{"gene":"TUSC3","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2009,"finding":"TUSC3 (and MagT1) function as plasma membrane Mg²⁺ transporters required for cellular magnesium influx. Knockdown of either protein significantly lowered total and free intracellular Mg²⁺ concentrations in mammalian cell lines, and morpholino knockdown in zebrafish caused early developmental arrest rescuable by excess Mg²⁺ or mammalian mRNA supplementation.","method":"Yeast complementation screen, siRNA knockdown with intracellular Mg²⁺ measurement, morpholino knockdown in zebrafish 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 knockdown with rescue), replicated across cell and animal models in single rigorous study","pmids":["19717468"],"is_preprint":false},{"year":2014,"finding":"Human N33/TUSC3 possesses a membrane-anchored N-terminal thioredoxin domain in the ER lumen that forms transient mixed disulfide complexes with OST substrates. X-ray crystal structures of complexes with two different peptide substrates reveal a defined peptide-binding groove adjacent to the active site that accommodates peptides in opposite orientations. N33/TUSC3 preferentially binds peptides bearing a hydrophobic residue two positions away from the cysteine forming the mixed disulfide, supporting a model in which it increases glycosylation efficiency for a subset of glycoproteins by slowing their folding.","method":"X-ray crystallography of peptide complexes, biochemical binding assays, structural and mutagenesis analysis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray crystal structures with two different substrate complexes plus biochemical validation; multiple orthogonal methods in a single rigorous study","pmids":["24685145"],"is_preprint":false},{"year":2014,"finding":"TUSC3 is a component of the oligosaccharyltransferase (OST) complex in mammalian prostate cancer cells and affects N-linked glycosylation. Loss of TUSC3 expression alters ER structure and ER stress response, resulting in increased Akt signaling.","method":"Co-immunoprecipitation to demonstrate OST complex membership, glycosylation assays, western blotting for ER stress markers and Akt signaling, loss-of-function in DU145 and PC3 cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating OST complex association plus functional readouts (glycosylation, ER stress, Akt), single lab with multiple orthogonal methods","pmids":["24435307"],"is_preprint":false},{"year":2013,"finding":"TUSC3 localizes to the endoplasmic reticulum as a subunit of the oligosaccharyltransferase complex in ovarian cancer cells, and its silencing alters glycosylation patterning and enhances cell proliferation and migration.","method":"Subcellular fractionation, co-immunofluorescence, co-immunoprecipitation, glycosylation assays, siRNA knockdown with proliferation and migration assays","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus fractionation for localization, glycosylation assay, functional readouts; single lab with multiple orthogonal methods","pmids":["23404293"],"is_preprint":false},{"year":2015,"finding":"Loss of TUSC3 in ovarian cancer cells alters the molecular response to ER stress and induces hallmarks of the epithelial-to-mesenchymal transition, establishing a mechanism by which TUSC3 deficiency drives malignant phenotype.","method":"Xenograft mouse model, loss-of-function studies, ER stress response assays, EMT marker analysis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft plus in vitro mechanistic assays, single lab with multiple readouts","pmids":["25735931"],"is_preprint":false},{"year":2017,"finding":"TUSC3 interacts with GLI1 in NSCLC cells as demonstrated by co-immunoprecipitation and immunofluorescence, and TUSC3 overexpression increases GLI1, SMO, PTCH1, and PTCH2 protein levels, implicating TUSC3 in Hedgehog signaling.","method":"Co-immunoprecipitation, immunofluorescence, western blotting, gain- and loss-of-function in NSCLC cells","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP and immunofluorescence for interaction, no in vitro reconstitution or mutagenesis, single lab","pmids":["28487226"],"is_preprint":false},{"year":2018,"finding":"miR-224/miR-520c-dependent TUSC3 deficiency in NSCLC enhances metastatic potential through alteration of three unfolded protein response pathways: ATF6α-dependent UPR is enhanced, while HRD1 affinity to substrates PERK, IRE1α, and p53 is weakened. The suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is responsible for enhanced metastasis.","method":"miRNA overexpression/inhibition, co-immunoprecipitation (HRD1 interactions), UPR pathway analysis, metastasis assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for HRD1 substrate interactions plus multiple UPR pathway readouts and functional metastasis assays, single lab with several orthogonal methods","pmids":["30504895"],"is_preprint":false},{"year":2019,"finding":"UHRF1 suppresses TUSC3 expression by interacting with methylated H3K14 and thereby suppressing acetylation of H3K14 by histone acetyltransferase KAT7, downstream of Wnt/c-Myc signaling; this UHRF1-KAT7-mediated epigenetic regulation of TUSC3 is required for colon cancer cell