{"gene":"MAGT1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2009,"finding":"MagT1 and TUSC3 function as mammalian plasma membrane Mg2+ transporters: knockdown of either protein significantly lowers total and free intracellular Mg2+ concentrations in mammalian cell lines; MagT1 was identified via yeast complementation screen and its expression is upregulated in low extracellular Mg2+; morpholino knockdown in zebrafish causes early developmental arrest rescued by excess Mg2+ or mammalian mRNA supplementation.","method":"Yeast complementation screen, siRNA knockdown with intracellular Mg2+ measurement (mag-fura 2), zebrafish morpholino knockdown with rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast complementation, mammalian knockdown with ion measurement, in vivo zebrafish rescue), foundational study replicated by subsequent work","pmids":["19717468"],"is_preprint":false},{"year":2011,"finding":"MAGT1 mediates a TCR-stimulated Mg2+ flux required for T cell activation; loss of MAGT1 abolishes this flux and attenuates PLCγ1 activation, identifying Mg2+ as a second messenger in the TCR signaling pathway.","method":"Intracellular Mg2+ flux measurement in T cells from XMEN patients (MAGT1-deficient), PLCγ1 phosphorylation assay, loss-of-function human patient cells","journal":"Magnesium research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient loss-of-function cells with defined signaling readouts, single lab but two orthogonal measurements","pmids":["21983175"],"is_preprint":false},{"year":2011,"finding":"MagT1 overexpression in TRPM7-knockout DT40 B cells augments Mg2+ uptake capacity and rescues growth impairment, demonstrating that MagT1 can partially substitute for TRPM7 as a Mg2+ uptake mechanism; MagT1 expression is upregulated in TRPM7-/- cells.","method":"Gene expression analysis, overexpression in TRPM7-/- cells with Mg2+ uptake measurement and cell growth assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue in defined knockout background with multiple readouts (Mg2+ uptake and growth), single lab","pmids":["21627970"],"is_preprint":false},{"year":2013,"finding":"Drosophila MagT1 (ortholog of mammalian MAGT1) is a magnesium-selective, non-voltage-dependent channel; its whole-cell currents are upregulated by PKC activation via PMA treatment; PKC-dependent modulation requires Ser100 and Ser108 phosphorylation sites (S100A and S108A mutants abolish PKC-dependent upregulation, while S35A does not).","method":"Patch-clamp electrophysiology in SH-SY5Y cells expressing wild-type or mutant dMagT1, PKC activator (PMA) treatment with inactive control (4α-PMA), site-directed mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with mutagenesis in a Drosophila ortholog, single lab","pmids":["23727583"],"is_preprint":false},{"year":2018,"finding":"Loss of MAGT1 in mouse B cells impairs Mg2+ homeostasis and increases Ca2+ influx after BCR stimulation, leading to increased phosphorylation of BCR-related proteins with differential effects on PKC activation; Magt1-knockout mice show increased CD19+ and marginal zone B cell frequencies and decreased plasma cell frequencies in spleen.","method":"Magt1-knockout mouse model, intracellular ion measurement, BCR stimulation assays, flow cytometry, Western blot for phosphoproteins","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with multiple orthogonal readouts (ion flux, phosphoprotein signaling, in vivo cell frequencies), rigorous controls","pmids":["29581357"],"is_preprint":false},{"year":2018,"finding":"MagT1 is essential for early Drosophila embryonic development; clonal analysis and RNAi knockdown in wing discs show that loss of MagT1 enhances/ectopically activates Wingless (Wnt) signaling and disrupts Decapentaplegic (BMP/TGF-β) signaling; magnesium transport is proportional to MagT1 expression levels in Drosophila S2 cells.","method":"Drosophila MagT1 mutant generation, clonal analysis, RNAi knockdown, signaling pathway readouts in wing primordia, Mg2+ transport assay in S2 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function with defined pathway epistasis in Drosophila ortholog, multiple readouts, single lab","pmids":["29959918"],"is_preprint":false},{"year":2019,"finding":"MAGT1 is the human functional homolog of yeast OST3/OST6 and acts as a subunit of the STT3B oligosaccharyltransferase (OST) complex; MAGT1 deficiency causes selective N-linked glycosylation defects in immune and non-immune glycoproteins including NKG2D and CD28; MAGT1-dependent glycosylation is sensitive to Mg2+ levels; MAGT1 function is partly interchangeable with paralog TUSC3 but they have different tissue distributions.","method":"MS-based glycoproteomics, CRISPR/Cas9 knockout cell lines, NK cell killing assays, RNA-seq, comparison with TUSC3","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (glycoproteomics, CRISPR KO, functional assays) in a single rigorous study, consistent with independent replication in PMID 31036665","pmids":["31337704"],"is_preprint":false},{"year":2019,"finding":"MAGT1 acts as a subunit of the STT3B OST complex mediating N-linked glycosylation; patient cells with MAGT1 mutations show defective post-translational glycosylation of GLUT1 and SHBG (STT3B complex substrates); MAGT1 deficiency is associated with compensatory upregulation of TUSC3.","method":"Serum transferrin glycosylation analysis in patients, glycosylation substrate analysis (GLUT1, SHBG), patient fibroblast functional studies, protein expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patient loss-of-function with multiple glycosylation substrates examined, independently consistent with PMID 31337704","pmids":["31036665"],"is_preprint":false},{"year":2022,"finding":"Reduced steady-state NKG2D (KLRK1) levels in MAGT1-deficient patients are caused by hypoglycosylation of NKG2D protein at a specific site; magnesium supplementation does not rescue NKG2D expression or the hypoglycosylation defect in CRISPR-engineered human cell lines or in an XMEN patient.","method":"CRISPR-engineered human cell lines, site-specific glycosylation mapping, flow cytometry for NKG2D surface expression, Mg2+ supplementation experiments in cells and patient","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR-engineered cells with site-specific glycosylation mapping plus patient validation; negative result for Mg2+ rescue rigorously established","pmids":["35182234"],"is_preprint":false},{"year":2019,"finding":"MagT1 knockdown in bone marrow mesenchymal stem cells (BMMSCs) reduces intracellular Mg2+, suppresses odontogenic differentiation markers (ALP, DMP-1, DSP), inhibits mineralization, and inactivates the ERK/MAPK signaling