{"gene":"TMX1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2004,"finding":"TMX1 (TMX) is a transmembrane oxidoreductase localized to the ER membrane with its N-terminal thioredoxin-like domain (CPAC active site) facing the ER lumen; recombinant TMX showed PDI-like refolding activity on scrambled RNase in vitro.","method":"Subcellular fractionation, membrane topology analysis, in vitro refolding assay (scrambled RNase)","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro enzymatic assay and fractionation in single lab, no mutagenesis or structural validation","pmids":["14871470"],"is_preprint":false},{"year":2011,"finding":"Palmitoylation of cysteine residue(s) adjacent to the transmembrane domain of TMX1 is required for its enrichment on the mitochondria-associated membrane (MAM); mutation of the palmitoylation site or chemical interference with palmitoylation disrupts MAM localization.","method":"Palmitoylation site mutagenesis, chemical inhibition of palmitoylation, subcellular fractionation/immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of palmitoylation site combined with chemical inhibitor, replicated across two ER oxidoreductases (TMX1 and calnexin), multiple orthogonal methods","pmids":["22045338"],"is_preprint":false},{"year":2015,"finding":"TMX1 forms functional complexes with the ER lectin calnexin and preferentially acts on cysteine-containing, membrane-anchored client proteins during folding, while ignoring the same cysteine-containing ectodomains when not membrane-tethered; TMX1 is the first topology-specific client protein redox catalyst in living cells.","method":"Co-immunoprecipitation (TMX1–calnexin complex), substrate specificity assays comparing membrane-anchored vs. soluble ectodomains, KD/KO with defined folding phenotype","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, multiple substrate pairs tested, topology-specificity demonstrated with two orthogonal methods in a single focused study","pmids":["26246604"],"is_preprint":false},{"year":2016,"finding":"TMX1 regulates ER-to-mitochondria Ca²⁺ flux at the MAM; its thioredoxin (CPAC) motif and palmitoylation-dependent MAM targeting are both required for this function. Low TMX1 reduces ER-mitochondria contacts, decreases mitochondrial Ca²⁺ uptake, shifts bioenergetics away from mitochondria, and reduces apoptosis progression.","method":"TMX1 knockout/knockdown, CPAC active-site mutant, palmitoylation mutant; Ca²⁺ imaging, mitochondrial ATP measurements, ER-mitochondria contact site quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Ca²⁺ imaging, bioenergetics, contact site imaging), active-site and palmitoylation mutants tested, functional rescue experiments","pmids":["27502484"],"is_preprint":false},{"year":2017,"finding":"TMX1 is reversibly oxidized in response to ER protein overload (brefeldin A-induced protein accumulation); oxidation precedes the classical ER stress marker BiP induction, and glutathione is involved in maintaining TMX1 in its reduced (basal) state.","method":"Redox state analysis (alkylation-based trapping), BFA treatment and washout, glutathione depletion experiments","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — redox trapping with pharmacological perturbation, single lab, two complementary approaches but no mutagenesis","pmids":["29123984"],"is_preprint":false},{"year":2018,"finding":"TMX1 acts as a topology-specific reductase in ERAD, preferentially reducing disulfide bonds of membrane-tethered misfolded polypeptides to facilitate their dislocation, while ignoring the same misfolded ectodomains when soluble.","method":"ERAD substrate degradation assays, membrane-anchored vs. soluble substrate comparisons, TMX1 knockdown with defined ERAD phenotype","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — extends and replicates the topology-specificity principle from PMID 26246604 into the ERAD context, two substrate classes, single lab","pmids":["29932915"],"is_preprint":false},{"year":2018,"finding":"TMX1 is expressed on the platelet surface and acts as an oxidase toward the αIIbβ3 integrin; TMX1-deficient platelets have increased free thiols on the β3 subunit, and recombinant extracellular TMX1 inhibits platelet aggregation, ATP release, αIIbβ3 activation, and P-selectin expression, making it the first identified negative (inhibitory) extracellular thiol isomerase regulator of platelet function.","method":"TMX1 knockout mouse model, recombinant extracellular domain protein (rTMX1) addition, anti-TMX1 antibody, thiol-labeling of αIIbβ3, platelet aggregation and ATP release assays, FeCl3 mesenteric arterial injury thrombosis model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse, recombinant protein rescue, specific antibody, thiol labeling, in vivo thrombosis model; multiple orthogonal approaches in a single focused study","pmids":["30425049"],"is_preprint":false},{"year":2012,"finding":"TMX1-deficient mice are highly susceptible to LPS/d-galactosamine-induced inflammatory liver injury, with enhanced p53-signaling pathway activation in the liver; TNF-α neutralization suppressed the toxic phenotype, indicating TMX1 protects against oxidative inflammatory damage downstream of TNF-α signaling.","method":"TMX1 knockout mouse model, LPS/GalN and thioacetamide liver injury models, liver transcriptional profiling, TNF-α neutralization","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined phenotypic readout and epistasis via TNF-α neutralization, single lab","pmids":["22924822"],"is_preprint":false},{"year":2024,"finding":"TMX1 directly engages the