proliferation.","method":"Co-immunoprecipitation (UHRF1-KAT7), ChIP assays for H3K14 methylation/acetylation, gain- and loss-of-function, proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP demonstrating epigenetic mechanism, functional rescue experiments, single lab with multiple orthogonal methods","pmids":["31582837"],"is_preprint":false},{"year":2020,"finding":"TUSC3 promotes cellular stemness and drug resistance to 5-FU and cisplatin in colorectal cancer cells through the Hedgehog signaling pathway, and co-immunoprecipitation and immunofluorescence assays reveal a direct interaction between TUSC3 and SMO protein.","method":"Co-immunoprecipitation, immunofluorescence, Hedgehog pathway agonist/inhibitor treatment, tissue microarray, gain- and loss-of-function assays","journal":"Carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP for TUSC3-SMO interaction, single lab, pathway rescue supports but doesn't rigorously establish mechanism","pmids":["32338281"],"is_preprint":false},{"year":2022,"finding":"In hepatocellular carcinoma, TUSC3 interacts with LIPC (lipase C, hepatic type) as shown by co-immunoprecipitation and immunofluorescence, and TUSC3 inhibits EMT progression through the LIPC/AKT axis.","method":"Co-immunoprecipitation, immunofluorescence, microarray analysis, gain- and loss-of-function, in vivo xenograft, western blot for AKT and EMT markers","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP for TUSC3-LIPC interaction with supporting functional data, single lab","pmids":["36274132"],"is_preprint":false},{"year":2025,"finding":"TUSC3 forms an ER-localized Mg²⁺ transport complex with ERMA; loss of TUSC3 leads to ER Mg²⁺ depletion, PERK-eIF2α pathway activation, synaptic dysfunction, and neuronal vulnerability. TUSC3 KO mice exhibit ID-like phenotypes (impaired learning, memory, stress adaptation, social behavior), and fibroblasts from TUSC3 mutant patients show ER Mg²⁺ deficiency and heightened ER stress. Magnesium supplementation restores ER Mg²⁺ levels, reduces ER stress, and rescues cognitive deficits.","method":"TUSC3 knockout mouse model, behavioral testing, ER Mg²⁺ measurement, PERK-eIF2α pathway analysis, patient fibroblast studies, Mg²⁺ supplementation rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with defined behavioral and molecular phenotypes, patient fibroblast validation, pharmacological rescue with multiple orthogonal readouts in a rigorous study","pmids":["41203647"],"is_preprint":false},{"year":2025,"finding":"TUSC3, as a component of the OST complex, regulates G2-to-G1 glucose trimming on N-glycosylated BMP4 (and its Drosophila homolog Dpp) to promote their entry into the ER quality control cycle. TUSC3 acts as a dosage-sensitive gatekeeper influencing whether BMP4 molecules undergo proper folding/secretion versus elimination by ERAD, thereby tuning BMP signaling.","method":"Loss- and gain-of-function genetic experiments in mammalian cells and Drosophila, biochemical glycan trimming assays, BMP signaling readouts","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical assays demonstrating glycan trimming regulation plus genetic epistasis in two model systems; preprint, not yet peer-reviewed","pmids":["41256443"],"is_preprint":true},{"year":2023,"finding":"Exogenous expression of TUSC3 in MAGT1-knockout NKL cells rescues immune deficiencies (including NKG2D expression) caused by MAGT1 loss, demonstrating functional redundancy between TUSC3 and MAGT1 in Mg²⁺ transport and N-linked glycosylation in immune cells. Epigenetic activation of TUSC3 with decitabine and panobinostat in MAGT1 KO/patient-derived lymphocytes and hepatocytes rescued relevant phenotypes.","method":"CRISPR/Cas9 KO of MAGT1, exogenous TUSC3 expression rescue, epigenetic drug treatment, western blot for NKG2D and glycosylation markers","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment (TUSC3 rescues MAGT1 KO phenotypes) plus pharmacological validation, single lab with multiple functional readouts","pmids":["37086924"],"is_preprint":false}],"current_model":"TUSC3 is an ER-resident subunit of the oligosaccharyltransferase (OST) complex that functions via a thioredoxin-like domain to form transient mixed disulfide complexes with nascent glycoprotein substrates, increasing N-glycosylation efficiency for a subset of proteins; it also forms an ER-localized Mg²⁺ transport complex with ERMA to maintain ER Mg²⁺ homeostasis, and its loss causes ER Mg²⁺ depletion, PERK-eIF2α-dependent ER stress, synaptic dysfunction, and cognitive deficits, while at the plasma membrane level TUSC3 (redundantly with MagT1) mediates cellular Mg²⁺ influx essential for vertebrate development."