-function genetic screens in haploid human KBM7 (FADD-deficient) cells identify SLC39A7 knockout as conferring necroptosis resistance by reducing TNFR1 surface levels. SLC-focused CRISPR screens show specificity for TNFR1- and FAS-mediated but not TRAIL-R1-mediated pathways. Mechanistically, SLC39A7 loss augments ER stress and impairs receptor trafficking.","method":"Genome-wide gene-trap screens, CRISPR/Cas9 KO, flow cytometry for surface receptor levels, cell death assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal genetic screens (gene-trap + CRISPR) with receptor surface level readout and death assay, mechanistic pathway specificity established","pmids":["30237509"],"is_preprint":false},{"year":2019,"finding":"Hypomorphic mutations in SLC39A7 in humans cause a block in B cell development resulting in absent B cells and agammaglobulinemia. CRISPR-Cas9 modeling in mice reproduced the B cell developmental block. B cells from mutant mice showed diminished cytoplasmic free zinc, increased phosphatase activity, and decreased phosphorylation of pre-B cell receptor and B cell receptor signaling molecules, establishing ZIP7 as a modulator of BCR signal strength via cytosolic Zn2+.","method":"Human genetics (autosomal recessive mutations), CRISPR-Cas9 mouse modeling, flow cytometry, phosphatase activity assay, phospho-western blot, intracellular zinc measurement","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — human disease genetics replicated by precise CRISPR mouse model with mechanistic biochemical follow-up, multiple orthogonal methods","pmids":["30718914"],"is_preprint":false},{"year":2019,"finding":"A phenotypic screen identified compounds that impair Notch trafficking and induce ER stress-mediated apoptosis via ZIP7. A compound-resistant cell line harbored a V430E mutation in ZIP7, conferring transferable resistance. An analog of the compound NVS-ZP7-4 photoaffinity-labeled ZIP7 in cells, indicating direct compound-ZIP7 interaction. NVS-ZP7-4 alters zinc levels in the ER.","method":"Phenotypic screen, drug-resistance mutation sequencing, photoaffinity labeling in cells, ER zinc measurement","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — photoaffinity labeling establishes direct compound-protein interaction; resistance mutation V430E provides orthogonal confirmation; ER zinc measurement links to mechanism","pmids":["30643281"],"is_preprint":false},{"year":2019,"finding":"ZIP7 localized on the ER is distinct from ZIP13 (which localizes to both ER and Golgi when co-expressed). ZIP7 depletion induces ER stress in mesenchymal stem cells inhibiting fibrogenic differentiation, whereas ZIP13 depletion does not induce ER stress, establishing non-redundant, compartment-specific roles for each transporter.","method":"Conditional co-expression, immunofluorescence localization, ER stress markers, differentiation assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization comparison + functional differentiation assay, single lab","pmids":["31412620"],"is_preprint":false},{"year":2021,"finding":"ZIP7 controls zinc transport from the ER to the cytosol and is required for ferroptosis in breast and renal cancer cells. Genetic or chemical inhibition of ZIP7 protects cells against ferroptosis; this protection is abolished by zinc supplementation. ZIP7 knockdown triggers ER stress including induction of HERPUD1 and ATF3, and knockdown of HERPUD1 abolishes the ferroptosis protection from ZIP7 inhibition, placing ZIP7 upstream of HERPUD1 in ferroptosis regulation.","method":"Genome-wide RNAi screen, siRNA knockdown, zinc supplementation rescue, ER stress marker induction, HERPUD1 knockdown epistasis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen + genetic epistasis (HERPUD1 KD) + zinc rescue, multiple orthogonal methods establishing pathway position","pmids":["33608508"],"is_preprint":false},{"year":2023,"finding":"NLRX1 physically interacts with SLC39A7 (ZIP7) and forms an NLRX1-SLC39A7 complex on the mitochondrial membrane of nucleus pulposus cells, modulating mitochondrial Zn2+ trafficking to orchestrate mitochondrial dynamics (DNM1L/DRP1, OPA1, OMA1) and mitophagy.","method":"Co-immunoprecipitation, mitochondrial fractionation, FRET/zinc sensors, mitophagy assays (mito-LC3II, mitoKeima), animal and in vitro models","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex + functional mitophagy readouts, single lab","pmids":["37876250"],"is_preprint":false},{"year":2024,"finding":"ZIP7 overexpression in Drosophila enhances ERAD by supplying Zn2+ to the Rpn11 Zn2+ metalloproteinase in the proteasome lid, facilitating deubiquitination of client proteins. In human cells, ZIP7 and cytosolic Zn2+ are rate-limiting for this deubiquitination step. ZIP7 overexpression in a Drosophila model of neurodegeneration (misfolded rhodopsin) degrades misfolded Rh1 and rescues photoreceptor viability and vision.","method":"Drosophila border cell migration genetics, proteasome deubiquitination assay, human cell Zn2+ manipulation, in vivo neurodegeneration model (rhodopsin misfolding)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical deubiquitination assay + in vivo neurodegeneration rescue + cross-species validation (Drosophila + human cells), multiple orthogonal methods establishing mechanism","pmids":["38670102"],"is_preprint":false},{"year":2024,"finding":"In diabetic cardiomyopathy (T2DM mouse model), ZIP7 is upregulated and mediates suppression of mitophagy via inhibition of the PINK1/Parkin pathway. ZIP7 cardiac-specific knockout (CRISPR-generated) prevents mitochondrial Zn2+ reduction, mitochondrial hyperpolarization, impaired PINK1/Parkin accumulation, and restores mitophagy, preventing cardiac dysfunction and fibrosis.","method":"CRISPR/Cas9 cardiac-specific KO mouse, echocardiography, mito-LC3II/mitoKeima/mitoQC mitophagy assays, DHE/mitoB ROS detection, mitochondrial Zn2+ measurement","journal":"Cardiovascular diabetology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cardiac-specific KO mouse with multiple mechanistic readouts (PINK1/Parkin, Zn2+ measurement, mitophagy flux assays), single lab but rigorous multi-method