CxxC motif of CD3δ (a TCR complex subunit); loss of TMX1 decreases surface TCR expression and destabilizes CD3ζ, impairing TCR assembly and T cell cytotoxicity as well as NFAT, NFκB, and AP1 signaling. Overexpression of CD3ζ rescues the phenotype, indicating TMX1 is required for TCR assembly but not for CD3ζ function per se.","method":"APEX2 proximity labeling screen (CD8α bait), CRISPR TMX1 deletion, CD3ζ overexpression rescue, surface TCR expression assays, T cell signaling readouts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — proximity labeling plus KO with functional rescue in preprint; mechanistically specific but not yet peer-reviewed and single lab","pmids":["39386445"],"is_preprint":true},{"year":2024,"finding":"TMX1 oxidizes ERp46 (inhibiting its reductase activity) and also re-oxidizes the αIIbβ3 disulfides that ERp46 reduces, thereby counterbalancing ERp46-mediated platelet activation; TMX1 deficiency increases free thiols on ERp46 in platelets, an effect reversed by addition of wild-type but not catalytically inactive TMX1.","method":"ERp46- and TMX1-deficient platelets, wild-type vs. inactive TMX1 protein addition, thiol labeling, reductase activity assays, platelet aggregation and clot retraction assays","journal":"Research and practice in thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual KO model, active-site mutant protein, thiol labeling and enzymatic assay; single lab with multiple orthogonal methods","pmids":["39247212"],"is_preprint":false},{"year":2025,"finding":"TMX1 binds FABP5 and competitively blocks interaction between FABP5 and the E3 ubiquitin ligase NEDD4, preventing K48-linked ubiquitination and degradation of FABP5, thereby enhancing FABP5-mediated inhibition of ferroptosis in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation (TMX1–FABP5 interaction), ubiquitination assays, TMX1 KD/OE with FABP5 KD rescue, in vivo xenograft model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and ubiquitination assay with rescue experiment, single lab, no structural validation","pmids":["41482143"],"is_preprint":false},{"year":2025,"finding":"CCT2 recruits TRIM28 to catalyze SUMO2 modification of TMX1, which inhibits TMX1 ubiquitination and stabilizes the protein; this stabilized TMX1 promotes ROS clearance, conferring resistance to third-generation EGFR tyrosine kinase inhibitors in NSCLC.","method":"CRISPR/Cas9 genome-wide screen, TMT proteomics, SUMO2 modification assays, ubiquitination assays, TMX1 KD with ROS measurements, xenograft models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics discovery plus biochemical validation of PTM axis (SUMOylation inhibiting ubiquitination), single lab","pmids":["41168408"],"is_preprint":false}],"current_model":"TMX1 is a transmembrane ER oxidoreductase (thioredoxin CPAC active site, ER-luminal domain) that is palmitoylated on cysteines adjacent to its transmembrane domain, directing it to the mitochondria-associated membrane (MAM), where it acts as a thiol-based modulator of ER-to-mitochondria Ca²⁺ flux and mitochondrial bioenergetics; within the ER it forms a complex with calnexin to preferentially reduce disulfide bonds of membrane-anchored client proteins during both productive folding and ERAD (topology-specific redox catalysis); on the platelet surface TMX1 oxidizes the αIIbβ3 integrin and ERp46 to negatively regulate platelet activation; in T cells it engages the CxxC motif of CD3δ to support TCR complex assembly; its redox state is reversibly controlled by ER protein load and glutathione; and its stability is post-translationally regulated by SUMO2 modification (via CCT2/TRIM28) that blocks ubiquitin-mediated degradation."},"narrative":{"mechanistic_narrative":"TMX1 is a transmembrane ER oxidoreductase whose N-terminal thioredoxin-like domain (CPAC active site) faces the ER lumen and possesses PDI-like disulfide-isomerase activity in vitro [PMID:14871470]. Palmitoylation of cysteines adjacent to its transmembrane domain targets a pool of TMX1 to the mitochondria-associated membrane (MAM), where both this lipid modification and the CPAC redox motif are required for TMX1 to sustain ER-to-mitochondria Ca²⁺ flux, mitochondrial Ca²⁺ uptake, and bioenergetic coupling, thereby promoting apoptotic progression [PMID:22045338, PMID:27502484]. Within the ER, TMX1 partners with the lectin calnexin and acts as a topology-specific redox catalyst, preferentially engaging the disulfide bonds of membrane-anchored client proteins while ignoring identical soluble ectodomains, a selectivity that operates both in productive folding and in the reductive dislocation of misfolded substrates during ERAD [PMID:26246604, PMID:29932915]. Its catalytic redox state is dynamic, becoming reversibly oxidized upon ER protein overload ahead of canonical stress markers and held reduced at baseline through glutathione [PMID:29123984]. Beyond the ER, TMX1 functions at the cell surface: it acts as an oxidase that re-oxidizes the αIIbβ3 integrin and inhibits ERp46, counterbalancing ERp46-driven platelet activation and thereby negatively regulating platelet aggregation and thrombosis [PMID:30425049, PMID:39247212]. TMX1 also protects against TNF-α-driven inflammatory liver injury [PMID:22924822], and its abundance is post-translationally controlled by a CCT2/TRIM28-catalyzed SUMO2 modification that blocks ubiquitin-mediated degradation [PMID:41168408].","teleology":[{"year":2004,"claim":"Establishing that TMX1 is a thioredoxin-family enzyme rather than an inert membrane protein answered whether it carries genuine redox catalytic