},"narrative":{"mechanistic_narrative":"TUSC3 is an endoplasmic reticulum-resident subunit of the oligosaccharyltransferase (OST) complex that couples N-linked glycosylation to magnesium homeostasis, and its loss is linked to intellectual disability and to cancer progression [PMID:24685145, PMID:24435307, PMID:41203647]. Within the OST complex, TUSC3 uses a membrane-anchored, ER-luminal thioredoxin domain to form transient mixed disulfide complexes with nascent glycoprotein substrates via a defined peptide-binding groove that recognizes peptides bearing a hydrophobic residue two positions from the substrate cysteine, thereby increasing glycosylation efficiency for a subset of glycoproteins by slowing their folding [PMID:24685145]. As an OST component it also regulates G2-to-G1 glucose trimming on N-glycosylated substrates such as BMP4, acting as a dosage-sensitive gatekeeper directing substrates toward folding/secretion versus ERAD elimination [PMID:41256443]. Independently, TUSC3 and its paralog MAGT1 function as magnesium transporters: at the plasma membrane both mediate cellular Mg²⁺ influx required for vertebrate development, and the two proteins are functionally redundant in immune cells, where exogenous TUSC3 rescues MAGT1-loss phenotypes [PMID:19717468, PMID:37086924]. TUSC3 additionally forms an ER-localized Mg²⁺ transport complex with ERMA, and its loss depletes ER Mg²⁺, activates the PERK-eIF2α arm of ER stress, and produces synaptic dysfunction and intellectual-disability-like cognitive deficits in knockout mice that are reversible by magnesium supplementation; patient fibroblasts recapitulate the ER Mg²⁺ deficiency and ER stress [PMID:41203647]. In cancers, TUSC3 loss alters the ER stress/unfolded protein response and downstream signaling, influencing proliferation, migration, epithelial-to-mesenchymal transition, and metastasis across ovarian, prostate, lung, colorectal, and hepatocellular models [PMID:24435307, PMID:23404293, PMID:25735931, PMID:30504895].","teleology":[{"year":2009,"claim":"Established TUSC3's first molecular function by showing it acts as a magnesium transporter required for cellular Mg²⁺ influx, defining a role independent of any glycosylation activity.","evidence":"Yeast complementation, siRNA knockdown with intracellular Mg²⁺ measurement, and morpholino knockdown in zebrafish with Mg²⁺ rescue","pmids":["19717468"],"confidence":"High","gaps":["Did not resolve whether Mg²⁺ transport is direct or via a complex","Subcellular site of transport (plasma membrane vs ER) not distinguished","Relationship to OST membership unaddressed"]},{"year":2013,"claim":"Localized TUSC3 to the ER as an OST subunit in cancer cells and tied its loss to altered glycosylation and increased proliferation/migration, framing it as a glycosylation-dependent tumor suppressor.","evidence":"Subcellular fractionation, co-immunofluorescence, reciprocal co-IP, glycosylation assays, and siRNA knockdown with functional readouts in ovarian cancer cells","pmids":["23404293"],"confidence":"Medium","gaps":["Which glycoproteins are affected not defined","Mechanism linking glycosylation to proliferation unresolved"]},{"year":2014,"claim":"Defined the catalytic-mechanistic basis of TUSC3's glycosylation role: an ER-luminal thioredoxin domain forms mixed disulfides with substrate peptides, explaining how it enhances glycosylation efficiency for select substrates.","evidence":"X-ray crystallography of two peptide-substrate complexes, biochemical binding assays, and mutagenesis","pmids":["24685145"],"confidence":"High","gaps":["In vivo substrate repertoire not enumerated","Quantitative contribution to glycosylation versus other OST subunits unclear"]},{"year":2014,"claim":"Confirmed OST complex membership in additional cancer cells and linked TUSC3 loss to ER structural change, ER stress, and Akt signaling, broadening its pathophysiological reach.","evidence":"Co-IP, glycosylation assays, and western blotting for ER stress and Akt markers in prostate cancer cell lines","pmids":["24435307"],"confidence":"Medium","gaps":["Direct link between glycosylation loss and Akt activation not mechanistically established"]},{"year":2015,"claim":"Connected TUSC3 deficiency to the ER stress response and EMT in vivo, providing a mechanism for malignant progression upon TUSC3 loss.","evidence":"Xenograft mouse model with loss-of-function, ER stress assays, and EMT marker analysis","pmids":["25735931"],"confidence":"Medium","gaps":["Specific UPR branch responsible not pinpointed in this study"]},{"year":2018,"claim":"Dissected which UPR branches drive TUSC3-loss metastasis, showing enhanced ATF6α signaling and weakened HRD1 substrate engagement converging on a suppressed p53-NM23H1/2 axis.","evidence":"miRNA gain/loss-of-function, HRD1 co-IP, UPR pathway analysis, and metastasis assays in NSCLC","pmids":["30504895"],"confidence":"Medium","gaps":["Direct biochemical effect of TUSC3 on HRD1 affinity not isolated","Generality beyond NSCLC unknown"]},{"year":2019,"claim":"Identified an upstream epigenetic mechanism silencing TUSC3, placing its expression under UHRF1-KAT7 control downstream of Wnt/c-Myc in colon cancer.","evidence":"UHRF1-KAT7 co-IP, ChIP for H3K14 methylation/acetylation, and gain/loss-of-function proliferation assays","pmids":["31582837"],"confidence":"Medium","gaps":["Does not address TUSC3's downstream effector mechanism","Direct UHRF1 occupancy at TUSC3 locus dynamics partially characterized"]},{"year":2023,"claim":"Demonstrated functional redundancy between TUSC3 and MAGT1 by rescuing MAGT1-KO immune phenotypes with exogenous TUSC3, unifying the two paralogs in Mg²⁺ transport and glycosylation.","evidence":"CRISPR/Cas9 MAGT1 knockout in NKL