study","pmids":["39511569"],"is_preprint":false},{"year":2024,"finding":"ACSL4 interacts with ZIP7 and VDAC3 in mouse liver and human hepatocytes, forming a complex at ER-mitochondria contact sites. Inhibition of ZIP7 reduces mitochondrial iron overload while elevating ER iron, and inhibition of ACSL4 reduces the ZIP7-VDAC3 interaction, implicating an ACSL4-ZIP7-VDAC3 axis in ER-to-mitochondria iron transfer under PFOS exposure.","method":"Co-immunoprecipitation, siRNA/inhibitor knockdown of ZIP7/VDAC3/ACSL4, organellar iron measurement, mouse liver model","journal":"The Science of the total environment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex + functional iron redistribution assay, single lab","pmids":["39579909"],"is_preprint":false},{"year":2025,"finding":"METTL9 methylates SLC39A7 at His45 and His49 residues (N1-histidine methylation), suppressing ferroptosis through the ER stress PERK/ATF4 pathway and downstream SLC7A11-mediated glutathione synthesis, and inhibiting adipogenic differentiation of mesenchymal stem cells.","method":"Methyltransferase assay (METTL9), site-specific methylation mapping (His45, His49), ferroptosis assay, ROS measurement, PERK/ATF4/SLC7A11 western blot, adipogenic differentiation assay in vitro and OVX mouse model","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — specific PTM sites identified biochemically + functional downstream pathway, single lab, in vitro and in vivo","pmids":["40414869"],"is_preprint":false},{"year":2024,"finding":"ZIP7 interacts with the transcription factor MAZ in the cytoplasm and facilitates its nuclear import. Nuclear MAZ promotes MYBL2 transcription, driving prostate cancer bone metastasis. ZIP7 silencing inhibits PCa cell migration/invasion in vitro and bone metastasis in vivo.","method":"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, RNA-seq, in vivo intra-arterial bone metastasis xenograft model, siRNA/inhibitor","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + fractionation + RNA-seq with in vivo validation, single lab","pmids":["42010154"],"is_preprint":false}],"current_model":"SLC39A7/ZIP7 is an endoplasmic reticulum (and Golgi)-resident zinc transporter that releases Zn2+ from intracellular stores into the cytosol following phosphorylation of conserved serine residues (S275/S276) by protein kinase CK2; the resulting cytosolic zinc wave inhibits phosphatases and activates multiple downstream signaling cascades (PI3K/AKT, MAPK/ERK, mTOR, tyrosine kinases, BCR signaling), regulates ERAD efficiency by supplying Zn2+ to the proteasomal deubiquitinase Rpn11, maintains ER proteostasis (preventing ER stress and PDI inhibition), controls death receptor trafficking and ferroptosis via HERPUD1/ER stress, modulates mitochondrial Zn2+ levels and PINK1/Parkin-dependent mitophagy, and is subject to PTM by METTL9-mediated N1-histidine methylation at His45/His49 that links it to ferroptosis resistance through PERK/ATF4/SLC7A11 signaling."},"narrative":{"mechanistic_narrative":"SLC39A7/ZIP7 is an endoplasmic reticulum- and Golgi-resident zinc transporter that releases Zn2+ from intracellular stores into the cytosol, thereby converting compartmentalized zinc into a cytosolic signaling event that governs cell proliferation, secretory-pathway proteostasis, and growth-factor signaling [PMID:14525538, PMID:15705588, PMID:18583420]. Gated zinc release is triggered by protein kinase CK2, which phosphorylates conserved serine residues (S275/S276 and additional sites) required for maximal ZIP7 activation; the resulting cytosolic zinc wave inhibits phosphatases and activates tyrosine kinases, AKT, ERK1/2, and the MAPK, mTOR, and PI3K/AKT pathways [PMID:22317921, PMID:28205653, PMID:28232492]. Through this signaling output ZIP7 is required for growth-factor receptor activation in tamoxifen-resistant breast cancer cells, insulin signaling and glucose-gene expression in muscle, and B cell receptor signal strength, where hypomorphic human SLC39A7 mutations cause a block in B cell development and agammaglobulinemia replicated in CRISPR mouse models [PMID:18583420, PMID:24265765, PMID:30718914]. A second, parallel role lies in maintaining ER zinc balance: loss of ZIP7 causes zinc to accumulate in the ER and depletes the cytosol, triggering ER stress, aggregation and inhibition of protein disulfide isomerase, and impaired proliferation that is rescued by restoring cytosolic zinc [PMID:28545780, PMID:29980658, PMID:27736879]. ER-derived cytosolic zinc is also rate-limiting for ERAD, supplying Zn2+ to the proteasomal deubiquitinase Rpn11 to clear misfolded clients [PMID:38670102], and ZIP7-dependent ER homeostasis controls death-receptor trafficking and necroptosis via TNFR1/FAS surface levels and HERPUD1-dependent ferroptosis [PMID:30237509, PMID:33608508]. ZIP7 additionally localizes to mitochondria where it shapes mitochondrial Zn2+ and PINK1/Parkin-dependent mitophagy [PMID:39511569]. Across organisms ZIP7 is essential for developmental zinc homeostasis and secretory trafficking, including Notch receptor processing in Drosophila [PMID:22912764, PMID:23785054].","teleology":[{"year":2004,"claim":"Established that ZIP7 is an intracellular-membrane protein that elevates cytosolic free zinc, defining it as a candidate store-release transporter rather than a plasma-membrane importer.","evidence":"Transient expression, Newport Green zinc dye, and immunolocalization in mammalian cells","pmids":["14525538"],"confidence":"Medium","gaps":["Direction and driving force of transport not resolved","Metalloprotease-like motif function not tested","No identification of the store compartment beyond ER"]},{"year":2005,"claim":"Demonstrated that endogenous ZIP7 releases zinc from the Golgi/ER lumen into cytoplasm and nucleus, and that its expression is zinc-repressed, defining it as a regulated store-release transporter.","evidence":"Subcellular fractionation, immunolocalization in CHO cells, and yeast Δzrt3 complementation","pmids":["15705588"],"confidence":"High","gaps":["Mechanism of activation/gating unknown","Transport stoichiometry not measured"]},{"year":2008,"claim":"Connected ZIP7-mediated zinc redistribution to downstream signaling