activity and where it resides.","evidence":"Subcellular fractionation, membrane topology mapping, and in vitro refolding of scrambled RNase by recombinant TMX","pmids":["14871470"],"confidence":"Medium","gaps":["No mutagenesis confirming the CPAC residues drive activity","No identification of physiological substrates","In vitro activity not linked to a cellular process"]},{"year":2011,"claim":"Identifying palmitoylation as the targeting signal explained how a single ER oxidoreductase is partitioned to the MAM, defining the structural basis for its later contact-site functions.","evidence":"Palmitoylation-site mutagenesis and chemical inhibition with fractionation/immunofluorescence, paralleled in calnexin","pmids":["22045338"],"confidence":"High","gaps":["Did not establish what TMX1 does at the MAM","Palmitoyltransferase responsible not identified"]},{"year":2012,"claim":"A knockout mouse showed TMX1 has a protective physiological role in vivo, linking its redox function to suppression of inflammatory tissue damage.","evidence":"TMX1-knockout mice in LPS/GalN and thioacetamide liver injury models with TNF-α neutralization epistasis","pmids":["22924822"],"confidence":"Medium","gaps":["Molecular substrate mediating protection unknown","Connection to ER/MAM redox catalysis not established","p53 activation correlative"]},{"year":2015,"claim":"Defining TMX1 as a topology-specific catalyst acting on membrane-anchored clients in complex with calnexin answered how the enzyme achieves substrate selectivity in living cells.","evidence":"Reciprocal Co-IP of TMX1–calnexin and substrate assays comparing membrane-anchored versus soluble ectodomains","pmids":["26246604"],"confidence":"High","gaps":["Structural basis of topology discrimination unresolved","Full client repertoire not defined"]},{"year":2016,"claim":"Functional dissection at the MAM established TMX1 as a thiol-based regulator of ER-mitochondria Ca²⁺ transfer and bioenergetics, tying its redox motif and palmitoylation to organelle communication and apoptosis.","evidence":"TMX1 KO/KD with CPAC and palmitoylation mutants, Ca²⁺ imaging, mitochondrial ATP measurement, and contact-site quantification","pmids":["27502484"],"confidence":"High","gaps":["Direct redox substrate at the MAM controlling Ca²⁺ flux not identified","Mechanism linking TMX1 redox state to contact-site formation unclear"]},{"year":2017,"claim":"Showing TMX1 oxidation precedes BiP induction positioned its redox state as an early sensor of ER protein load buffered by glutathione.","evidence":"Alkylation-based redox trapping with brefeldin A treatment/washout and glutathione depletion","pmids":["29123984"],"confidence":"Medium","gaps":["No mutagenesis of the responsive cysteines","Downstream consequences of oxidation not defined"]},{"year":2018,"claim":"Extending topology-specific reduction into ERAD answered whether TMX1's selectivity principle operates in protein degradation as well as folding.","evidence":"ERAD substrate degradation assays comparing membrane-tethered versus soluble misfolded polypeptides under TMX1 knockdown","pmids":["29932915"],"confidence":"Medium","gaps":["Single lab","Coupling between disulfide reduction and dislocation machinery not detailed"]},{"year":2018,"claim":"Identifying surface TMX1 as an oxidase of αIIbβ3 revealed an unexpected extracellular, anti-thrombotic role, the first inhibitory thiol isomerase regulator of platelets.","evidence":"TMX1 KO mouse, recombinant extracellular domain, anti-TMX1 antibody, β3 thiol labeling, aggregation/ATP-release assays, and FeCl3 thrombosis model","pmids":["30425049"],"confidence":"High","gaps":["How an ER oxidoreductase reaches the platelet surface unclear","Full set of surface substrates not mapped"]},{"year":2024,"claim":"Defining TMX1's interplay with ERp46 explained how opposing thiol enzymes set platelet integrin activation thresholds.","evidence":"ERp46- and TMX1-deficient platelets, wild-type versus catalytically inactive TMX1 protein, thiol labeling, reductase assays, aggregation and clot retraction","pmids":["39247212"],"confidence":"Medium","gaps":["Stoichiometry of TMX1/ERp46 regulation in vivo unknown","Single lab"]},{"year":2024,"claim":"A proximity-labeling screen placed TMX1 at the TCR, showing it engages the CD3δ CxxC motif to support receptor assembly and T cell signaling.","evidence":"APEX2 proximity labeling with CD8α bait, CRISPR TMX1 deletion, CD3ζ overexpression rescue, surface TCR and signaling readouts (preprint)","pmids":["39386445"],"confidence":"Medium","gaps":["Not peer-reviewed and single lab","Direct redox chemistry on CD3δ not demonstrated","Generality across T cell subsets untested"]},{"year":2025,"claim":"Discovery of TMX1 binding FABP5 and a CCT2/TRIM28 SUMO2 axis revealed how TMX1 abundance is post-translationally controlled and links it to ferroptosis resistance and drug tolerance in cancer.","evidence":"Co-IP, ubiquitination/SUMOylation assays, KD/OE with rescue, ROS measurements, and xenograft models in HCC and NSCLC","pmids":["41482143","41168408"],"confidence":"Medium","gaps":["Whether TMX1 redox activity is required for the FABP5 and ROS effects not separated from scaffolding","No structural validation of the interactions","Single lab each"]},{"year":null,"claim":"How TMX1 is trafficked among the ER lumen, MAM, and the cell surface, and which physiological substrates it acts on at each location, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking ER, MAM, and surface pools","Surface-targeting mechanism unknown","Comprehensive substrate map across compartments lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5,6,9]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,6,9]},{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,8]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]}],"complexes":["TMX1–calnexin complex","TCR–CD3 complex"],"partners":["CANX","CD3D","ERP46","ITGB3","FABP5","TRIM28","CCT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H3N1","full_name":"Thioredoxin-related transmembrane protein 1","aliases":["Protein disulfide-isomerase TMX1","Thioredoxin domain-containing protein 1","Transmembrane Trx-related protein"],"length_aa":280,"mass_kda":31.8,"function":"Thiredoxin domain-containing protein that participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyze dithiol-disulfide exchange reactions (PubMed:11152479, PubMed:37648867). Acts as a key inhibitor of the alternative triglyceride biosynthesis pathway by inhibiting the activity of TMEM68/DIESL at the endoplasmic reticulum, thereby restricting accumulation of triacylglycerol (PubMed:37648867). The alternative triglyceride biosynthesis pathway mediates formation of triacylglycerol from diacylglycerol and membrane phospholipids (PubMed:37648867). Acts as a protein disulfide isomerase by catalyzing formation or reduction of disulfide bonds (PubMed:22228764, PubMed:29932915). Specifically mediates formation of disulfide bonds of transmembrane proteins at the endoplasmic reticulum membrane (PubMed:22228764). Involved in endoplasmic reticulum-associated degradation (ERAD) via its protein disulfide isomerase activity by acting on folding-defective polypeptides at the endoplasmic reticulum membrane (PubMed:29932915). Acts as a negative regulator of platelet aggregation following secretion in the extracellular space (PubMed:30425049). Acts as a regulator of endoplasmic reticulum-mitochondria contact sites via its ability to regulate redox signals (PubMed:27502484, PubMed:31304984). Regulates endoplasmic reticulum-mitochondria Ca(2+) flux (PubMed:27502484)","subcellular_location":"Endoplasmic reticulum membrane; Mitochondrion membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/Q9H3N1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMX1","classification":"Not Classified","n_dependent_lines":95,"n_total_lines":1208,"dependency_fraction":0.07864238410596026},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":4.0},{"gene":"RAB11A","stoichiometry":4.0},{"gene":"ANKRD46","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"KRTCAP2","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"SEC61B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMX1","total_profiled":1310},"omim":[{"mim_id":"621380","title":"TRANSMEMBRANE PROTEIN 68; TMEM68","url":"https://www.omim.org/entry/621380"},{"mim_id":"610527","title":"THIOREDOXIN-RELATED TRANSMEMBRANE PROTEIN 1; TMX1","url":"https://www.omim.org/entry/610527"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMX1"},"hgnc":{"alias_symbol":["TMX","PDIA11"],"prev_symbol":["TXNDC","TXNDC1"]},"alphafold":{"accession":"Q9H3N1","domains":[{"cath_id":"3.40.30.10","chopping":"33-147","consensus_level":"high","plddt":94.1443,"start":33,"end":147},{"cath_id":"-","chopping":"149-207","consensus_level":"medium","plddt":93.0086,"start":149,"end":207}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H3N1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H3N1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H3N1-F1-predicted_aligned_error_v6.png","plddt_mean":76.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMX1","jax_strain_url":"https://www.jax.org/strain/search?query=TMX1"},"sequence":{"accession":"Q9H3N1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H3N1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H3N1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H3N1"}},"corpus_meta":[{"pmid":"22045338","id":"PMC_22045338","title":"Palmitoylated TMX and calnexin target to the mitochondria-associated membrane.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22045338","citation_count":196,"is_preprint":false},{"pmid":"27502484","id":"PMC_27502484","title":"TMX1 determines cancer cell metabolism as a thiol-based modulator of ER-mitochondria Ca2+ flux.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27502484","citation_count":129,"is_preprint":false},{"pmid":"23274958","id":"PMC_23274958","title":"Biodegradation of the neonicotinoid insecticide thiamethoxam by the nitrogen-fixing and plant-growth-promoting rhizobacterium Ensifer adhaerens strain TMX-23.","date":"2012","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/23274958","citation_count":71,"is_preprint":false},{"pmid":"32415712","id":"PMC_32415712","title":"Development of CDK2 and CDK5 Dual Degrader TMX-2172.","date":"2020","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/32415712","citation_count":63,"is_preprint":false},{"pmid":"30425049","id":"PMC_30425049","title":"The transmembrane protein disulfide isomerase TMX1 negatively regulates platelet responses.","date":"2018","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/30425049","citation_count":41,"is_preprint":false},{"pmid":"32878123","id":"PMC_32878123","title":"Thioredoxin-Related Transmembrane Proteins: TMX1 and Little Brothers TMX2, TMX3, TMX4 and TMX5.