cells, exogenous TUSC3 rescue, epigenetic drug activation, and western blot for NKG2D/glycosylation markers","pmids":["37086924"],"confidence":"Medium","gaps":["Extent of redundancy in non-immune tissues not defined","Whether endogenous TUSC3 normally compensates for MAGT1 in vivo unclear"]},{"year":2025,"claim":"Established TUSC3's ER magnesium-transport function and its disease relevance, showing ERMA-complex formation, ER Mg²⁺ depletion, PERK-eIF2α stress, and reversible cognitive deficits, linking TUSC3 to intellectual disability.","evidence":"TUSC3 knockout mouse with behavioral testing, ER Mg²⁺ measurement, PERK-eIF2α analysis, patient fibroblast studies, and magnesium-supplementation rescue","pmids":["41203647"],"confidence":"High","gaps":["Stoichiometry and transport mechanism of the TUSC3-ERMA complex not resolved","Relationship between ER Mg²⁺ role and OST glycosylation role not integrated"]},{"year":2025,"claim":"Linked TUSC3's OST function to developmental signaling control by showing it regulates glucose trimming on N-glycosylated BMP4 to tune ER quality control and BMP output.","evidence":"Loss/gain-of-function in mammalian cells and Drosophila, biochemical glycan trimming assays, and BMP signaling readouts (preprint)","pmids":["41256443"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Direct enzymatic role of TUSC3 in trimming versus accessory role not separated","Substrate scope beyond BMP4/Dpp untested"]},{"year":null,"claim":"How TUSC3's two molecular activities — OST-associated glycosylation/disulfide chemistry and Mg²⁺ transport — are mechanistically coordinated within the same protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure or assay distinguishing whether the thioredoxin domain and Mg²⁺ transport are coupled or independent","Whether ER Mg²⁺ depletion versus glycosylation defects drives each disease phenotype is unseparated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,10,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,10]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2,3,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,3,11]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4,6,10]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,10]}],"complexes":["oligosaccharyltransferase (OST) complex","TUSC3-ERMA ER Mg²⁺ transport complex"],"partners":["ERMA","MAGT1","GLI1","SMO","LIPC","HRD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13454","full_name":"Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit TUSC3","aliases":["Magnesium uptake/transporter TUSC3","Protein N33","Tumor suppressor candidate 3"],"length_aa":348,"mass_kda":39.7,"function":"Acts as accessory component 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. Involved in N-glycosylation of STT3B-dependent substrates. Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with MAGT1. 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 (PubMed:19717468)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q13454/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TUSC3","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"STT3B","stoichiometry":4.0},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"RPN2","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TUSC3","total_profiled":1310},"omim":[{"mim_id":"615596","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iw, AUTOSOMAL RECESSIVE; CDG1WAR","url":"https://www.omim.org/entry/615596"},{"mim_id":"614440","title":"PLECKSTRIN AND SEC7 DOMAINS-CONTAINING PROTEIN 3; PSD3","url":"https://www.omim.org/entry/614440"},{"mim_id":"612789","title":"DEAFNESS, AUTOSOMAL RECESSIVE 71; DFNB71","url":"https://www.omim.org/entry/612789"},{"mim_id":"611093","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 7; MRT7","url":"https://www.omim.org/entry/611093"},{"mim_id":"601385","title":"TUMOR SUPPRESSOR CANDIDATE 3; TUSC3","url":"https://www.omim.org/entry/601385"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TUSC3"},"hgnc":{"alias_symbol":["MGC13453","N33","OST3A","MRT7","MagT2","SLC58A2"],"prev_symbol":["MRT22"]},"alphafold":{"accession":"Q13454","domains":[{"cath_id":"3.40.30.10","chopping":"42-185","consensus_level":"high","plddt":92.2901,"start":42,"end":185},{"cath_id":"-","chopping":"221-335","consensus_level":"high","plddt":87.4969,"start":221,"end":335}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13454","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13454-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13454-F1-predicted_aligned_error_v6.png","plddt_mean":84.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TUSC3","jax_strain_url":"https://www.jax.org/strain/search?query=TUSC3"},"sequence":{"accession":"Q13454","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13454.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13454/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13454"}},"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":"18452889","id":"PMC_18452889","title":"A defect in the TUSC3 gene is associated with autosomal recessive mental retardation.