pathway; ERK/MAPK pathway activation is required downstream of MagT1-mediated Mg2+ transport for odontogenic differentiation.","method":"shRNA lentiviral knockdown, intracellular Mg2+ measurement, Western blot for ERK phosphorylation and differentiation markers, flow cytometry, RNA-seq","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined knockdown with multiple markers and pathway analysis, single lab","pmids":["30704530"],"is_preprint":false},{"year":2021,"finding":"MAGT1 knockdown in HeLa cells causes S-phase arrest and apoptosis, reduces ERK1/2 and p38 phosphorylation, increases p21 expression, and alters expression of cell cycle regulators (cyclin-A1, cyclin-B1, MYC, cyclin-D1, cyclin-E1, CDK2); MAGT1 is required for HPV E6/E7-dependent cell cycle progression.","method":"siRNA knockdown, cell cycle analysis by flow cytometry, Western blot for MAPK phosphorylation and cell cycle proteins, RNA-seq","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined knockdown with multiple orthogonal readouts (cell cycle, apoptosis, signaling), single lab","pmids":["34499581"],"is_preprint":false},{"year":2023,"finding":"MAGT1 deficiency in platelets causes defective N-glycosylation of glycoprotein Ibα, glycoprotein VI, and integrin αIIb, leading to impaired platelet aggregation, integrin αIIbβ3 activation, calcium mobilization, PKC activity, and absent PAR1-AP responses; these defects were corrected after hematopoietic stem cell transplantation.","method":"Platelet function testing (aggregation, calcium flux, integrin activation), N-glycan analysis by mass spectrometry, Western blot for glycoprotein molecular weights, pre/post-HSCT comparison","journal":"Journal of thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient loss-of-function with mechanistic pre/post-HSCT rescue and multiple glycoprotein substrates, single lab","pmids":["37207862"],"is_preprint":false},{"year":2023,"finding":"MAGT1-deficient mice show accelerated arterial thrombosis, shortened bleeding time, and increased GPVI-dependent platelet aggregation due to increased Ca2+ influx and hyperphosphorylation of Syk, LAT, and PLCγ2; the inhibitory PKC loop is impaired; MgCl2 supplementation or TRPC6 channel blockade normalizes aggregation; haploinsufficiency of TRPC6 in Magt1-/- mice normalizes GPVI signaling and thrombus formation in vivo, establishing functional linkage between MAGT1 and TRPC6.","method":"Magt1-knockout mouse model, in vivo arterial thrombosis models, transient MCAO stroke model, platelet signaling (phospho-Western blot), Ca2+ flux measurement, pharmacological inhibition, TRPC6/Magt1 double-mutant mice, human XMEN patient platelet validation","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with genetic epistasis (double mutant), pharmacological rescue, in vivo models, and human patient validation using multiple orthogonal methods","pmids":["37381987"],"is_preprint":false},{"year":2008,"finding":"MagT1 protein is expressed in rumen epithelial cells and functions as a Mg2+ influx transporter; its protein abundance is regulated by extracellular Mg2+ concentration (decreased by low Mg2+, increased by high Mg2+); functional Mg2+ transport capacity is correspondingly altered.","method":"RT-PCR, Western blot, flow cytometry, immunocytochemistry, intracellular Mg2+ measurement with mag-fura 2","journal":"Magnesium research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods confirming expression and functional transport activity with dose-response, single lab","pmids":["18705540"],"is_preprint":false},{"year":2024,"finding":"MagT1 mediates Mg2+ uptake required for N-linked glycosylation of SPARC (secreted protein acidic and rich in cysteine); SPARC glycosylation affects its extracellular secretion and mineral deposition; established using RNAi knockdown and glycosylation inhibitors in the context of magnesium-impregnated membrane-driven osteogenesis.","method":"RNAi knockdown, glycosylation inhibitors, immunostaining, DDC-SEM for mineral deposition, in vivo rat skull defect model","journal":"Advanced healthcare materials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined knockdown with specific substrate (SPARC) glycosylation readout and functional consequence, single lab","pmids":["39632347"],"is_preprint":false},{"year":2017,"finding":"miR-199a-5p directly targets MAGT1 mRNA and suppresses its expression post-transcriptionally, validated by luciferase reporter assay; this mechanism contributes to reduced MAGT1 protein (without mRNA change) and functional depletion of CD8+ T cells in chronic HBV infection.","method":"Luciferase reporter assay, lentiviral overexpression/knockdown of miR-199a-5p, qRT-PCR for mRNA, Western blot for protein, immune function assays","journal":"Scientific reports / Magnesium research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validation of direct miRNA-target interaction confirmed by two independent papers (PMID 31038761, PMID 33210605), functional consequence demonstrated","pmids":["29051561","31038761","33210605"],"is_preprint":false}],"current_model":"MAGT1 is a plasma membrane Mg2+-selective transporter and an obligate subunit of the STT3B oligosaccharyltransferase (OST-B) complex that mediates N-linked glycosylation of specific substrates (including NKG2D, CD28, SPARC, platelet glycoproteins); it provides a TCR-stimulated Mg2+ flux required for proximal PLCγ1 activation in T cells, modulates Ca2+/Mg2+ homeostasis and PKC-dependent signaling in B cells and platelets, and is functionally linked to TRPC6 in platelet cation balance; its expression is upregulated transcriptionally in low extracellular Mg2+ and post-transcriptionally regulated by miR-199a-5p, and PKC phosphorylation at conserved serine residues can upregulate its channel activity."