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32878123","citation_count":39,"is_preprint":false},{"pmid":"14871470","id":"PMC_14871470","title":"TMX, a human transmembrane oxidoreductase of the thioredoxin family: the possible role in disulfide-linked protein folding in the endoplasmic reticulum.","date":"2004","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/14871470","citation_count":38,"is_preprint":false},{"pmid":"28341495","id":"PMC_28341495","title":"A phase 2 study of TMX-101, intravesical imiquimod, for the treatment of carcinoma in situ bladder cancer.","date":"2016","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28341495","citation_count":34,"is_preprint":false},{"pmid":"23206424","id":"PMC_23206424","title":"Results of a phase 1 dose escalation study of intravesical TMX-101 in patients with nonmuscle invasive bladder cancer.","date":"2012","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/23206424","citation_count":32,"is_preprint":false},{"pmid":"35157166","id":"PMC_35157166","title":"Hyaluronic acid-coated chitosan nanoparticles as targeted-carrier of tamoxifen against MCF7 and TMX-resistant MCF7 cells.","date":"2022","source":"Journal of materials science. Materials in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35157166","citation_count":30,"is_preprint":false},{"pmid":"26246604","id":"PMC_26246604","title":"Division of labor among oxidoreductases: TMX1 preferentially acts on transmembrane polypeptides.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26246604","citation_count":24,"is_preprint":false},{"pmid":"33139042","id":"PMC_33139042","title":"An endophytic bacterial strain, Enterobacter cloacae TMX-6, enhances the degradation of thiamethoxam in rice plants.","date":"2020","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/33139042","citation_count":23,"is_preprint":false},{"pmid":"12035045","id":"PMC_12035045","title":"Tamoxifen (TMX)/Fas induced growth inhibition of human cholangiocarcinoma (HCC) by gamma interferon (IFN-gamma).","date":"2002","source":"Annals of 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pigs.","date":"2011","source":"BJU international","url":"https://pubmed.ncbi.nlm.nih.gov/21314886","citation_count":7,"is_preprint":false},{"pmid":"34075672","id":"PMC_34075672","title":"Copper stimulates neonicotinoid insecticide thiacloprid degradation by Ensifer adhaerens TMX-23.","date":"2021","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34075672","citation_count":6,"is_preprint":false},{"pmid":"29500135","id":"PMC_29500135","title":"Pharmacokinetics and pharmacodynamics of intravesical and intravenous TMX-101 and TMX-202 in a F344 rat model.","date":"2018","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29500135","citation_count":3,"is_preprint":false},{"pmid":"39247212","id":"PMC_39247212","title":"Transmembrane thiol isomerase TMX1 counterbalances the effect of ERp46 to inhibit platelet activation and integrin αIIbβ3 function.","date":"2024","source":"Research and practice in thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/39247212","citation_count":3,"is_preprint":false},{"pmid":"28847748","id":"PMC_28847748","title":"Estradiol (E2)- and tamoxifen (Tmx)-bound ER-alpha (ERα) interact differentially with histone deacetylases 1 and 3 (HDACs 1 and 3).","date":"2017","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28847748","citation_count":2,"is_preprint":false},{"pmid":"39386445","id":"PMC_39386445","title":"TMX1, a disulfide oxidoreductase, is necessary for T cell function through regulation of CD3ζ.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39386445","citation_count":1,"is_preprint":false},{"pmid":"41482143","id":"PMC_41482143","title":"TMX1 promotes the progression of hepatocellular carcinoma by inhibiting ferroptosis via stabilizing FABP5.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41482143","citation_count":0,"is_preprint":false},{"pmid":"41168408","id":"PMC_41168408","title":"CRISPR/Cas9 library screening uncovered CCT2 as a critical driver of acquired resistance to EGFR-targeted therapy by stabilizing TMX1 in non-small cell lung cancer.","date":"2025","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/41168408","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.25.690477","title":"“Eating to Survive… or not? feeding compensation and toxicity in a songbird exposed to thiamethoxam treated seeds”","date":"2025-11-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.25.690477","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16999,"output_tokens":3261,"usd":0.049956,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10795,"output_tokens":3787,"usd":0.074325,"stage2_stop_reason":"end_turn"},"total_usd":0.124281,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"TMX1 (TMX) is a transmembrane oxidoreductase localized to the ER membrane with its N-terminal thioredoxin-like domain (CPAC active site) facing the ER lumen; recombinant TMX showed PDI-like refolding activity on scrambled RNase in vitro.\",\n      \"method\": \"Subcellular fractionation, membrane topology analysis, in vitro refolding assay (scrambled RNase)\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro enzymatic assay and fractionation in single lab, no mutagenesis or structural validation\",\n      \"pmids\": [\"14871470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Palmitoylation of cysteine residue(s) adjacent to the transmembrane domain of TMX1 is required for its enrichment on the mitochondria-associated membrane (MAM); mutation of the palmitoylation site or chemical interference with palmitoylation disrupts MAM localization.