by showing it is required for growth-factor receptor activation, framing zinc as a second messenger downstream of ZIP7.","evidence":"siRNA knockdown and phospho-western for EGFR/IGF-IR/Src/HER receptors in tamoxifen-resistant MCF7 cells","pmids":["18583420"],"confidence":"Medium","gaps":["Phosphatase targets of cytosolic zinc not directly identified","Single cell-line context"]},{"year":2012,"claim":"Identified the activation mechanism: CK2 phosphorylation of conserved serines gates ER zinc release that activates tyrosine kinases, AKT, and ERK — converting ZIP7 from a passive transporter to a signal-gated channel.","evidence":"Proximity ligation, pharmacological CK2 inhibition, phospho-site mutagenesis, and zinc imaging; plus in vivo zebrafish morpholino knockdown with zinc rescue","pmids":["22317921","22912764"],"confidence":"High","gaps":["Structural basis of phospho-gating unresolved","Whether CK2 acts directly on ZIP7 in all cell types not established"]},{"year":2013,"claim":"Extended ZIP7 function to secretory-pathway trafficking and tissue-specific signaling, linking ER zinc homeostasis to Notch receptor processing and to insulin/glucose signaling in muscle.","evidence":"Drosophila Catsup forward-genetic loss-of-function with Notch localization; siRNA knockdown with glycogen synthesis and phospho-AKT readouts in muscle cells","pmids":["23785054","24265765"],"confidence":"Medium","gaps":["Direct mechanism linking ER zinc to receptor trafficking not defined","Glucose-gene regulation pathway not mapped"]},{"year":2017,"claim":"Defined the full phospho-site requirement and the pathway output, and revealed the ER zinc-PDI axis whereby ZIP7 loss causes ER zinc accumulation, PDI inhibition, and ER stress.","evidence":"Phospho-site mutagenesis with phospho-protein arrays; mesenchymal and intestinal conditional KO mice with PDI aggregation assays and ER stress markers; CK2α-dependent FRET zinc redistribution in cardiomyocytes","pmids":["28205653","28545780","27736879","28232492"],"confidence":"High","gaps":["Quantitative contribution of each phospho-site unclear","How ER zinc excess inhibits PDI mechanistically beyond aggregation not fully detailed"]},{"year":2018,"claim":"Confirmed by genetic ablation that impaired ER-to-cytosol zinc transport is the causal driver of ER stress and proliferation defects, and broadened roles to myogenesis, death-receptor trafficking, and mitochondrial zinc.","evidence":"Gene ablation with zinc-rescue epistasis; siRNA in myoblasts; haploid gene-trap and CRISPR screens with surface receptor flow cytometry; cardiomyocyte fractionation showing mitochondrial localization","pmids":["29980658","30206294","30237509","29307859"],"confidence":"High","gaps":["Mechanism of TNFR1/FAS trafficking dependence on ER zinc not resolved","Mitochondrial localization function not yet defined at this stage"]},{"year":2019,"claim":"Linked ZIP7 to human disease and provided a directly-binding chemical probe, establishing ZIP7 as a druggable target whose loss impairs BCR signaling via cytosolic zinc.","evidence":"Human autosomal-recessive genetics with CRISPR mouse modeling and phosphatase/phospho-BCR assays; phenotypic screen with V430E resistance mutation and photoaffinity labeling by NVS-ZP7-4; ZIP7/ZIP13 compartment-specific comparison","pmids":["30718914","30643281","31412620"],"confidence":"High","gaps":["Structure of ZIP7 with bound inhibitor not determined","Phosphatase substrates of zinc in B cells not enumerated"]},{"year":2021,"claim":"Positioned ZIP7 upstream of HERPUD1 in a zinc/ER-stress axis controlling ferroptosis, identifying a defined genetic epistasis for ZIP7-dependent cell death sensitivity.","evidence":"Genome-wide RNAi screen, siRNA knockdown, zinc-rescue, and HERPUD1 knockdown epistasis in breast and renal cancer cells","pmids":["33608508"],"confidence":"High","gaps":["How HERPUD1 induction executes ferroptosis downstream not detailed","Connection between ER zinc and lipid peroxidation unresolved"]},{"year":2023,"claim":"Identified mitochondrial protein complexes for ZIP7, implicating it in mitochondrial zinc and iron trafficking, dynamics, and mitophagy.","evidence":"Co-IP of NLRX1-SLC39A7 with mitophagy assays in nucleus pulposus cells; later ACSL4-ZIP7-VDAC3 Co-IP at ER-mitochondria contacts with organellar iron measurement","pmids":["37876250","39579909"],"confidence":"Medium","gaps":["Co-IP complexes lack reciprocal/structural validation","Whether ZIP7 transports iron or only zinc at these sites not established"]},{"year":2024,"claim":"Defined a proteostasis output (ERAD via Rpn11 zinc supply) and additional mitophagy and metastasis roles, showing cytosolic zinc from ZIP7 is rate-limiting for deubiquitination.","evidence":"Drosophila genetics and proteasome deubiquitination assays with human cell zinc manipulation and in vivo rhodopsin rescue; cardiac-specific KO mouse with PINK1/Parkin and mitophagy flux assays; Co-IP/fractionation/RNA-seq for MAZ-MYBL2 in prostate metastasis","pmids":["38670102","39511569","42010154"],"confidence":"High","gaps":["Direct demonstration that ZIP7 delivers Zn2+ to Rpn11 in human cells inferred from rate-limiting epistasis","Contradictory mitophagy effects across tissues not reconciled"]},{"year":2025,"claim":"Added a post-translational regulatory layer: METTL9-mediated histidine methylation of ZIP7 couples it to PERK/ATF4/SLC7A11 ferroptosis-resistance signaling.","evidence":"METTL9 methyltransferase assay, His45/His49 mapping, ferroptosis and PERK/ATF4/SLC7A11 readouts in vitro and OVX mouse model","pmids":["40414869"],"confidence":"Medium","gaps":["Effect of His methylation on ZIP7 transport activity not measured","Single-lab finding without independent confirmation"]},{"year":null,"claim":"How a single ER/Golgi zinc transporter selectively partitions its cytosolic zinc output between phosphatase-inhibition signaling, ER proteostasis/ERAD, ferroptosis control, and mitochondrial dynamics across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of human ZIP7 or its transport mechanism","Direct zinc substrates/targets of cytosolic phosphatases not enumerated","Tissue-specific opposing mitophagy roles