},"narrative":{"mechanistic_narrative":"MAGT1 is a dual-function membrane protein that operates both as a magnesium transporter and as an accessory subunit of the protein N-glycosylation machinery, linking cellular Mg2+ status to immune and developmental signaling [PMID:19717468, PMID:31337704]. It was first defined as a mammalian plasma-membrane Mg2+ transporter whose loss lowers total and free intracellular Mg2+ and whose expression is induced by low extracellular Mg2+, with an essential developmental role demonstrated by zebrafish knockdown [PMID:19717468]. In parallel, MAGT1 is the human functional homolog of yeast OST3/OST6 and an obligate subunit of the STT3B oligosaccharyltransferase complex, mediating selective N-linked glycosylation of specific substrates including NKG2D, CD28, GLUT1, SHBG, SPARC, and platelet glycoproteins; its paralog TUSC3 is partly interchangeable and compensatorily upregulated upon MAGT1 loss [PMID:31337704, PMID:31036665, PMID:37207862, PMID:39632347]. The glycosylation role can be uncoupled from Mg2+ supply: hypoglycosylation of NKG2D in MAGT1-deficient cells is not rescued by magnesium [PMID:35182234]. Functionally, MAGT1 provides a TCR-stimulated Mg2+ flux required for PLCγ1 activation in T cells [PMID:21983175], shapes Ca2+/Mg2+ balance and PKC-dependent signaling in B cells and platelets [PMID:29581357, PMID:37381987], and is functionally linked to the TRPC6 channel in platelet cation balance and thrombosis, where TRPC6 haploinsufficiency normalizes GPVI signaling in Magt1-null mice [PMID:37381987]. Loss of MAGT1 perturbs ERK/MAPK-dependent differentiation and cell-cycle progression in several cell types [PMID:30704530, PMID:34499581]. Expression is regulated post-transcriptionally by miR-199a-5p [PMID:29051561, PMID:31038761, PMID:33210605] and channel activity is upregulated by PKC phosphorylation at conserved serine residues [PMID:23727583].","teleology":[{"year":2008,"claim":"Established that MagT1 is a regulatable Mg2+ influx transporter at the protein level, answering whether it functions in cellular magnesium handling and responds to ambient Mg2+.","evidence":"RT-PCR, Western blot, immunocytochemistry and mag-fura 2 ion measurement in rumen epithelial cells","pmids":["18705540"],"confidence":"Medium","gaps":["Channel/transporter mechanism not resolved structurally","Single tissue context"]},{"year":2009,"claim":"Defined MagT1 (and TUSC3) as bona fide mammalian plasma-membrane Mg2+ transporters with an essential in vivo developmental requirement, anchoring its transport function across species.","evidence":"Yeast complementation screen, siRNA knockdown with intracellular Mg2+ measurement, zebrafish morpholino knockdown with Mg2+/mRNA rescue","pmids":["19717468"],"confidence":"High","gaps":["Did not distinguish direct channel activity from indirect effects","Substrate selectivity and gating mechanism unaddressed"]},{"year":2011,"claim":"Connected MAGT1-mediated Mg2+ flux to a defined signaling output by showing TCR-stimulated Mg2+ entry is required for PLCγ1 activation, establishing Mg2+ as a second messenger in T cells.","evidence":"Mg2+ flux and PLCγ1 phosphorylation assays in MAGT1-deficient XMEN patient T cells","pmids":["21983175"],"confidence":"Medium","gaps":["Mechanistic link between Mg2+ and PLCγ1 not defined","Single lab"]},{"year":2011,"claim":"Showed MagT1 can substitute for a distinct Mg2+ uptake channel (TRPM7), supporting a genuine transport function with overlapping physiological roles.","evidence":"Overexpression in TRPM7-knockout DT40 B cells with Mg2+ uptake and growth rescue","pmids":["21627970"],"confidence":"Medium","gaps":["Functional substitution does not prove identical transport mechanism","Heterologous overexpression system"]},{"year":2013,"claim":"Provided direct electrophysiological evidence that MagT1 is a Mg2+-selective non-voltage-dependent channel and identified PKC phosphosites controlling its activity.","evidence":"Patch-clamp of Drosophila MagT1 in SH-SY5Y cells with PMA activation and Ser-to-Ala mutagenesis (S100A, S108A)","pmids":["23727583"],"confidence":"Medium","gaps":["Demonstrated in Drosophila ortholog, not mammalian protein","PKC isoform and in vivo relevance unresolved"]},{"year":2017,"claim":"Identified a post-transcriptional control mechanism, showing miR-199a-5p directly suppresses MAGT1 protein and links its depletion to T-cell dysfunction in disease.","evidence":"Luciferase reporter assay, miRNA overexpression/knockdown, qRT-PCR and Western blot in CD8+ T cells","pmids":["29051561","31038761","33210605"],"confidence":"Medium","gaps":["Whether miRNA regulation operates in healthy tissue physiology unclear","Downstream consequences mostly correlative"]},{"year":2018,"claim":"Used a clean knockout mouse to show MAGT1 shapes B-cell Ca2+/Mg2+ homeostasis and PKC-dependent BCR signaling and alters B-cell subset composition in vivo.","evidence":"Magt1-knockout mouse, ion measurement, BCR stimulation, phosphoprotein Western blots, flow cytometry","pmids":["29581357"],"confidence":"High","gaps":["Whether B-cell phenotype reflects transport or glycosylation function not separated","Causal chain from ion flux to subset frequencies incomplete"]},{"year":2018,"claim":"Demonstrated an essential developmental role with specific pathway epistasis, linking MagT1 to Wingless/Wnt and Decapentaplegic/BMP signaling during morphogenesis.","evidence":"Drosophila clonal analysis, RNAi in wing discs, signaling readouts, S2 cell Mg2+ transport assay","pmids":["29959918"],"confidence":"Medium","gaps":["Molecular mechanism linking Mg2+/MagT1 to Wnt and BMP unresolved","Drosophila ortholog only"]},{"year":2019,"claim":"Resolved the second core function: MAGT1 is the OST3/OST6 homolog and an STT3B oligosaccharyltransferase subunit driving selective N-glycosylation, reframing XMEN as a glycosylation disorder.","evidence":"Glycoproteomics, CRISPR knockouts, NK killing assays, RNA-seq, patient transferrin/GLUT1/SHBG glycosylation analyses, TUSC3 comparison","pmids":["31337704","31036665"],"confidence":"High","gaps":["How the transporter and glycosylation activities are coordinated mechanistically","Determinants of substrate selectivity within STT3B unclear"]},{"year":2019,"claim":"Linked MagT1-dependent Mg2+ transport to ERK/MAPK-driven osteogenic/odontogenic differentiation, extending its role to stem cell fate.","evidence":"shRNA knockdown in BMMSCs, Mg2+ measurement, ERK phospho-Western, differentiation markers, RNA-seq","pmids":["30704530"],"confidence":"Medium","gaps":["Whether effect is transport- or glycosylation-mediated not distinguished","Single lab"]},{"year":2021,"claim":"Implicated MAGT1 in cell-cycle progression and survival, showing its loss arrests S phase, induces apoptosis and dampens MAPK signaling in HPV-driven cells.","evidence":"siRNA knockdown in HeLa, cell cycle and apoptosis flow cytometry, Western blots for MAPK and cyclins, RNA-seq","pmids":["34499581"],"confidence":"Medium","gaps":["Direct molecular driver of cell-cycle arrest not identified","Transport vs glycosylation contribution unresolved"]},{"year":2022,"claim":"Uncoupled the two functions by showing the NKG2D hypoglycosylation defect is site-specific and is NOT rescued by magnesium, establishing the glycosylation defect as Mg2+-independent.","evidence":"CRISPR-engineered human cells, site-specific glycosylation mapping, NKG2D flow cytometry, Mg2+ supplementation in cells and patient","pmids":["35182234"],"confidence":"High","gaps":["Why some substrate glycosylation responds to Mg2+ while NKG2D