\",\n      \"method\": \"Palmitoylation site mutagenesis, chemical inhibition of palmitoylation, subcellular fractionation/immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of palmitoylation site combined with chemical inhibitor, replicated across two ER oxidoreductases (TMX1 and calnexin), multiple orthogonal methods\",\n      \"pmids\": [\"22045338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMX1 forms functional complexes with the ER lectin calnexin and preferentially acts on cysteine-containing, membrane-anchored client proteins during folding, while ignoring the same cysteine-containing ectodomains when not membrane-tethered; TMX1 is the first topology-specific client protein redox catalyst in living cells.\",\n      \"method\": \"Co-immunoprecipitation (TMX1–calnexin complex), substrate specificity assays comparing membrane-anchored vs. soluble ectodomains, KD/KO with defined folding phenotype\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, multiple substrate pairs tested, topology-specificity demonstrated with two orthogonal methods in a single focused study\",\n      \"pmids\": [\"26246604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TMX1 regulates ER-to-mitochondria Ca²⁺ flux at the MAM; its thioredoxin (CPAC) motif and palmitoylation-dependent MAM targeting are both required for this function. Low TMX1 reduces ER-mitochondria contacts, decreases mitochondrial Ca²⁺ uptake, shifts bioenergetics away from mitochondria, and reduces apoptosis progression.\",\n      \"method\": \"TMX1 knockout/knockdown, CPAC active-site mutant, palmitoylation mutant; Ca²⁺ imaging, mitochondrial ATP measurements, ER-mitochondria contact site quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Ca²⁺ imaging, bioenergetics, contact site imaging), active-site and palmitoylation mutants tested, functional rescue experiments\",\n      \"pmids\": [\"27502484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TMX1 is reversibly oxidized in response to ER protein overload (brefeldin A-induced protein accumulation); oxidation precedes the classical ER stress marker BiP induction, and glutathione is involved in maintaining TMX1 in its reduced (basal) state.\",\n      \"method\": \"Redox state analysis (alkylation-based trapping), BFA treatment and washout, glutathione depletion experiments\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — redox trapping with pharmacological perturbation, single lab, two complementary approaches but no mutagenesis\",\n      \"pmids\": [\"29123984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMX1 acts as a topology-specific reductase in ERAD, preferentially reducing disulfide bonds of membrane-tethered misfolded polypeptides to facilitate their dislocation, while ignoring the same misfolded ectodomains when soluble.\",\n      \"method\": \"ERAD substrate degradation assays, membrane-anchored vs. soluble substrate comparisons, TMX1 knockdown with defined ERAD phenotype\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — extends and replicates the topology-specificity principle from PMID 26246604 into the ERAD context, two substrate classes, single lab\",\n      \"pmids\": [\"29932915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMX1 is expressed on the platelet surface and acts as an oxidase toward the αIIbβ3 integrin; TMX1-deficient platelets have increased free thiols on the β3 subunit, and recombinant extracellular TMX1 inhibits platelet aggregation, ATP release, αIIbβ3 activation, and P-selectin expression, making it the first identified negative (inhibitory) extracellular thiol isomerase regulator of platelet function.\",\n      \"method\": \"TMX1 knockout mouse model, recombinant extracellular domain protein (rTMX1) addition, anti-TMX1 antibody, thiol-labeling of αIIbβ3, platelet aggregation and ATP release assays, FeCl3 mesenteric arterial injury thrombosis model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse, recombinant protein rescue, specific antibody, thiol labeling, in vivo thrombosis model; multiple orthogonal approaches in a single focused study\",\n      \"pmids\": [\"30425049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TMX1-deficient mice are highly susceptible to LPS/d-galactosamine-induced inflammatory liver injury, with enhanced p53-signaling pathway activation in the liver; TNF-α neutralization suppressed the toxic phenotype, indicating TMX1 protects against oxidative inflammatory damage downstream of TNF-α signaling.\",\n      \"method\": \"TMX1 knockout mouse model, LPS/GalN and thioacetamide liver injury models, liver transcriptional profiling, TNF-α neutralization\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined phenotypic readout and epistasis via TNF-α neutralization, single lab\",\n      \"pmids\": [\"22924822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMX1 directly engages the CxxC motif of CD3δ (a TCR complex subunit); loss of TMX1 decreases surface TCR expression and destabilizes CD3ζ, impairing TCR assembly and T cell cytotoxicity as well as NFAT, NFκB, and AP1 signaling. Overexpression of CD3ζ rescues the phenotype, indicating TMX1 is required for TCR assembly but not for CD3ζ function per se.\",\n      \"method\": \"APEX2 proximity labeling screen (CD8α bait), CRISPR TMX1 deletion, CD3ζ overexpression rescue, surface TCR expression assays, T cell signaling readouts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — proximity labeling plus KO with functional rescue in preprint; mechanistically specific but not yet peer-reviewed and single lab\",\n      \"pmids\": [\"39386445\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMX1 oxidizes ERp46 (inhibiting its reductase activity) and also re-oxidizes the αIIbβ3 disulfides that ERp46 reduces, thereby counterbalancing ERp46-mediated platelet activation; TMX1 deficiency increases free thiols on ERp46 in platelets, an effect reversed by addition of wild-type but not catalytically inactive TMX1.