not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,11,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,3,10,12,18]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,5,7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[13,20,22,23]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,9,16]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,10,12,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[15,19]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[21]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[20,22]}],"complexes":["NLRX1-SLC39A7 complex","ACSL4-ZIP7-VDAC3 complex"],"partners":["CSNK2A1","NLRX1","VDAC3","ACSL4","MAZ","METTL9"],"other_free_text":[]}},"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 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The protein contains a conserved HEXPHEXGD metalloprotease motif in transmembrane domain V and a consensus zinc-transport sequence in transmembrane domain IV.\",\n      \"method\": \"Transient expression in mammalian cells, fluorescent zinc dye (Newport Green), immunolocalization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization and functional zinc transport assay in mammalian cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"14525538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Endogenous ZIP7 associates with the Golgi apparatus and transports zinc from the Golgi into the cytoplasm. In a yeast Δzrt3 mutant defective in vacuolar zinc release, ZIP7 expression decreased accumulated vacuolar zinc and increased nuclear/cytoplasmic labile zinc. ZIP7 protein expression is repressed under zinc-rich conditions but its intracellular localization is unaffected by zinc status.\",\n      \"method\": \"Subcellular fractionation, immunolocalization in CHO cells, yeast complementation assay (Δzrt3), V5-tagged overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization + functional yeast complementation + mammalian zinc transport assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"15705588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ZIP7 knockdown (siRNA) in tamoxifen-resistant MCF7 (TamR) breast cancer cells reduces intracellular zinc levels and abolishes activation of EGFR, IGF-IR, Src, HER2, HER3, and HER4, demonstrating that ZIP7-mediated zinc redistribution from intracellular stores to the cytoplasm is required for zinc-induced phosphatase inhibition and downstream growth factor receptor activation.\",\n      \"method\": \"siRNA knockdown, western blot for receptor phosphorylation, intracellular zinc measurement\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with defined molecular phenotype (receptor phosphorylation), single lab, multiple receptors tested\",\n      \"pmids\": [\"18583420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Protein kinase CK2 phosphorylates evolutionarily conserved residues in ZIP7 on the endoplasmic reticulum, triggering gated release of Zn2+ from ER stores into the cytosol, which activates tyrosine kinases and phosphorylation of AKT and ERK1/2. CK2 was identified as the responsible kinase by pharmacological inhibition, proximity ligation assay, and site-directed mutagenesis of the phosphorylation sites.\",\n      \"method\": \"Proximity ligation assay, pharmacological CK2 inhibition, site-directed mutagenesis, phospho-western blot, intracellular zinc imaging\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of phosphorylation sites + proximity ligation + pharmacological inhibition, multiple orthogonal methods establishing the CK2-ZIP7-zinc signaling axis\",\n      \"pmids\": [\"22317921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Morpholino-mediated knockdown of zip7 in zebrafish causes morphological defects (reduced head size, smaller eyes, shorter palates, curved spinal cord) accompanied by reduced zinc concentrations in brain, eyes, and gills as measured by synchrotron radiation X-ray fluorescence, and these defects are partially rescued by zinc supplementation, establishing an in vivo requirement for Zip7 in developmental zinc homeostasis.\",\n      \"method\": \"Morpholino antisense knockdown in zebrafish, synchrotron radiation X-ray fluorescence (SR-XRF), zinc rescue experiment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with elemental analysis and zinc rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"22912764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila, loss of Catsup (the ZIP7 ortholog) causes Notch receptor to accumulate abnormally in the ER and Golgi, impairing Notch signaling, and elevates ER stress, linking ZIP7-dependent zinc homeostasis to secretory pathway protein trafficking and Notch receptor processing.\",\n      \"method\": \"Forward genetic screen, immunofluorescence localization of Notch in mutant epithelia, ER stress markers\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined trafficking phenotype in Drosophila ortholog, single lab\",\n      \"pmids\": [\"23785054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"siRNA knockdown of Zip7 in skeletal muscle cells downregulates expression of glucose metabolism genes (including Glut4, Insr, Irs1, Irs2) and reduces insulin-stimulated glycogen synthesis and AKT phosphorylation, placing ZIP7 upstream of insulin signaling and glucose uptake in skeletal muscle.\",\n      \"method\": \"siRNA knockdown, RT-PCR, western blot, glycogen synthesis assay, phospho-AKT immunoblot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple downstream readouts, single lab\",\n      \"pmids\": [\"24265765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZIP7 co-localizes with CLN6 (a disease-associated protein) at the ER/Golgi in neurons and astrocytes. Loss of Zip7 accompanies aberrant biometal accumulation in CLN6-variant NCL, and treatment with ZnII(atsm) upregulates Zip7, promotes zinc redistribution, and restores zinc-dependent functions in Cln6-deficient mouse neurons and astrocytes.