does not","Therapeutic implications beyond NKG2D"]},{"year":2023,"claim":"Extended the glycosylation function to platelet biology, showing MAGT1 deficiency hypoglycosylates GPIbα, GPVI and integrin αIIb with functional aggregation defects correctable by transplantation.","evidence":"Platelet aggregation, calcium flux, integrin activation, N-glycan mass spectrometry, pre/post-HSCT comparison in patients","pmids":["37207862"],"confidence":"Medium","gaps":["Single patient/lab context","Relative contribution of each hypoglycosylated glycoprotein unclear"]},{"year":2023,"claim":"Established a genetic and functional link between MAGT1 and the TRPC6 channel in platelet cation balance, showing MAGT1 loss causes Ca2+-overload-driven hyperactive GPVI signaling and prothrombotic phenotypes correctable by TRPC6 reduction.","evidence":"Magt1-knockout mice, in vivo thrombosis and stroke models, platelet phospho-Western, Ca2+ flux, TRPC6/Magt1 double mutants, pharmacology, XMEN patient platelets","pmids":["37381987"],"confidence":"High","gaps":["Physical versus functional nature of MAGT1-TRPC6 interaction not defined","How Mg2+ deficit drives Ca2+ overload mechanistically unresolved"]},{"year":2024,"claim":"Connected MagT1-driven Mg2+ uptake to SPARC N-glycosylation, secretion and mineral deposition, integrating its transport and glycosylation roles in osteogenesis.","evidence":"RNAi knockdown, glycosylation inhibitors, immunostaining, DDC-SEM and rat skull defect model","pmids":["39632347"],"confidence":"Medium","gaps":["Whether SPARC glycosylation depends on Mg2+ flux or STT3B activity not separated","Single lab"]},{"year":null,"claim":"It remains unresolved how MAGT1's Mg2+ transport activity and its STT3B oligosaccharyltransferase subunit role are mechanistically coordinated, and what structural features govern its substrate selectivity and Mg2+ dependence.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating transport and glycosylation functions","Substrate selectivity rules of MAGT1-STT3B undefined","Mechanism by which Mg2+ levels influence only a subset of glycosylation substrates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,3,13]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,7,8,11]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,7,8,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,4,6]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,5]}],"complexes":["STT3B oligosaccharyltransferase (OST-B) complex"],"partners":["TUSC3","TRPC6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H0U3","full_name":"Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit MAGT1","aliases":["Implantation-associated protein","IAP","Magnesium transporter protein 1","MagT1"],"length_aa":335,"mass_kda":38.0,"function":"Accessory component of the STT3B-containing form of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains (PubMed:31831667). Involved in N-glycosylation of STT3B-dependent substrates (PubMed:31831667). Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with TUSC3. In its oxidized form proposed to form transient mixed disulfides with a glycoprotein substrate to facilitate access of STT3B to the unmodified acceptor site. Also has oxidoreductase-independent functions in the STT3B-containing OST complex possibly involving substrate recognition. Could indirectly play a role in Mg(2+) transport in epithelial cells (Probable)","subcellular_location":"Cell membrane; Endoplasmic reticulum; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9H0U3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAGT1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DAD1","stoichiometry":10.0},{"gene":"STT3B","stoichiometry":10.0},{"gene":"DDOST","stoichiometry":4.0},{"gene":"RPN1","stoichiometry":4.0},{"gene":"RPN2","stoichiometry":4.0},{"gene":"CCDC47","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"FKBP8","stoichiometry":0.2},{"gene":"NSDHL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAGT1","total_profiled":1310},"omim":[{"mim_id":"611817","title":"KILLER CELL LECTIN-LIKE RECEPTOR, SUBFAMILY K, MEMBER 1; KLRK1","url":"https://www.omim.org/entry/611817"},{"mim_id":"601385","title":"TUMOR SUPPRESSOR CANDIDATE 3; TUSC3","url":"https://www.omim.org/entry/601385"},{"mim_id":"301031","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Icc; CDG1CC","url":"https://www.omim.org/entry/301031"},{"mim_id":"300853","title":"IMMUNODEFICIENCY, X-LINKED, WITH MAGNESIUM DEFECT, EPSTEIN-BARR VIRUS INFECTION, AND NEOPLASIA; XMEN","url":"https://www.omim.org/entry/300853"},{"mim_id":"300716","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 95; XLID95","url":"https://www.omim.org/entry/300716"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAGT1"},"hgnc":{"alias_symbol":["DKFZp564K142","IAP","OST3B","MRX95","SLC58A1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H0U3","domains":[{"cath_id":"3.40.30.10","chopping":"29-175","consensus_level":"high","plddt":90.5754,"start":29,"end":175},{"cath_id":"-","chopping":"211-325","consensus_level":"high","plddt":87.0367,"start":211,"end":325}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0U3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0U3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0U3-F1-predicted_aligned_error_v6.png","plddt_mean":85.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAGT1","jax_strain_url":"https://www.jax.org/strain/search?query=MAGT1"},"sequence":{"accession":"Q9H0U3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0U3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0U3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0U3"}},"corpus_meta":[{"pmid":"19717468","id":"PMC_19717468","title":"Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19717468","citation_count":166,"is_preprint":false},{"pmid":"31337704","id":"PMC_31337704","title":"Magnesium transporter 1 (MAGT1) deficiency causes selective defects in N-linked glycosylation and expression of immune-response genes.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31337704","citation_count":83,"is_preprint":false},{"pmid":"31036665","id":"PMC_31036665","title":"Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31036665","citation_count":80,"is_preprint":false},{"pmid":"21983175","id":"PMC_21983175","title":"Loss of MAGT1 abrogates the Mg2+ flux required for T cell signaling and leads to a novel human primary immunodeficiency.","date":"2011","source":"Magnesium research","url":"https://pubmed.ncbi.nlm.nih.gov/21983175","citation_count":54,"is_preprint":false},{"pmid":"25504528","id":"PMC_25504528","title":"Identification of a novel mutation in MAGT1 and progressive multifocal leucoencephalopathy in a 58-year-old man with XMEN disease.","date":"2014","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25504528","citation_count":52,"is_preprint":false},{"pmid":"21627970","id":"PMC_21627970","title":"The Mg2+ transporter MagT1 partially rescues cell growth and Mg2+ uptake in cells lacking the channel-kinase TRPM7.