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18452889","citation_count":119,"is_preprint":false},{"pmid":"28288641","id":"PMC_28288641","title":"SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis.","date":"2017","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28288641","citation_count":88,"is_preprint":false},{"pmid":"27071482","id":"PMC_27071482","title":"TUSC3 promotes colorectal cancer progression and epithelial-mesenchymal transition (EMT) through WNT/β-catenin and MAPK signalling.","date":"2016","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27071482","citation_count":85,"is_preprint":false},{"pmid":"24685145","id":"PMC_24685145","title":"Structural basis of substrate specificity of human oligosaccharyl transferase subunit N33/Tusc3 and its role in regulating protein N-glycosylation.","date":"2014","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/24685145","citation_count":75,"is_preprint":false},{"pmid":"9671399","id":"PMC_9671399","title":"Concordant methylation of the ER and N33 genes in glioblastoma multiforme.","date":"1998","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9671399","citation_count":68,"is_preprint":false},{"pmid":"24435307","id":"PMC_24435307","title":"TUSC3 loss alters the ER stress response and accelerates prostate cancer growth in vivo.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/24435307","citation_count":54,"is_preprint":false},{"pmid":"29790668","id":"PMC_29790668","title":"The effects of aberrant expression of LncRNA DGCR5/miR-873-5p/TUSC3 in lung cancer cell progression.","date":"2018","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29790668","citation_count":45,"is_preprint":false},{"pmid":"30504895","id":"PMC_30504895","title":"miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30504895","citation_count":44,"is_preprint":false},{"pmid":"25735931","id":"PMC_25735931","title":"Tumor suppressor candidate 3 (TUSC3) prevents the epithelial-to-mesenchymal transition and inhibits tumor growth by modulating the endoplasmic reticulum stress response in ovarian cancer cells.","date":"2015","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25735931","citation_count":44,"is_preprint":false},{"pmid":"21739581","id":"PMC_21739581","title":"A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation in a consanguineous Iranian family.","date":"2011","source":"American journal of medical genetics. 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magnesium influx. Knockdown of either protein significantly lowered total and free intracellular Mg²⁺ concentrations in mammalian cell lines, and morpholino knockdown in zebrafish caused early developmental arrest rescuable by excess Mg²⁺ or mammalian mRNA supplementation.\",\n      \"method\": \"Yeast complementation screen, siRNA knockdown with intracellular Mg²⁺ measurement, morpholino knockdown in zebrafish 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 knockdown with rescue), replicated across cell and animal models in single rigorous study\",\n      \"pmids\": [\"19717468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human N33/TUSC3 possesses a membrane-anchored N-terminal thioredoxin domain in the ER lumen that forms transient mixed disulfide complexes with OST substrates. X-ray crystal structures of complexes with two different peptide substrates reveal a defined peptide-binding groove adjacent to the active site that accommodates peptides in opposite orientations. N33/TUSC3 preferentially binds peptides bearing a hydrophobic residue two positions away from the cysteine forming the mixed disulfide, supporting a model in which it increases glycosylation efficiency for a subset of glycoproteins by slowing their folding.\",\n      \"method\": \"X-ray crystallography of peptide complexes, biochemical binding assays, structural and mutagenesis analysis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray crystal structures with two different substrate complexes plus biochemical validation; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"24685145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TUSC3 is a component of the oligosaccharyltransferase (OST) complex in mammalian prostate cancer cells and affects N-linked glycosylation. Loss of TUSC3 expression alters ER structure and ER stress response, resulting in increased Akt signaling.\",\n      \"method\": \"Co-immunoprecipitation to demonstrate OST complex membership, glycosylation assays, western blotting for ER stress markers and Akt signaling, loss-of-function in DU145 and PC3 cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating OST complex association plus functional readouts (glycosylation, ER stress, Akt), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24435307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TUSC3 localizes to the endoplasmic reticulum as a subunit of the oligosaccharyltransferase complex in ovarian cancer cells, and its silencing alters glycosylation patterning and enhances cell proliferation and migration.