\",\n      \"method\": \"ERp46- and TMX1-deficient platelets, wild-type vs. inactive TMX1 protein addition, thiol labeling, reductase activity assays, platelet aggregation and clot retraction assays\",\n      \"journal\": \"Research and practice in thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual KO model, active-site mutant protein, thiol labeling and enzymatic assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39247212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMX1 binds FABP5 and competitively blocks interaction between FABP5 and the E3 ubiquitin ligase NEDD4, preventing K48-linked ubiquitination and degradation of FABP5, thereby enhancing FABP5-mediated inhibition of ferroptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (TMX1–FABP5 interaction), ubiquitination assays, TMX1 KD/OE with FABP5 KD rescue, in vivo xenograft model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and ubiquitination assay with rescue experiment, single lab, no structural validation\",\n      \"pmids\": [\"41482143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCT2 recruits TRIM28 to catalyze SUMO2 modification of TMX1, which inhibits TMX1 ubiquitination and stabilizes the protein; this stabilized TMX1 promotes ROS clearance, conferring resistance to third-generation EGFR tyrosine kinase inhibitors in NSCLC.\",\n      \"method\": \"CRISPR/Cas9 genome-wide screen, TMT proteomics, SUMO2 modification assays, ubiquitination assays, TMX1 KD with ROS measurements, xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics discovery plus biochemical validation of PTM axis (SUMOylation inhibiting ubiquitination), single lab\",\n      \"pmids\": [\"41168408\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMX1 is a transmembrane ER oxidoreductase (thioredoxin CPAC active site, ER-luminal domain) that is palmitoylated on cysteines adjacent to its transmembrane domain, directing it to the mitochondria-associated membrane (MAM), where it acts as a thiol-based modulator of ER-to-mitochondria Ca²⁺ flux and mitochondrial bioenergetics; within the ER it forms a complex with calnexin to preferentially reduce disulfide bonds of membrane-anchored client proteins during both productive folding and ERAD (topology-specific redox catalysis); on the platelet surface TMX1 oxidizes the αIIbβ3 integrin and ERp46 to negatively regulate platelet activation; in T cells it engages the CxxC motif of CD3δ to support TCR complex assembly; its redox state is reversibly controlled by ER protein load and glutathione; and its stability is post-translationally regulated by SUMO2 modification (via CCT2/TRIM28) that blocks ubiquitin-mediated degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMX1 is a transmembrane ER oxidoreductase whose N-terminal thioredoxin-like domain (CPAC active site) faces the ER lumen and possesses PDI-like disulfide-isomerase activity in vitro [#0]. Palmitoylation of cysteines adjacent to its transmembrane domain targets a pool of TMX1 to the mitochondria-associated membrane (MAM), where both this lipid modification and the CPAC redox motif are required for TMX1 to sustain ER-to-mitochondria Ca²⁺ flux, mitochondrial Ca²⁺ uptake, and bioenergetic coupling, thereby promoting apoptotic progression [#1, #3]. Within the ER, TMX1 partners with the lectin calnexin and acts as a topology-specific redox catalyst, preferentially engaging the disulfide bonds of membrane-anchored client proteins while ignoring identical soluble ectodomains, a selectivity that operates both in productive folding and in the reductive dislocation of misfolded substrates during ERAD [#2, #5]. Its catalytic redox state is dynamic, becoming reversibly oxidized upon ER protein overload ahead of canonical stress markers and held reduced at baseline through glutathione [#4]. Beyond the ER, TMX1 functions at the cell surface: it acts as an oxidase that re-oxidizes the αIIbβ3 integrin and inhibits ERp46, counterbalancing ERp46-driven platelet activation and thereby negatively regulating platelet aggregation and thrombosis [#6, #9]. TMX1 also protects against TNF-α-driven inflammatory liver injury [#7], and its abundance is post-translationally controlled by a CCT2/TRIM28-catalyzed SUMO2 modification that blocks ubiquitin-mediated degradation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that TMX1 is a thioredoxin-family enzyme rather than an inert membrane protein answered whether it carries genuine redox catalytic activity and where it resides.\",\n      \"evidence\": \"Subcellular fractionation, membrane topology mapping, and in vitro refolding of scrambled RNase by recombinant TMX\",\n      \"pmids\": [\"14871470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis confirming the CPAC residues drive activity\", \"No identification of physiological substrates\", \"In vitro activity not linked to a cellular process\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying palmitoylation as the targeting signal explained how a single ER oxidoreductase is partitioned to the MAM, defining the structural basis for its later contact-site functions.\",\n      \"evidence\": \"Palmitoylation-site mutagenesis and chemical inhibition with fractionation/immunofluorescence, paralleled in calnexin\",\n      \"pmids\": [\"22045338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish what TMX1 does at the MAM\", \"Palmitoyltransferase responsible not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A knockout mouse showed TMX1 has a protective physiological role in vivo, linking its redox function to suppression of inflammatory tissue damage.