\",\n      \"method\": \"Immunofluorescence co-localization, metal analysis, pharmacological rescue (ZnII(atsm)) in primary mouse neurons\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization with disease protein + pharmacological rescue, single lab, two orthogonal methods\",\n      \"pmids\": [\"24581221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Intestinal epithelium-specific knockout of Zip7 in mice triggers ER stress in proliferative progenitor cells, causes cell death of progenitors, loss of Olfm4+ intestinal stem cells, and degeneration of Paneth cells, establishing ZIP7 as essential for intestinal epithelial homeostasis through maintenance of ER function.\",\n      \"method\": \"Conditional knockout mouse (intestinal epithelium-specific), histology, immunofluorescence, ER stress markers\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse with defined cellular phenotypes and ER stress mechanism, multiple cell types and markers assessed\",\n      \"pmids\": [\"27736879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Site-directed mutagenesis of ZIP7 phosphorylation sites (S275, S276, and two additional predicted sites) demonstrates that all four residues are required for maximal ZIP7 activation and zinc release from intracellular stores. Phospho-protein arrays identify MAPK, mTOR, and PI3K-AKT as major downstream pathways activated by ZIP7-mediated zinc release.\",\n      \"method\": \"Site-directed mutagenesis, phospho-protein arrays, intracellular zinc imaging\",\n      \"journal\": \"Metallomics : integrated biometal science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific phosphorylation residues with functional readout (zinc release + pathway arrays), single lab but multiple sites tested\",\n      \"pmids\": [\"28205653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZIP7 ablation in collagen 1-expressing mesenchymal stem cells causes dermal dysplasia in mice. Loss of ZIP7 causes zinc accumulation in the ER, leading to zinc-dependent aggregation and inhibition of protein disulfide isomerase (PDI), resulting in ER dysfunction and impaired cell proliferation.\",\n      \"method\": \"Conditional knockout mouse (mesenchymal), subcellular zinc measurement, PDI aggregation/activity assay, histology\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with in vitro mechanistic follow-up (PDI inhibition assay), multiple orthogonal methods establishing ER zinc-PDI axis\",\n      \"pmids\": [\"28545780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In hyperglycemic cardiomyocytes, ZIP7 is phosphorylated (CK2α-dependent) and redistributes cytosolic free Zn2+ from the ER to the cytosol as shown by FRET-based Zn2+ sensors. siRNA silencing of CK2α suppresses this redistribution. ZIP7 and ZnT7 are also localized to the sarco(endo)plasmic reticulum in cardiomyocytes by fractionation.\",\n      \"method\": \"FRET-based Zn2+ sensors, siRNA knockdown of CK2α, subcellular fractionation, phospho-western blot\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — FRET sensors + siRNA epistasis + fractionation, multiple orthogonal methods in one study, single lab\",\n      \"pmids\": [\"28232492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Genetic ablation of SLC39A7 decreases cytosolic zinc, increases ER zinc levels, impairs cell proliferation, and induces ER stress. Increasing cytosolic zinc rescues both the ER stress and impaired proliferation, confirming impaired zinc transport as the causal mechanism.\",\n      \"method\": \"Genetic ablation (KO), intracellular zinc measurement, ER stress markers, proliferation assay, zinc supplementation rescue\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple phenotypes and zinc-rescue epistasis confirming mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"29980658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZIP7 and ZnT7 are localized to both the sarco(endo)plasmic reticulum and mitochondria in cardiomyocytes, as confirmed by fluorescence imaging and biochemical fractionation. In hyperglycemic cells, ZIP7 is decreased and ZnT7 is increased in mitochondrial fractions, associated with elevated mitochondrial Zn2+, increased ROS, and altered S(E)R-mitochondria coupling proteins.\",\n      \"method\": \"Fluorescence microscopy, subcellular fractionation, western blot of mitochondrial fractions, ROS measurement\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual localization confirmed by fractionation + fluorescence, functional correlations, single lab\",\n      \"pmids\": [\"29307859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Zinc promotes myoblast proliferation and differentiation via ZIP7-mediated activation of the PI3K/AKT pathway. siRNA depletion of ZIP7 reduces PI3K/AKT signaling and significantly reduces multinucleated myofibre and myotube formation.\",\n      \"method\": \"siRNA knockdown, western blot for pAKT, multinucleation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with defined signaling and differentiation phenotypes, single lab\",\n      \"pmids\": [\"30206294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function genetic screens in haploid human KBM7 (FADD-deficient) cells identify SLC39A7 knockout as conferring necroptosis resistance by reducing TNFR1 surface levels. SLC-focused CRISPR screens show specificity for TNFR1- and FAS-mediated but not TRAIL-R1-mediated pathways. Mechanistically, SLC39A7 loss augments ER stress and impairs receptor trafficking.\",\n      \"method\": \"Genome-wide gene-trap screens, CRISPR/Cas9 KO, flow cytometry for surface receptor levels, cell death assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal genetic screens (gene-trap + CRISPR) with receptor surface level readout and death assay, mechanistic pathway specificity established\",\n      \"pmids\": [\"30237509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hypomorphic mutations in SLC39A7 in humans cause a block in B cell development resulting in absent B cells and agammaglobulinemia. CRISPR-Cas9 modeling in mice reproduced the B cell developmental block. B cells from mutant mice showed diminished cytoplasmic free zinc, increased phosphatase activity, and decreased phosphorylation of pre-B cell receptor and B cell receptor signaling molecules, establishing ZIP7 as a modulator of BCR signal strength via cytosolic Zn2+.