{"gene":"TXNDC11","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2004,"finding":"TXNDC11 (EFP1) was identified as a binding partner of Duox1/Duox2 (thyroid oxidase) proteins via yeast two-hybrid screening using the EF-hand fragment of dog Duox1 as bait. EFP1 belongs to the thioredoxin-related protein family with conserved active site and folding structures. Co-immunoprecipitation confirmed interaction in transfected COS cells and primary human thyrocytes. EFP1 also interacts with TPO but not thyroglobulin. Immunofluorescence showed co-localization of EFP1 and Duox inside transfected cells. EFP1 was not sufficient to induce Duox plasma membrane expression or H2O2 production.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in two cell systems (COS cells and primary thyrocytes) plus yeast two-hybrid, single lab","pmids":["15561711"],"is_preprint":false},{"year":2016,"finding":"TXNDC11 was identified through parallel genome-wide CRISPR/Cas9 and haploid gene-trap forward genetic screens as required for ERAD of MHC class I molecules. The gene encodes an EDEM2/3-associated disulfide reductase functioning in the canonical glycoprotein ERAD pathway.","method":"Genome-wide CRISPR/Cas9 forward genetic screen, haploid gene-trap mutagenesis screen","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent genome-wide genetic screens with >70% concordance, but mechanistic characterization is limited to the brief description of disulfide reductase activity without in vitro reconstitution","pmids":["27283361"],"is_preprint":false},{"year":2018,"finding":"TXNDC11 associates with EDEM1 and EDEM2 and enhances their mannosidase activity on glycoprotein substrates (but not on free N-glycans). The EDEMs associate with oxidoreductases including protein disulfide isomerase and especially TXNDC11 to enhance glycoprotein mannosidase activity, which is further stimulated when the substrate glycoprotein is in an unfolded/denatured state.","method":"In vitro mannosidase activity assay, co-immunoprecipitation, denatured vs. native glycoprotein substrate comparison","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with denatured substrates, single lab, multiple orthogonal conditions tested","pmids":["30374462"],"is_preprint":false},{"year":2020,"finding":"EDEM2 forms a stable disulfide bond with TXNDC11 via C558 on EDEM2 (outside the mannosidase homology domain) linked to C692 in the Trx5 domain of TXNDC11 (the sole CXXC motif-containing domain). This covalent disulfide bond is essential for EDEM2 mannosidase activity (Man9GlcNAc2 → Man8GlcNAc2 isomer B) and subsequent gpERAD in HCT116 cells. The purified EDEM2-TXNDC11 complex exhibited α1,2-mannosidase activity in vitro, converting Man9 to Man8B.","method":"Gene knockout (HCT116 cells), site-directed mutagenesis of cysteine residues, purification of EDEM2-TXNDC11 complex from transfected cells, in vitro mannosidase activity assay with pyridylamine-labeled substrates","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified complex, mutagenesis identifying specific disulfide-bonded cysteines, KO cell validation, multiple orthogonal methods in a single rigorous study","pmids":["32065582"],"is_preprint":false},{"year":2021,"finding":"EDEM2 stably disulfide-bonded to TXNDC11 is responsible for the first step of sequential N-glycan mannose trimming (M9→M8B) in gpERAD; EDEM3 and EDEM1 are responsible for the subsequent step (M8B→M7/M6/M5). This places TXNDC11-EDEM2 complex as the initiator of the gpERAD oligosaccharide processing route.","method":"Genetic epistasis via gene knockout, in vitro mannosidase assay with purified proteins, pyridylamine-labeled oligosaccharide substrates","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified proteins, pathway placement by KO epistasis, replicates and extends findings from prior study by same group","pmids":["34698634"],"is_preprint":false},{"year":2022,"finding":"TXNDC11 is an ER stress-inducible gene regulated by the IRE1-sXBP1 pathway: its promoter contains a functional unfolded protein response element (UPRE), and ER stress increases TXNDC11 mRNA and luciferase reporter activity via this UPRE. TXNDC11 deficiency in HEK293 cells increased full-length protein levels and delayed degradation of ER-resident stress sensors ATF6α, CREB3, and CREB3L2, indicating TXNDC11 promotes their turnover.","method":"RT-PCR, Western blot, luciferase reporter assay with UPRE, cycloheximide chase in TXNDC11-deficient vs. wild-type HEK293 cells","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with defined phenotypic readout (protein stability), reporter assay confirming UPRE functionality, multiple orthogonal