\",\n      \"method\": \"Subcellular fractionation, co-immunofluorescence, co-immunoprecipitation, glycosylation assays, siRNA knockdown with proliferation and migration assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus fractionation for localization, glycosylation assay, functional readouts; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23404293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of TUSC3 in ovarian cancer cells alters the molecular response to ER stress and induces hallmarks of the epithelial-to-mesenchymal transition, establishing a mechanism by which TUSC3 deficiency drives malignant phenotype.\",\n      \"method\": \"Xenograft mouse model, loss-of-function studies, ER stress response assays, EMT marker analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft plus in vitro mechanistic assays, single lab with multiple readouts\",\n      \"pmids\": [\"25735931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TUSC3 interacts with GLI1 in NSCLC cells as demonstrated by co-immunoprecipitation and immunofluorescence, and TUSC3 overexpression increases GLI1, SMO, PTCH1, and PTCH2 protein levels, implicating TUSC3 in Hedgehog signaling.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, western blotting, gain- and loss-of-function in NSCLC cells\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP and immunofluorescence for interaction, no in vitro reconstitution or mutagenesis, single lab\",\n      \"pmids\": [\"28487226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-224/miR-520c-dependent TUSC3 deficiency in NSCLC enhances metastatic potential through alteration of three unfolded protein response pathways: ATF6α-dependent UPR is enhanced, while HRD1 affinity to substrates PERK, IRE1α, and p53 is weakened. The suppressed p53-NM23H1/2 pathway by TUSC3 deficiency is responsible for enhanced metastasis.\",\n      \"method\": \"miRNA overexpression/inhibition, co-immunoprecipitation (HRD1 interactions), UPR pathway analysis, metastasis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for HRD1 substrate interactions plus multiple UPR pathway readouts and functional metastasis assays, single lab with several orthogonal methods\",\n      \"pmids\": [\"30504895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UHRF1 suppresses TUSC3 expression by interacting with methylated H3K14 and thereby suppressing acetylation of H3K14 by histone acetyltransferase KAT7, downstream of Wnt/c-Myc signaling; this UHRF1-KAT7-mediated epigenetic regulation of TUSC3 is required for colon cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (UHRF1-KAT7), ChIP assays for H3K14 methylation/acetylation, gain- and loss-of-function, proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP demonstrating epigenetic mechanism, functional rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31582837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TUSC3 promotes cellular stemness and drug resistance to 5-FU and cisplatin in colorectal cancer cells through the Hedgehog signaling pathway, and co-immunoprecipitation and immunofluorescence assays reveal a direct interaction between TUSC3 and SMO protein.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, Hedgehog pathway agonist/inhibitor treatment, tissue microarray, gain- and loss-of-function assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP for TUSC3-SMO interaction, single lab, pathway rescue supports but doesn't rigorously establish mechanism\",\n      \"pmids\": [\"32338281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In hepatocellular carcinoma, TUSC3 interacts with LIPC (lipase C, hepatic type) as shown by co-immunoprecipitation and immunofluorescence, and TUSC3 inhibits EMT progression through the LIPC/AKT axis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, microarray analysis, gain- and loss-of-function, in vivo xenograft, western blot for AKT and EMT markers\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP for TUSC3-LIPC interaction with supporting functional data, single lab\",\n      \"pmids\": [\"36274132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TUSC3 forms an ER-localized Mg²⁺ transport complex with ERMA; loss of TUSC3 leads to ER Mg²⁺ depletion, PERK-eIF2α pathway activation, synaptic dysfunction, and neuronal vulnerability. TUSC3 KO mice exhibit ID-like phenotypes (impaired learning, memory, stress adaptation, social behavior), and fibroblasts from TUSC3 mutant patients show ER Mg²⁺ deficiency and heightened ER stress. Magnesium supplementation restores ER Mg²⁺ levels, reduces ER stress, and rescues cognitive deficits.\",\n      \"method\": \"TUSC3 knockout mouse model, behavioral testing, ER Mg²⁺ measurement, PERK-eIF2α pathway analysis, patient fibroblast studies, Mg²⁺ supplementation rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with defined behavioral and molecular phenotypes, patient fibroblast validation, pharmacological rescue with multiple orthogonal readouts in a rigorous study\",\n      \"pmids\": [\"41203647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TUSC3, as a component of the OST complex, regulates G2-to-G1 glucose trimming on N-glycosylated BMP4 (and its Drosophila homolog Dpp) to promote their entry into the ER quality control cycle. TUSC3 acts as a dosage-sensitive gatekeeper influencing whether BMP4 molecules undergo proper folding/secretion versus elimination by ERAD, thereby tuning BMP signaling.