\",\n      \"method\": \"Human genetics (autosomal recessive mutations), CRISPR-Cas9 mouse modeling, flow cytometry, phosphatase activity assay, phospho-western blot, intracellular zinc measurement\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human disease genetics replicated by precise CRISPR mouse model with mechanistic biochemical follow-up, multiple orthogonal methods\",\n      \"pmids\": [\"30718914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A phenotypic screen identified compounds that impair Notch trafficking and induce ER stress-mediated apoptosis via ZIP7. A compound-resistant cell line harbored a V430E mutation in ZIP7, conferring transferable resistance. An analog of the compound NVS-ZP7-4 photoaffinity-labeled ZIP7 in cells, indicating direct compound-ZIP7 interaction. NVS-ZP7-4 alters zinc levels in the ER.\",\n      \"method\": \"Phenotypic screen, drug-resistance mutation sequencing, photoaffinity labeling in cells, ER zinc measurement\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — photoaffinity labeling establishes direct compound-protein interaction; resistance mutation V430E provides orthogonal confirmation; ER zinc measurement links to mechanism\",\n      \"pmids\": [\"30643281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZIP7 localized on the ER is distinct from ZIP13 (which localizes to both ER and Golgi when co-expressed). ZIP7 depletion induces ER stress in mesenchymal stem cells inhibiting fibrogenic differentiation, whereas ZIP13 depletion does not induce ER stress, establishing non-redundant, compartment-specific roles for each transporter.\",\n      \"method\": \"Conditional co-expression, immunofluorescence localization, ER stress markers, differentiation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization comparison + functional differentiation assay, single lab\",\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 required for ferroptosis in breast and renal cancer cells. Genetic or chemical inhibition of ZIP7 protects cells against ferroptosis; this protection is abolished by zinc supplementation. ZIP7 knockdown triggers ER stress including induction of HERPUD1 and ATF3, and knockdown of HERPUD1 abolishes the ferroptosis protection from ZIP7 inhibition, placing ZIP7 upstream of HERPUD1 in ferroptosis regulation.\",\n      \"method\": \"Genome-wide RNAi screen, siRNA knockdown, zinc supplementation rescue, ER stress marker induction, HERPUD1 knockdown epistasis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen + genetic epistasis (HERPUD1 KD) + zinc rescue, multiple orthogonal methods establishing pathway position\",\n      \"pmids\": [\"33608508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NLRX1 physically interacts with SLC39A7 (ZIP7) and forms an NLRX1-SLC39A7 complex on the mitochondrial membrane of nucleus pulposus cells, modulating mitochondrial Zn2+ trafficking to orchestrate mitochondrial dynamics (DNM1L/DRP1, OPA1, OMA1) and mitophagy.\",\n      \"method\": \"Co-immunoprecipitation, mitochondrial fractionation, FRET/zinc sensors, mitophagy assays (mito-LC3II, mitoKeima), animal and in vitro models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex + functional mitophagy readouts, single lab\",\n      \"pmids\": [\"37876250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZIP7 overexpression in Drosophila enhances ERAD by supplying Zn2+ to the Rpn11 Zn2+ metalloproteinase in the proteasome lid, facilitating deubiquitination of client proteins. In human cells, ZIP7 and cytosolic Zn2+ are rate-limiting for this deubiquitination step. ZIP7 overexpression in a Drosophila model of neurodegeneration (misfolded rhodopsin) degrades misfolded Rh1 and rescues photoreceptor viability and vision.\",\n      \"method\": \"Drosophila border cell migration genetics, proteasome deubiquitination assay, human cell Zn2+ manipulation, in vivo neurodegeneration model (rhodopsin misfolding)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical deubiquitination assay + in vivo neurodegeneration rescue + cross-species validation (Drosophila + human cells), multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"38670102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In diabetic cardiomyopathy (T2DM mouse model), ZIP7 is upregulated and mediates suppression of mitophagy via inhibition of the PINK1/Parkin pathway. ZIP7 cardiac-specific knockout (CRISPR-generated) prevents mitochondrial Zn2+ reduction, mitochondrial hyperpolarization, impaired PINK1/Parkin accumulation, and restores mitophagy, preventing cardiac dysfunction and fibrosis.\",\n      \"method\": \"CRISPR/Cas9 cardiac-specific KO mouse, echocardiography, mito-LC3II/mitoKeima/mitoQC mitophagy assays, DHE/mitoB ROS detection, mitochondrial Zn2+ measurement\",\n      \"journal\": \"Cardiovascular diabetology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cardiac-specific KO mouse with multiple mechanistic readouts (PINK1/Parkin, Zn2+ measurement, mitophagy flux assays), single lab but rigorous multi-method study\",\n      \"pmids\": [\"39511569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSL4 interacts with ZIP7 and VDAC3 in mouse liver and human hepatocytes, forming a complex at ER-mitochondria contact sites. Inhibition of ZIP7 reduces mitochondrial iron overload while elevating ER iron, and inhibition of ACSL4 reduces the ZIP7-VDAC3 interaction, implicating an ACSL4-ZIP7-VDAC3 axis in ER-to-mitochondria iron transfer under PFOS exposure.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/inhibitor knockdown of ZIP7/VDAC3/ACSL4, organellar iron measurement, mouse liver model\",\n      \"journal\": \"The Science of the total environment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex + functional iron redistribution assay, single lab\",\n      \"pmids\": [\"39579909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL9 methylates SLC39A7 at His45 and His49 residues (N1-histidine methylation), suppressing ferroptosis through the ER stress PERK/ATF4 pathway and downstream SLC7A11-mediated glutathione synthesis, and inhibiting adipogenic differentiation of mesenchymal stem cells.