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21627970","citation_count":50,"is_preprint":false},{"pmid":"34086870","id":"PMC_34086870","title":"CRISPR-targeted MAGT1 insertion restores XMEN patient hematopoietic stem cells and lymphocytes.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/34086870","citation_count":30,"is_preprint":false},{"pmid":"18705540","id":"PMC_18705540","title":"Expression and functional activity of the Na/Mg exchanger, TRPM7 and MagT1 are changed to regulate Mg homeostasis and transport in rumen epithelial cells.","date":"2008","source":"Magnesium research","url":"https://pubmed.ncbi.nlm.nih.gov/18705540","citation_count":26,"is_preprint":false},{"pmid":"32669871","id":"PMC_32669871","title":"Sevoflurane Regulates Glioma Progression by Circ_0002755/miR-628-5p/MAGT1 Axis.","date":"2020","source":"Cancer management and 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38896122","citation_count":5,"is_preprint":false},{"pmid":"37706151","id":"PMC_37706151","title":"CD5 B-Cell Predominant Primary Immunodeficiency: Part of the Spectrum of MAGT1 Deficiency.","date":"2023","source":"Therapeutic advances in allergy and rhinology","url":"https://pubmed.ncbi.nlm.nih.gov/37706151","citation_count":5,"is_preprint":false},{"pmid":"35430713","id":"PMC_35430713","title":"Long non-coding RNA FLVCR1-AS1 functions as a ceRNA to aggravate cervical cancer cell growth by the miR-381-3p/MAGT1 axis.","date":"2022","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/35430713","citation_count":5,"is_preprint":false},{"pmid":"34868726","id":"PMC_34868726","title":"Successful Anti-SARS-CoV-2 Spike Protein Antibody Response to Vaccination in MAGT1 Deficiency.","date":"2021","source":"Allergy & rhinology (Providence, 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41777878","citation_count":0,"is_preprint":false},{"pmid":"39836832","id":"PMC_39836832","title":"Loss-of-function variant in MAGT1 leading to XMEN disease in a Colombian patient with a common variable immunodeficiency.","date":"2024","source":"Biomedica : revista del Instituto Nacional de Salud","url":"https://pubmed.ncbi.nlm.nih.gov/39836832","citation_count":0,"is_preprint":false},{"pmid":"41899319","id":"PMC_41899319","title":"Modifier-Sensitive Phenotypic Divergence in XMEN Disease (MAGT1 Deficiency): Neurodegenerative and Immuno-Hematologic Trajectories.","date":"2026","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41899319","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25098,"output_tokens":4371,"usd":0.07043,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12330,"output_tokens":5126,"usd":0.0949,"stage2_stop_reason":"end_turn"},"total_usd":0.16533,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"MagT1 and TUSC3 function as mammalian plasma membrane Mg2+ transporters: knockdown of either protein significantly lowers total and free intracellular Mg2+ concentrations in mammalian cell lines; MagT1 was identified via yeast complementation screen and its expression is upregulated in low extracellular Mg2+; morpholino knockdown in zebrafish causes early developmental arrest rescued by excess Mg2+ or mammalian mRNA supplementation.\",\n      \"method\": \"Yeast complementation screen, siRNA knockdown with intracellular Mg2+ measurement (mag-fura 2), zebrafish morpholino knockdown with rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast complementation, mammalian knockdown with ion measurement, in vivo zebrafish rescue), foundational study replicated by subsequent work\",\n      \"pmids\": [\"19717468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MAGT1 mediates a TCR-stimulated Mg2+ flux required for T cell activation; loss of MAGT1 abolishes this flux and attenuates PLCγ1 activation, identifying Mg2+ as a second messenger in the TCR signaling pathway.\",\n      \"method\": \"Intracellular Mg2+ flux measurement in T cells from XMEN patients (MAGT1-deficient), PLCγ1 phosphorylation assay, loss-of-function human patient cells\",\n      \"journal\": \"Magnesium research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient loss-of-function cells with defined signaling readouts, single lab but two orthogonal measurements\",\n      \"pmids\": [\"21983175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MagT1 overexpression in TRPM7-knockout DT40 B cells augments Mg2+ uptake capacity and rescues growth impairment, demonstrating that MagT1 can partially substitute for TRPM7 as a Mg2+ uptake mechanism; MagT1 expression is upregulated in TRPM7-/- cells.\",\n      \"method\": \"Gene expression analysis, overexpression in TRPM7-/- cells with Mg2+ uptake measurement and cell growth assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue in defined knockout background with multiple readouts (Mg2+ uptake and growth), single lab\",\n      \"pmids\": [\"21627970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila MagT1 (ortholog of mammalian MAGT1) is a magnesium-selective, non-voltage-dependent channel; its whole-cell currents are upregulated by PKC activation via PMA treatment; PKC-dependent modulation requires Ser100 and Ser108 phosphorylation sites (S100A and S108A mutants abolish PKC-dependent upregulation, while S35A does not).\",\n      \"method\": \"Patch-clamp electrophysiology in SH-SY5Y cells expressing wild-type or mutant dMagT1, PKC activator (PMA) treatment with inactive control (4α-PMA), site-directed mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with mutagenesis in a Drosophila ortholog, single lab\",\n      \"pmids\": [\"23727583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of MAGT1 in mouse B cells impairs Mg2+ homeostasis and increases Ca2+ influx after BCR stimulation, leading to increased phosphorylation of BCR-related proteins with differential effects on PKC activation; Magt1-knockout mice show increased CD19+ and marginal zone B cell frequencies and decreased plasma cell frequencies in spleen.\",\n      \"method\": \"Magt1-knockout mouse model, intracellular ion measurement, BCR stimulation assays, flow cytometry, Western blot for phosphoproteins\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with multiple orthogonal readouts (ion flux, phosphoprotein signaling, in vivo cell frequencies), rigorous controls\",\n      \"pmids\": [\"29581357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MagT1 is essential for early Drosophila embryonic development; clonal analysis and RNAi knockdown in wing discs show that loss of MagT1 enhances/ectopically activates Wingless (Wnt) signaling and disrupts Decapentaplegic (BMP/TGF-β) signaling; magnesium transport is proportional to MagT1 expression levels in Drosophila S2 cells.