\",\n      \"method\": \"Loss- and gain-of-function genetic experiments in mammalian cells and Drosophila, biochemical glycan trimming assays, BMP signaling readouts\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical assays demonstrating glycan trimming regulation plus genetic epistasis in two model systems; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41256443\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Exogenous expression of TUSC3 in MAGT1-knockout NKL cells rescues immune deficiencies (including NKG2D expression) caused by MAGT1 loss, demonstrating functional redundancy between TUSC3 and MAGT1 in Mg²⁺ transport and N-linked glycosylation in immune cells. Epigenetic activation of TUSC3 with decitabine and panobinostat in MAGT1 KO/patient-derived lymphocytes and hepatocytes rescued relevant phenotypes.\",\n      \"method\": \"CRISPR/Cas9 KO of MAGT1, exogenous TUSC3 expression rescue, epigenetic drug treatment, western blot for NKG2D and glycosylation markers\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment (TUSC3 rescues MAGT1 KO phenotypes) plus pharmacological validation, single lab with multiple functional readouts\",\n      \"pmids\": [\"37086924\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TUSC3 is an ER-resident subunit of the oligosaccharyltransferase (OST) complex that functions via a thioredoxin-like domain to form transient mixed disulfide complexes with nascent glycoprotein substrates, increasing N-glycosylation efficiency for a subset of proteins; it also forms an ER-localized Mg²⁺ transport complex with ERMA to maintain ER Mg²⁺ homeostasis, and its loss causes ER Mg²⁺ depletion, PERK-eIF2α-dependent ER stress, synaptic dysfunction, and cognitive deficits, while at the plasma membrane level TUSC3 (redundantly with MagT1) mediates cellular Mg²⁺ influx essential for vertebrate development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TUSC3 is an endoplasmic reticulum-resident subunit of the oligosaccharyltransferase (OST) complex that couples N-linked glycosylation to magnesium homeostasis, and its loss is linked to intellectual disability and to cancer progression [#1, #2, #10]. Within the OST complex, TUSC3 uses a membrane-anchored, ER-luminal thioredoxin domain to form transient mixed disulfide complexes with nascent glycoprotein substrates via a defined peptide-binding groove that recognizes peptides bearing a hydrophobic residue two positions from the substrate cysteine, thereby increasing glycosylation efficiency for a subset of glycoproteins by slowing their folding [#1]. As an OST component it also regulates G2-to-G1 glucose trimming on N-glycosylated substrates such as BMP4, acting as a dosage-sensitive gatekeeper directing substrates toward folding/secretion versus ERAD elimination [#11]. Independently, TUSC3 and its paralog MAGT1 function as magnesium transporters: at the plasma membrane both mediate cellular Mg²⁺ influx required for vertebrate development, and the two proteins are functionally redundant in immune cells, where exogenous TUSC3 rescues MAGT1-loss phenotypes [#0, #12]. TUSC3 additionally forms an ER-localized Mg²⁺ transport complex with ERMA, and its loss depletes ER Mg²⁺, activates the PERK-eIF2α arm of ER stress, and produces synaptic dysfunction and intellectual-disability-like cognitive deficits in knockout mice that are reversible by magnesium supplementation; patient fibroblasts recapitulate the ER Mg²⁺ deficiency and ER stress [#10]. In cancers, TUSC3 loss alters the ER stress/unfolded protein response and downstream signaling, influencing proliferation, migration, epithelial-to-mesenchymal transition, and metastasis across ovarian, prostate, lung, colorectal, and hepatocellular models [#2, #3, #4, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established TUSC3's first molecular function by showing it acts as a magnesium transporter required for cellular Mg²⁺ influx, defining a role independent of any glycosylation activity.\",\n      \"evidence\": \"Yeast complementation, siRNA knockdown with intracellular Mg²⁺ measurement, and morpholino knockdown in zebrafish with Mg²⁺ rescue\",\n      \"pmids\": [\"19717468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether Mg²⁺ transport is direct or via a complex\", \"Subcellular site of transport (plasma membrane vs ER) not distinguished\", \"Relationship to OST membership unaddressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Localized TUSC3 to the ER as an OST subunit in cancer cells and tied its loss to altered glycosylation and increased proliferation/migration, framing it as a glycosylation-dependent tumor suppressor.\",\n      \"evidence\": \"Subcellular fractionation, co-immunofluorescence, reciprocal co-IP, glycosylation assays, and siRNA knockdown with functional readouts in ovarian cancer cells\",\n      \"pmids\": [\"23404293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which glycoproteins are affected not defined\", \"Mechanism linking glycosylation to proliferation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the catalytic-mechanistic basis of TUSC3's glycosylation role: an ER-luminal thioredoxin domain forms mixed disulfides with substrate peptides, explaining how it enhances glycosylation efficiency for select substrates.