\",\n      \"method\": \"Methyltransferase assay (METTL9), site-specific methylation mapping (His45, His49), ferroptosis assay, ROS measurement, PERK/ATF4/SLC7A11 western blot, adipogenic differentiation assay in vitro and OVX mouse model\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — specific PTM sites identified biochemically + functional downstream pathway, single lab, in vitro and in vivo\",\n      \"pmids\": [\"40414869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZIP7 interacts with the transcription factor MAZ in the cytoplasm and facilitates its nuclear import. Nuclear MAZ promotes MYBL2 transcription, driving prostate cancer bone metastasis. ZIP7 silencing inhibits PCa cell migration/invasion in vitro and bone metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, RNA-seq, in vivo intra-arterial bone metastasis xenograft model, siRNA/inhibitor\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + fractionation + RNA-seq with in vivo validation, single lab\",\n      \"pmids\": [\"42010154\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC39A7/ZIP7 is an endoplasmic reticulum (and Golgi)-resident zinc transporter that releases Zn2+ from intracellular stores into the cytosol following phosphorylation of conserved serine residues (S275/S276) by protein kinase CK2; the resulting cytosolic zinc wave inhibits phosphatases and activates multiple downstream signaling cascades (PI3K/AKT, MAPK/ERK, mTOR, tyrosine kinases, BCR signaling), regulates ERAD efficiency by supplying Zn2+ to the proteasomal deubiquitinase Rpn11, maintains ER proteostasis (preventing ER stress and PDI inhibition), controls death receptor trafficking and ferroptosis via HERPUD1/ER stress, modulates mitochondrial Zn2+ levels and PINK1/Parkin-dependent mitophagy, and is subject to PTM by METTL9-mediated N1-histidine methylation at His45/His49 that links it to ferroptosis resistance through PERK/ATF4/SLC7A11 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC39A7/ZIP7 is an endoplasmic reticulum- and Golgi-resident zinc transporter that releases Zn2+ from intracellular stores into the cytosol, thereby converting compartmentalized zinc into a cytosolic signaling event that governs cell proliferation, secretory-pathway proteostasis, and growth-factor signaling [#0, #1, #2]. Gated zinc release is triggered by protein kinase CK2, which phosphorylates conserved serine residues (S275/S276 and additional sites) required for maximal ZIP7 activation; the resulting cytosolic zinc wave inhibits phosphatases and activates tyrosine kinases, AKT, ERK1/2, and the MAPK, mTOR, and PI3K/AKT pathways [#3, #9, #11]. Through this signaling output ZIP7 is required for growth-factor receptor activation in tamoxifen-resistant breast cancer cells, insulin signaling and glucose-gene expression in muscle, and B cell receptor signal strength, where hypomorphic human SLC39A7 mutations cause a block in B cell development and agammaglobulinemia replicated in CRISPR mouse models [#2, #6, #16]. A second, parallel role lies in maintaining ER zinc balance: loss of ZIP7 causes zinc to accumulate in the ER and depletes the cytosol, triggering ER stress, aggregation and inhibition of protein disulfide isomerase, and impaired proliferation that is rescued by restoring cytosolic zinc [#10, #12, #8]. ER-derived cytosolic zinc is also rate-limiting for ERAD, supplying Zn2+ to the proteasomal deubiquitinase Rpn11 to clear misfolded clients [#21], and ZIP7-dependent ER homeostasis controls death-receptor trafficking and necroptosis via TNFR1/FAS surface levels and HERPUD1-dependent ferroptosis [#15, #19]. ZIP7 additionally localizes to mitochondria where it shapes mitochondrial Zn2+ and PINK1/Parkin-dependent mitophagy [#22]. Across organisms ZIP7 is essential for developmental zinc homeostasis and secretory trafficking, including Notch receptor processing in Drosophila [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that ZIP7 is an intracellular-membrane protein that elevates cytosolic free zinc, defining it as a candidate store-release transporter rather than a plasma-membrane importer.\",\n      \"evidence\": \"Transient expression, Newport Green zinc dye, and immunolocalization in mammalian cells\",\n      \"pmids\": [\"14525538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction and driving force of transport not resolved\", \"Metalloprotease-like motif function not tested\", \"No identification of the store compartment beyond ER\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that endogenous ZIP7 releases zinc from the Golgi/ER lumen into cytoplasm and nucleus, and that its expression is zinc-repressed, defining it as a regulated store-release transporter.\",\n      \"evidence\": \"Subcellular fractionation, immunolocalization in CHO cells, and yeast Δzrt3 complementation\",\n      \"pmids\": [\"15705588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of activation/gating unknown\", \"Transport stoichiometry not measured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected ZIP7-mediated zinc redistribution to downstream signaling by showing it is required for growth-factor receptor activation, framing zinc as a second messenger downstream of ZIP7.\",\n      \"evidence\": \"siRNA knockdown and phospho-western for EGFR/IGF-IR/Src/HER receptors in tamoxifen-resistant MCF7 cells\",\n      \"pmids\": [\"18583420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphatase targets of cytosolic zinc not directly identified\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the activation mechanism: CK2 phosphorylation of conserved serines gates ER zinc release that activates tyrosine kinases, AKT, and ERK — converting ZIP7 from a passive transporter to a signal-gated channel.\",\n      \"evidence\": \"Proximity ligation, pharmacological CK2 inhibition, phospho-site mutagenesis, and zinc imaging; plus in vivo zebrafish morpholino knockdown with zinc rescue\",\n      \"pmids\": [\"22317921\", \"22912764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of phospho-gating unresolved\", \"Whether CK2 acts directly on ZIP7 in all cell types not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended ZIP7 function to secretory-pathway trafficking and tissue-specific signaling, linking ER zinc homeostasis to Notch receptor processing and to insulin/glucose signaling in muscle.