methods, single lab","pmids":["36152228"],"is_preprint":false},{"year":2026,"finding":"TXNDC11 deficiency (unlike SEL1L or Hrd1 deficiency) did not increase NFE2L1 protein expression in HEK293 cells, indicating TXNDC11-mediated ERAD is not required for NFE2L1 degradation, in contrast to CREB3/ATF6 family members whose stability is regulated by TXNDC11.","method":"ERAD-deficient HEK293 cell lines, Western blot, proteasome inhibitor treatments","journal":"Biological & pharmaceutical bulletin","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (Western blot), negative finding for NFE2L1 but informative for substrate specificity","pmids":["41656087"],"is_preprint":false},{"year":2026,"finding":"LOX protein was not increased in EDEM2- or TXNDC11-deficient HEK293 cells (in contrast to SEL1L- or Hrd1-deficient cells), indicating that the EDEM2-TXNDC11 mannose trimming arm of ERAD is not required for LOX protein regulation.","method":"ERAD-deficient HEK293 cell lines (EDEM2 KO, TXNDC11 KO), Western blot, comparison with SEL1L/Hrd1 KO","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method, negative finding informative for substrate specificity of TXNDC11-EDEM2 complex","pmids":["41518417"],"is_preprint":false}],"current_model":"TXNDC11 is an ER-resident, thioredoxin domain-containing protein that forms a stable disulfide bond between its Trx5 domain (C692) and EDEM2 (C558), constituting the EDEM2-TXNDC11 complex that catalyzes the first step of N-glycan mannose trimming (Man9GlcNAc2 → Man8GlcNAc2 isomer B) required to initiate glycoprotein ERAD; its expression is induced by ER stress via the IRE1-sXBP1/UPRE pathway, it interacts with Duox proteins in thyroid tissue, and it promotes the turnover of ER-resident transcription factors ATF6α, CREB3, and CREB3L2, though its ERAD activity is substrate-selective."},"narrative":{"mechanistic_narrative":"TXNDC11 is an ER-resident, thioredoxin domain-containing protein that initiates the N-glycan mannose-trimming step required to commit misfolded glycoproteins to ER-associated degradation (ERAD) [PMID:27283361, PMID:34698634]. It functions as an obligate partner of the mannosidase EDEM2, forming a stable intermolecular disulfide bond between C692 in its Trx5 domain (its sole CXXC-containing domain) and C558 of EDEM2; this covalent linkage is essential for the complex's α1,2-mannosidase activity, which converts Man9GlcNAc2 to the Man8GlcNAc2 isomer B [PMID:32065582]. The purified EDEM2-TXNDC11 complex catalyzes this first trimming step, while subsequent trimming is carried out by EDEM3 and EDEM1, placing the TXNDC11-EDEM2 complex at the entry point of the gpERAD oligosaccharide-processing route [PMID:34698634]; TXNDC11 also associates with and stimulates the glycoprotein mannosidase activity of EDEM1 and EDEM2, particularly toward unfolded substrates [PMID:30374462]. TXNDC11 is itself an ER stress-inducible gene, transcriptionally upregulated through a functional UPRE in its promoter via the IRE1-sXBP1 pathway, and it promotes turnover of the ER-resident transcription factors ATF6α, CREB3, and CREB3L2, with substrate selectivity that excludes NFE2L1 and LOX [PMID:36152228, PMID:41656087, PMID:41518417]. An earlier identification described TXNDC11 (EFP1) as a thioredoxin-related interactor of the thyroid oxidases Duox1/Duox2 and TPO in thyrocytes [PMID:15561711].","teleology":[{"year":2004,"claim":"Before any ERAD role was known, the question was what protein TXNDC11 (EFP1) physically engages; identifying it as a thioredoxin-related binding partner of thyroid oxidases established it as a redox-active interactor in the ER/thyroid context.","evidence":"Yeast two-hybrid with Duox1 EF-hand bait, reciprocal Co-IP in COS cells and primary thyrocytes, immunofluorescence co-localization","pmids":["15561711"],"confidence":"Medium","gaps":["No catalytic activity or redox mechanism demonstrated","Functional consequence of Duox/TPO binding not established","ER glycoprotein role not yet recognized"]},{"year":2016,"claim":"Unbiased forward genetics asked which genes are required for glycoprotein ERAD and identified TXNDC11 as an EDEM2/3-associated factor needed to degrade MHC class I, linking it to the canonical gpERAD pathway.","evidence":"Parallel genome-wide CRISPR/Cas9 and haploid gene-trap screens for ERAD of MHC class I","pmids":["27283361"],"confidence":"Medium","gaps":["Disulfide reductase activity asserted but not reconstituted in vitro","Direct biochemical partnership with EDEM2 not yet mapped","Substrate scope undefined"]},{"year":2018,"claim":"To define what TXNDC11 contributes biochemically, this work showed it associates with EDEM1/EDEM2 and