\",\n      \"evidence\": \"X-ray crystallography of two peptide-substrate complexes, biochemical binding assays, and mutagenesis\",\n      \"pmids\": [\"24685145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrate repertoire not enumerated\", \"Quantitative contribution to glycosylation versus other OST subunits unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed OST complex membership in additional cancer cells and linked TUSC3 loss to ER structural change, ER stress, and Akt signaling, broadening its pathophysiological reach.\",\n      \"evidence\": \"Co-IP, glycosylation assays, and western blotting for ER stress and Akt markers in prostate cancer cell lines\",\n      \"pmids\": [\"24435307\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between glycosylation loss and Akt activation not mechanistically established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected TUSC3 deficiency to the ER stress response and EMT in vivo, providing a mechanism for malignant progression upon TUSC3 loss.\",\n      \"evidence\": \"Xenograft mouse model with loss-of-function, ER stress assays, and EMT marker analysis\",\n      \"pmids\": [\"25735931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific UPR branch responsible not pinpointed in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Dissected which UPR branches drive TUSC3-loss metastasis, showing enhanced ATF6α signaling and weakened HRD1 substrate engagement converging on a suppressed p53-NM23H1/2 axis.\",\n      \"evidence\": \"miRNA gain/loss-of-function, HRD1 co-IP, UPR pathway analysis, and metastasis assays in NSCLC\",\n      \"pmids\": [\"30504895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical effect of TUSC3 on HRD1 affinity not isolated\", \"Generality beyond NSCLC unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an upstream epigenetic mechanism silencing TUSC3, placing its expression under UHRF1-KAT7 control downstream of Wnt/c-Myc in colon cancer.\",\n      \"evidence\": \"UHRF1-KAT7 co-IP, ChIP for H3K14 methylation/acetylation, and gain/loss-of-function proliferation assays\",\n      \"pmids\": [\"31582837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address TUSC3's downstream effector mechanism\", \"Direct UHRF1 occupancy at TUSC3 locus dynamics partially characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated functional redundancy between TUSC3 and MAGT1 by rescuing MAGT1-KO immune phenotypes with exogenous TUSC3, unifying the two paralogs in Mg²⁺ transport and glycosylation.\",\n      \"evidence\": \"CRISPR/Cas9 MAGT1 knockout in NKL cells, exogenous TUSC3 rescue, epigenetic drug activation, and western blot for NKG2D/glycosylation markers\",\n      \"pmids\": [\"37086924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Extent of redundancy in non-immune tissues not defined\", \"Whether endogenous TUSC3 normally compensates for MAGT1 in vivo unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established TUSC3's ER magnesium-transport function and its disease relevance, showing ERMA-complex formation, ER Mg²⁺ depletion, PERK-eIF2α stress, and reversible cognitive deficits, linking TUSC3 to intellectual disability.\",\n      \"evidence\": \"TUSC3 knockout mouse with behavioral testing, ER Mg²⁺ measurement, PERK-eIF2α analysis, patient fibroblast studies, and magnesium-supplementation rescue\",\n      \"pmids\": [\"41203647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and transport mechanism of the TUSC3-ERMA complex not resolved\", \"Relationship between ER Mg²⁺ role and OST glycosylation role not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked TUSC3's OST function to developmental signaling control by showing it regulates glucose trimming on N-glycosylated BMP4 to tune ER quality control and BMP output.\",\n      \"evidence\": \"Loss/gain-of-function in mammalian cells and Drosophila, biochemical glycan trimming assays, and BMP signaling readouts (preprint)\",\n      \"pmids\": [\"41256443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Direct enzymatic role of TUSC3 in trimming versus accessory role not separated\", \"Substrate scope beyond BMP4/Dpp untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TUSC3's two molecular activities — OST-associated glycosylation/disulfide chemistry and Mg²⁺ transport — are mechanistically coordinated within the same protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure or assay distinguishing whether the thioredoxin domain and Mg²⁺ transport are coupled or independent\", \"Whether ER Mg²⁺ depletion versus glycosylation defects drives each disease phenotype is unseparated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 10, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2, 3, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 3, 11]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4, 6, 10]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [\"oligosaccharyltransferase (OST) complex\", \"TUSC3-ERMA ER Mg²⁺ transport complex\"],\n    \"partners\": [\"ERMA\", \"MAGT1\", \"GLI1\", \"SMO\", \"LIPC\", \"HRD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}