\",\n      \"evidence\": \"Drosophila Catsup forward-genetic loss-of-function with Notch localization; siRNA knockdown with glycogen synthesis and phospho-AKT readouts in muscle cells\",\n      \"pmids\": [\"23785054\", \"24265765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking ER zinc to receptor trafficking not defined\", \"Glucose-gene regulation pathway not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the full phospho-site requirement and the pathway output, and revealed the ER zinc-PDI axis whereby ZIP7 loss causes ER zinc accumulation, PDI inhibition, and ER stress.\",\n      \"evidence\": \"Phospho-site mutagenesis with phospho-protein arrays; mesenchymal and intestinal conditional KO mice with PDI aggregation assays and ER stress markers; CK2α-dependent FRET zinc redistribution in cardiomyocytes\",\n      \"pmids\": [\"28205653\", \"28545780\", \"27736879\", \"28232492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each phospho-site unclear\", \"How ER zinc excess inhibits PDI mechanistically beyond aggregation not fully detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed by genetic ablation that impaired ER-to-cytosol zinc transport is the causal driver of ER stress and proliferation defects, and broadened roles to myogenesis, death-receptor trafficking, and mitochondrial zinc.\",\n      \"evidence\": \"Gene ablation with zinc-rescue epistasis; siRNA in myoblasts; haploid gene-trap and CRISPR screens with surface receptor flow cytometry; cardiomyocyte fractionation showing mitochondrial localization\",\n      \"pmids\": [\"29980658\", \"30206294\", \"30237509\", \"29307859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TNFR1/FAS trafficking dependence on ER zinc not resolved\", \"Mitochondrial localization function not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked ZIP7 to human disease and provided a directly-binding chemical probe, establishing ZIP7 as a druggable target whose loss impairs BCR signaling via cytosolic zinc.\",\n      \"evidence\": \"Human autosomal-recessive genetics with CRISPR mouse modeling and phosphatase/phospho-BCR assays; phenotypic screen with V430E resistance mutation and photoaffinity labeling by NVS-ZP7-4; ZIP7/ZIP13 compartment-specific comparison\",\n      \"pmids\": [\"30718914\", \"30643281\", \"31412620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of ZIP7 with bound inhibitor not determined\", \"Phosphatase substrates of zinc in B cells not enumerated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned ZIP7 upstream of HERPUD1 in a zinc/ER-stress axis controlling ferroptosis, identifying a defined genetic epistasis for ZIP7-dependent cell death sensitivity.\",\n      \"evidence\": \"Genome-wide RNAi screen, siRNA knockdown, zinc-rescue, and HERPUD1 knockdown epistasis in breast and renal cancer cells\",\n      \"pmids\": [\"33608508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HERPUD1 induction executes ferroptosis downstream not detailed\", \"Connection between ER zinc and lipid peroxidation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified mitochondrial protein complexes for ZIP7, implicating it in mitochondrial zinc and iron trafficking, dynamics, and mitophagy.\",\n      \"evidence\": \"Co-IP of NLRX1-SLC39A7 with mitophagy assays in nucleus pulposus cells; later ACSL4-ZIP7-VDAC3 Co-IP at ER-mitochondria contacts with organellar iron measurement\",\n      \"pmids\": [\"37876250\", \"39579909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP complexes lack reciprocal/structural validation\", \"Whether ZIP7 transports iron or only zinc at these sites not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a proteostasis output (ERAD via Rpn11 zinc supply) and additional mitophagy and metastasis roles, showing cytosolic zinc from ZIP7 is rate-limiting for deubiquitination.\",\n      \"evidence\": \"Drosophila genetics and proteasome deubiquitination assays with human cell zinc manipulation and in vivo rhodopsin rescue; cardiac-specific KO mouse with PINK1/Parkin and mitophagy flux assays; Co-IP/fractionation/RNA-seq for MAZ-MYBL2 in prostate metastasis\",\n      \"pmids\": [\"38670102\", \"39511569\", \"42010154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that ZIP7 delivers Zn2+ to Rpn11 in human cells inferred from rate-limiting epistasis\", \"Contradictory mitophagy effects across tissues not reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a post-translational regulatory layer: METTL9-mediated histidine methylation of ZIP7 couples it to PERK/ATF4/SLC7A11 ferroptosis-resistance signaling.\",\n      \"evidence\": \"METTL9 methyltransferase assay, His45/His49 mapping, ferroptosis and PERK/ATF4/SLC7A11 readouts in vitro and OVX mouse model\",\n      \"pmids\": [\"40414869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect of His methylation on ZIP7 transport activity not measured\", \"Single-lab finding without independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single ER/Golgi zinc transporter selectively partitions its cytosolic zinc output between phosphatase-inhibition signaling, ER proteostasis/ERAD, ferroptosis control, and mitochondrial dynamics across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of human ZIP7 or its transport mechanism\", \"Direct zinc substrates/targets of cytosolic phosphatases not enumerated\", \"Tissue-specific opposing mitophagy roles not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 11, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 3, 10, 12, 18]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 5, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [13, 20, 22, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 9, 16]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 10, 12, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20, 22]}\n    ],\n    \"complexes\": [\"NLRX1-SLC39A7 complex\", \"ACSL4-ZIP7-VDAC3 complex\"],\n    \"partners\": [\"CSNK2A1\", \"NLRX1\", \"VDAC3\", \"ACSL4\", \"MAZ\", \"METTL9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}