\",\n      \"method\": \"Drosophila MagT1 mutant generation, clonal analysis, RNAi knockdown, signaling pathway readouts in wing primordia, Mg2+ transport assay in S2 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function with defined pathway epistasis in Drosophila ortholog, multiple readouts, single lab\",\n      \"pmids\": [\"29959918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGT1 is the human functional homolog of yeast OST3/OST6 and acts as a subunit of the STT3B oligosaccharyltransferase (OST) complex; MAGT1 deficiency causes selective N-linked glycosylation defects in immune and non-immune glycoproteins including NKG2D and CD28; MAGT1-dependent glycosylation is sensitive to Mg2+ levels; MAGT1 function is partly interchangeable with paralog TUSC3 but they have different tissue distributions.\",\n      \"method\": \"MS-based glycoproteomics, CRISPR/Cas9 knockout cell lines, NK cell killing assays, RNA-seq, comparison with TUSC3\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (glycoproteomics, CRISPR KO, functional assays) in a single rigorous study, consistent with independent replication in PMID 31036665\",\n      \"pmids\": [\"31337704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAGT1 acts as a subunit of the STT3B OST complex mediating N-linked glycosylation; patient cells with MAGT1 mutations show defective post-translational glycosylation of GLUT1 and SHBG (STT3B complex substrates); MAGT1 deficiency is associated with compensatory upregulation of TUSC3.\",\n      \"method\": \"Serum transferrin glycosylation analysis in patients, glycosylation substrate analysis (GLUT1, SHBG), patient fibroblast functional studies, protein expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patient loss-of-function with multiple glycosylation substrates examined, independently consistent with PMID 31337704\",\n      \"pmids\": [\"31036665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Reduced steady-state NKG2D (KLRK1) levels in MAGT1-deficient patients are caused by hypoglycosylation of NKG2D protein at a specific site; magnesium supplementation does not rescue NKG2D expression or the hypoglycosylation defect in CRISPR-engineered human cell lines or in an XMEN patient.\",\n      \"method\": \"CRISPR-engineered human cell lines, site-specific glycosylation mapping, flow cytometry for NKG2D surface expression, Mg2+ supplementation experiments in cells and patient\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR-engineered cells with site-specific glycosylation mapping plus patient validation; negative result for Mg2+ rescue rigorously established\",\n      \"pmids\": [\"35182234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MagT1 knockdown in bone marrow mesenchymal stem cells (BMMSCs) reduces intracellular Mg2+, suppresses odontogenic differentiation markers (ALP, DMP-1, DSP), inhibits mineralization, and inactivates the ERK/MAPK signaling pathway; ERK/MAPK pathway activation is required downstream of MagT1-mediated Mg2+ transport for odontogenic differentiation.\",\n      \"method\": \"shRNA lentiviral knockdown, intracellular Mg2+ measurement, Western blot for ERK phosphorylation and differentiation markers, flow cytometry, RNA-seq\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined knockdown with multiple markers and pathway analysis, single lab\",\n      \"pmids\": [\"30704530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAGT1 knockdown in HeLa cells causes S-phase arrest and apoptosis, reduces ERK1/2 and p38 phosphorylation, increases p21 expression, and alters expression of cell cycle regulators (cyclin-A1, cyclin-B1, MYC, cyclin-D1, cyclin-E1, CDK2); MAGT1 is required for HPV E6/E7-dependent cell cycle progression.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis by flow cytometry, Western blot for MAPK phosphorylation and cell cycle proteins, RNA-seq\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined knockdown with multiple orthogonal readouts (cell cycle, apoptosis, signaling), single lab\",\n      \"pmids\": [\"34499581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAGT1 deficiency in platelets causes defective N-glycosylation of glycoprotein Ibα, glycoprotein VI, and integrin αIIb, leading to impaired platelet aggregation, integrin αIIbβ3 activation, calcium mobilization, PKC activity, and absent PAR1-AP responses; these defects were corrected after hematopoietic stem cell transplantation.\",\n      \"method\": \"Platelet function testing (aggregation, calcium flux, integrin activation), N-glycan analysis by mass spectrometry, Western blot for glycoprotein molecular weights, pre/post-HSCT comparison\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient loss-of-function with mechanistic pre/post-HSCT rescue and multiple glycoprotein substrates, single lab\",\n      \"pmids\": [\"37207862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAGT1-deficient mice show accelerated arterial thrombosis, shortened bleeding time, and increased GPVI-dependent platelet aggregation due to increased Ca2+ influx and hyperphosphorylation of Syk, LAT, and PLCγ2; the inhibitory PKC loop is impaired; MgCl2 supplementation or TRPC6 channel blockade normalizes aggregation; haploinsufficiency of TRPC6 in Magt1-/- mice normalizes GPVI signaling and thrombus formation in vivo, establishing functional linkage between MAGT1 and TRPC6.\",\n      \"method\": \"Magt1-knockout mouse model, in vivo arterial thrombosis models, transient MCAO stroke model, platelet signaling (phospho-Western blot), Ca2+ flux measurement, pharmacological inhibition, TRPC6/Magt1 double-mutant mice, human XMEN patient platelet validation\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with genetic epistasis (double mutant), pharmacological rescue, in vivo models, and human patient validation using multiple orthogonal methods\",\n      \"pmids\": [\"37381987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MagT1 protein is expressed in rumen epithelial cells and functions as a Mg2+ influx transporter; its protein abundance is regulated by extracellular Mg2+ concentration (decreased by low Mg2+, increased by high Mg2+); functional Mg2+ transport capacity is correspondingly altered.