\",\n      \"evidence\": \"TMX1-knockout mice in LPS/GalN and thioacetamide liver injury models with TNF-α neutralization epistasis\",\n      \"pmids\": [\"22924822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate mediating protection unknown\", \"Connection to ER/MAM redox catalysis not established\", \"p53 activation correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining TMX1 as a topology-specific catalyst acting on membrane-anchored clients in complex with calnexin answered how the enzyme achieves substrate selectivity in living cells.\",\n      \"evidence\": \"Reciprocal Co-IP of TMX1–calnexin and substrate assays comparing membrane-anchored versus soluble ectodomains\",\n      \"pmids\": [\"26246604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of topology discrimination unresolved\", \"Full client repertoire not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Functional dissection at the MAM established TMX1 as a thiol-based regulator of ER-mitochondria Ca²⁺ transfer and bioenergetics, tying its redox motif and palmitoylation to organelle communication and apoptosis.\",\n      \"evidence\": \"TMX1 KO/KD with CPAC and palmitoylation mutants, Ca²⁺ imaging, mitochondrial ATP measurement, and contact-site quantification\",\n      \"pmids\": [\"27502484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct redox substrate at the MAM controlling Ca²⁺ flux not identified\", \"Mechanism linking TMX1 redox state to contact-site formation unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing TMX1 oxidation precedes BiP induction positioned its redox state as an early sensor of ER protein load buffered by glutathione.\",\n      \"evidence\": \"Alkylation-based redox trapping with brefeldin A treatment/washout and glutathione depletion\",\n      \"pmids\": [\"29123984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis of the responsive cysteines\", \"Downstream consequences of oxidation not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extending topology-specific reduction into ERAD answered whether TMX1's selectivity principle operates in protein degradation as well as folding.\",\n      \"evidence\": \"ERAD substrate degradation assays comparing membrane-tethered versus soluble misfolded polypeptides under TMX1 knockdown\",\n      \"pmids\": [\"29932915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Coupling between disulfide reduction and dislocation machinery not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying surface TMX1 as an oxidase of αIIbβ3 revealed an unexpected extracellular, anti-thrombotic role, the first inhibitory thiol isomerase regulator of platelets.\",\n      \"evidence\": \"TMX1 KO mouse, recombinant extracellular domain, anti-TMX1 antibody, β3 thiol labeling, aggregation/ATP-release assays, and FeCl3 thrombosis model\",\n      \"pmids\": [\"30425049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an ER oxidoreductase reaches the platelet surface unclear\", \"Full set of surface substrates not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining TMX1's interplay with ERp46 explained how opposing thiol enzymes set platelet integrin activation thresholds.\",\n      \"evidence\": \"ERp46- and TMX1-deficient platelets, wild-type versus catalytically inactive TMX1 protein, thiol labeling, reductase assays, aggregation and clot retraction\",\n      \"pmids\": [\"39247212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of TMX1/ERp46 regulation in vivo unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A proximity-labeling screen placed TMX1 at the TCR, showing it engages the CD3δ CxxC motif to support receptor assembly and T cell signaling.\",\n      \"evidence\": \"APEX2 proximity labeling with CD8α bait, CRISPR TMX1 deletion, CD3ζ overexpression rescue, surface TCR and signaling readouts (preprint)\",\n      \"pmids\": [\"39386445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not peer-reviewed and single lab\", \"Direct redox chemistry on CD3δ not demonstrated\", \"Generality across T cell subsets untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery of TMX1 binding FABP5 and a CCT2/TRIM28 SUMO2 axis revealed how TMX1 abundance is post-translationally controlled and links it to ferroptosis resistance and drug tolerance in cancer.\",\n      \"evidence\": \"Co-IP, ubiquitination/SUMOylation assays, KD/OE with rescue, ROS measurements, and xenograft models in HCC and NSCLC\",\n      \"pmids\": [\"41482143\", \"41168408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TMX1 redox activity is required for the FABP5 and ROS effects not separated from scaffolding\", \"No structural validation of the interactions\", \"Single lab each\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMX1 is trafficked among the ER lumen, MAM, and the cell surface, and which physiological substrates it acts on at each location, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking ER, MAM, and surface pools\", \"Surface-targeting mechanism unknown\", \"Comprehensive substrate map across compartments lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5, 6, 9]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 6, 9]},\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"TMX1–calnexin complex\", \"TCR–CD3 complex\"],\n    \"partners\": [\"CANX\", \"CD3D\", \"ERP46\", \"ITGB3\", \"FABP5\", \"TRIM28\", \"CCT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}