\",\n      \"method\": \"RT-PCR, Western blot, flow cytometry, immunocytochemistry, intracellular Mg2+ measurement with mag-fura 2\",\n      \"journal\": \"Magnesium research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods confirming expression and functional transport activity with dose-response, single lab\",\n      \"pmids\": [\"18705540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MagT1 mediates Mg2+ uptake required for N-linked glycosylation of SPARC (secreted protein acidic and rich in cysteine); SPARC glycosylation affects its extracellular secretion and mineral deposition; established using RNAi knockdown and glycosylation inhibitors in the context of magnesium-impregnated membrane-driven osteogenesis.\",\n      \"method\": \"RNAi knockdown, glycosylation inhibitors, immunostaining, DDC-SEM for mineral deposition, in vivo rat skull defect model\",\n      \"journal\": \"Advanced healthcare materials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined knockdown with specific substrate (SPARC) glycosylation readout and functional consequence, single lab\",\n      \"pmids\": [\"39632347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-199a-5p directly targets MAGT1 mRNA and suppresses its expression post-transcriptionally, validated by luciferase reporter assay; this mechanism contributes to reduced MAGT1 protein (without mRNA change) and functional depletion of CD8+ T cells in chronic HBV infection.\",\n      \"method\": \"Luciferase reporter assay, lentiviral overexpression/knockdown of miR-199a-5p, qRT-PCR for mRNA, Western blot for protein, immune function assays\",\n      \"journal\": \"Scientific reports / Magnesium research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validation of direct miRNA-target interaction confirmed by two independent papers (PMID 31038761, PMID 33210605), functional consequence demonstrated\",\n      \"pmids\": [\"29051561\", \"31038761\", \"33210605\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAGT1 is a plasma membrane Mg2+-selective transporter and an obligate subunit of the STT3B oligosaccharyltransferase (OST-B) complex that mediates N-linked glycosylation of specific substrates (including NKG2D, CD28, SPARC, platelet glycoproteins); it provides a TCR-stimulated Mg2+ flux required for proximal PLCγ1 activation in T cells, modulates Ca2+/Mg2+ homeostasis and PKC-dependent signaling in B cells and platelets, and is functionally linked to TRPC6 in platelet cation balance; its expression is upregulated transcriptionally in low extracellular Mg2+ and post-transcriptionally regulated by miR-199a-5p, and PKC phosphorylation at conserved serine residues can upregulate its channel activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAGT1 is a dual-function membrane protein that operates both as a magnesium transporter and as an accessory subunit of the protein N-glycosylation machinery, linking cellular Mg2+ status to immune and developmental signaling [#0, #6]. It was first defined as a mammalian plasma-membrane Mg2+ transporter whose loss lowers total and free intracellular Mg2+ and whose expression is induced by low extracellular Mg2+, with an essential developmental role demonstrated by zebrafish knockdown [#0]. In parallel, MAGT1 is the human functional homolog of yeast OST3/OST6 and an obligate subunit of the STT3B oligosaccharyltransferase complex, mediating selective N-linked glycosylation of specific substrates including NKG2D, CD28, GLUT1, SHBG, SPARC, and platelet glycoproteins; its paralog TUSC3 is partly interchangeable and compensatorily upregulated upon MAGT1 loss [#6, #7, #11, #14]. The glycosylation role can be uncoupled from Mg2+ supply: hypoglycosylation of NKG2D in MAGT1-deficient cells is not rescued by magnesium [#8]. Functionally, MAGT1 provides a TCR-stimulated Mg2+ flux required for PLCγ1 activation in T cells [#1], shapes Ca2+/Mg2+ balance and PKC-dependent signaling in B cells and platelets [#4, #12], and is functionally linked to the TRPC6 channel in platelet cation balance and thrombosis, where TRPC6 haploinsufficiency normalizes GPVI signaling in Magt1-null mice [#12]. Loss of MAGT1 perturbs ERK/MAPK-dependent differentiation and cell-cycle progression in several cell types [#9, #10]. Expression is regulated post-transcriptionally by miR-199a-5p [#15] and channel activity is upregulated by PKC phosphorylation at conserved serine residues [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that MagT1 is a regulatable Mg2+ influx transporter at the protein level, answering whether it functions in cellular magnesium handling and responds to ambient Mg2+.\",\n      \"evidence\": \"RT-PCR, Western blot, immunocytochemistry and mag-fura 2 ion measurement in rumen epithelial cells\",\n      \"pmids\": [\"18705540\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Channel/transporter mechanism not resolved structurally\", \"Single tissue context\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined MagT1 (and TUSC3) as bona fide mammalian plasma-membrane Mg2+ transporters with an essential in vivo developmental requirement, anchoring its transport function across species.\",\n      \"evidence\": \"Yeast complementation screen, siRNA knockdown with intracellular Mg2+ measurement, zebrafish morpholino knockdown with Mg2+/mRNA rescue\",\n      \"pmids\": [\"19717468\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not distinguish direct channel activity from indirect effects\", \"Substrate selectivity and gating mechanism unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected MAGT1-mediated Mg2+ flux to a defined signaling output by showing TCR-stimulated Mg2+ entry is required for PLCγ1 activation, establishing Mg2+ as a second messenger in T cells.\",\n      \"evidence\": \"Mg2+ flux and PLCγ1 phosphorylation assays in MAGT1-deficient XMEN patient T cells\",\n      \"pmids\": [\"21983175\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic link between Mg2+ and PLCγ1 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed MagT1 can substitute for a distinct Mg2+ uptake channel (TRPM7), supporting a genuine transport function with overlapping physiological roles.\",\n      \"evidence\": \"Overexpression in TRPM7-knockout DT40 B cells with Mg2+ uptake and growth rescue\",\n      \"pmids\": [\"21627970\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional substitution does not prove identical transport mechanism\", \"Heterologous overexpression system\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided direct electrophysiological evidence that MagT1 is a Mg2+-selective non-voltage-dependent channel and identified PKC phosphosites controlling its activity.\",\n      \"evidence\": \"Patch-clamp of Drosophila MagT1 in SH-SY5Y cells with PMA activation and Ser-to-Ala mutagenesis (S100A, S108A)\",\n      \"pmids\": [\"23727583\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Demonstrated in Drosophila ortholog, not mammalian protein\", \"PKC isoform and in vivo relevance unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a post-transcriptional control mechanism, showing miR-199a-5p directly suppresses MAGT1 protein and links its depletion to T-cell dysfunction in disease.\",\n      \"evidence\": \"Luciferase reporter assay, miRNA overexpression/knockdown, qRT-PCR and Western blot in CD8+ T cells\",\n      \"pmids\": [\"29051561\", \"31038761\", \"33210605\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether miRNA regulation operates in healthy tissue physiology unclear\", \"Downstream consequences mostly correlative\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Used a clean knockout mouse to show MAGT1 shapes B-cell Ca2+/Mg2+ homeostasis and PKC-dependent BCR signaling and alters B-cell subset composition in vivo.\",\n      \"evidence\": \"Magt1-knockout mouse, ion measurement, BCR stimulation, phosphoprotein Western blots, flow cytometry\",\n      \"pmids\": [\"29581357\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether B-cell phenotype reflects transport or glycosylation function not separated\", \"Causal chain from ion flux to subset frequencies incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated an essential developmental role with specific pathway epistasis, linking MagT1 to Wingless/Wnt and Decapentaplegic/BMP signaling during morphogenesis.\",\n      \"evidence\": \"Drosophila clonal analysis, RNAi in wing discs, signaling readouts, S2 cell Mg2+ transport assay\",\n      \"pmids\": [\"29959918\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism linking Mg2+/MagT1 to Wnt and BMP unresolved\", \"Drosophila ortholog only\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the second core function: MAGT1 is the OST3/OST6 homolog and an STT3B oligosaccharyltransferase subunit driving selective N-glycosylation, reframing XMEN as a glycosylation disorder.\",\n      \"evidence\": \"Glycoproteomics, CRISPR knockouts, NK killing assays, RNA-seq, patient transferrin/GLUT1/SHBG glycosylation analyses, TUSC3 comparison\",\n      \"pmids\": [\"31337704\", \"31036665\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How the transporter and glycosylation activities are coordinated mechanistically\", \"Determinants of substrate selectivity within STT3B unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked MagT1-dependent Mg2+ transport to ERK/MAPK-driven osteogenic/odontogenic differentiation, extending its role to stem cell fate.\",\n      \"evidence\": \"shRNA knockdown in BMMSCs, Mg2+ measurement, ERK phospho-Western, differentiation markers, RNA-seq\",\n      \"pmids\": [\"30704530\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether effect is transport- or glycosylation-mediated not distinguished\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated MAGT1 in cell-cycle progression and survival, showing its loss arrests S phase, induces apoptosis and dampens MAPK signaling in HPV-driven cells.\",\n      \"evidence\": \"siRNA knockdown in HeLa, cell cycle and apoptosis flow cytometry, Western blots for MAPK and cyclins, RNA-seq\",\n      \"pmids\": [\"34499581\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular driver of cell-cycle arrest not identified\", \"Transport vs glycosylation contribution unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncoupled the two functions by showing the NKG2D hypoglycosylation defect is site-specific and is NOT rescued by magnesium, establishing the glycosylation defect as Mg2+-independent.\",\n      \"evidence\": \"CRISPR-engineered human cells, site-specific glycosylation mapping, NKG2D flow cytometry, Mg2+ supplementation in cells and patient\",\n      \"pmids\": [\"35182234\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Why some substrate glycosylation responds to Mg2+ while NKG2D does not\", \"Therapeutic implications beyond NKG2D\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the glycosylation function to platelet biology, showing MAGT1 deficiency hypoglycosylates GPIbα, GPVI and integrin αIIb with functional aggregation defects correctable by transplantation.\",\n      \"evidence\": \"Platelet aggregation, calcium flux, integrin activation, N-glycan mass spectrometry, pre/post-HSCT comparison in patients\",\n      \"pmids\": [\"37207862\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single patient/lab context\", \"Relative contribution of each hypoglycosylated glycoprotein unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a genetic and functional link between MAGT1 and the TRPC6 channel in platelet cation balance, showing MAGT1 loss causes Ca2+-overload-driven hyperactive GPVI signaling and prothrombotic phenotypes correctable by TRPC6 reduction.\",\n      \"evidence\": \"Magt1-knockout mice, in vivo thrombosis and stroke models, platelet phospho-Western, Ca2+ flux, TRPC6/Magt1 double mutants, pharmacology, XMEN patient platelets\",\n      \"pmids\": [\"37381987\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Physical versus functional nature of MAGT1-TRPC6 interaction not defined\", \"How Mg2+ deficit drives Ca2+ overload mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected MagT1-driven Mg2+ uptake to SPARC N-glycosylation, secretion and mineral deposition, integrating its transport and glycosylation roles in osteogenesis.\",\n      \"evidence\": \"RNAi knockdown, glycosylation inhibitors, immunostaining, DDC-SEM and rat skull defect model\",\n      \"pmids\": [\"39632347\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether SPARC glycosylation depends on Mg2+ flux or STT3B activity not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how MAGT1's Mg2+ transport activity and its STT3B oligosaccharyltransferase subunit role are mechanistically coordinated, and what structural features govern its substrate selectivity and Mg2+ dependence.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model integrating transport and glycosylation functions\", \"Substrate selectivity rules of MAGT1-STT3B undefined\", \"Mechanism by which Mg2+ levels influence only a subset of glycosylation substrates unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 3, 13]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 7, 8, 11]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 7, 8, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [\"STT3B oligosaccharyltransferase (OST-B) complex\"],\n    \"partners\": [\"TUSC3\", \"TRPC6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}