enhances their mannosidase activity on glycoprotein (not free-glycan) substrates, identifying it as a functional oxidoreductase cofactor of the EDEMs.","evidence":"In vitro mannosidase assays with native vs. denatured glycoprotein substrates, Co-IP","pmids":["30374462"],"confidence":"Medium","gaps":["The molecular nature of the EDEM-TXNDC11 linkage not resolved","Specific cysteines and bond not identified","Step in the trimming cascade not assigned"]},{"year":2020,"claim":"The mechanistic basis of the partnership was resolved by showing a stable intermolecular disulfide bond (EDEM2 C558–TXNDC11 Trx5 C692) is required for mannosidase activity, converting an associative cofactor model into a defined covalent catalytic complex.","evidence":"HCT116 knockouts, cysteine site-directed mutagenesis, purification of the EDEM2-TXNDC11 complex, in vitro α1,2-mannosidase assay with pyridylamine-labeled substrates","pmids":["32065582"],"confidence":"High","gaps":["Mechanism by which the disulfide bond activates EDEM2 catalysis not structurally defined","Whether TXNDC11 redox chemistry actively forms/maintains the bond not shown"]},{"year":2021,"claim":"To place the complex in the pathway, epistasis showed EDEM2-TXNDC11 performs the first trimming step (M9→M8B) while EDEM3/EDEM1 act subsequently, identifying TXNDC11 as the initiator of the gpERAD oligosaccharide route.","evidence":"Knockout epistasis and in vitro mannosidase assays with purified proteins and pyridylamine-labeled oligosaccharides","pmids":["34698634"],"confidence":"High","gaps":["Determinants of substrate selection at the first step unknown","How trimming output is handed to downstream lectins/ERAD machinery not addressed"]},{"year":2022,"claim":"This work asked how TXNDC11 is regulated and what it degrades, showing it is an IRE1-sXBP1/UPRE-induced gene that promotes turnover of ER-resident transcription factors ATF6α, CREB3, and CREB3L2, embedding it in UPR feedback.","evidence":"RT-PCR, Western blot, UPRE luciferase reporter, cycloheximide chase in TXNDC11-deficient vs. WT HEK293 cells","pmids":["36152228"],"confidence":"Medium","gaps":["Whether these substrates are degraded via the EDEM2 mannose-trimming arm specifically not separated","Direct physical engagement with the transcription factors not shown"]},{"year":2026,"claim":"To test the breadth of TXNDC11-dependent ERAD, two studies showed NFE2L1 and LOX are NOT stabilized by TXNDC11 (or EDEM2) loss, unlike SEL1L/Hrd1 loss, establishing that the EDEM2-TXNDC11 arm is substrate-selective rather than a general ERAD requirement.","evidence":"Western blot of NFE2L1 and LOX in TXNDC11/EDEM2 KO vs. SEL1L/Hrd1 KO HEK293 cells with proteasome inhibitor controls","pmids":["41656087","41518417"],"confidence":"Low","gaps":["Single-method (Western blot) negative findings without orthogonal confirmation","Rules governing which substrates require the mannose-trimming arm undefined","Mechanistic basis of selectivity not addressed"]},{"year":null,"claim":"How TXNDC11's thioredoxin/CXXC redox chemistry mechanistically activates EDEM2 mannosidase catalysis, what determines substrate selectivity of the trimming arm, and how its earlier Duox/TPO association relates to its ERAD function remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the EDEM2-TXNDC11 complex","Catalytic redox cycle of TXNDC11 not demonstrated","Connection between thyroid oxidase binding and gpERAD role unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[2,3,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5]}],"complexes":["EDEM2-TXNDC11 complex"],"partners":["EDEM2","EDEM1","DUOX1","DUOX2","TPO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PKC3","full_name":"Thioredoxin domain-containing protein 11","aliases":["EF-hand-binding protein 1"],"length_aa":985,"mass_kda":110.5,"function":"May act as a redox regulator involved in DUOX proteins folding. The interaction with DUOX1 and DUOX2 suggest that it belongs to a multiprotein complex constituting the thyroid H(2)O(2) generating system. It is however not sufficient to assist DUOX1 and DUOX2 in H(2)O(2) generation","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6PKC3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TXNDC11","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":[],"url":"https://opencell.sf.czbiohub.org/search/TXNDC11","total_profiled":1310},"omim":[{"mim_id":"617792","title":"THIOREDOXIN DOMAIN-CONTAINING PROTEIN 11; TXNDC11","url":"https://www.omim.org/entry/617792"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TXNDC11"},"hgnc":{"alias_symbol":["EFP1"],"prev_symbol":[]},"alphafold":{"accession":"Q6PKC3","domains":[{"cath_id":"3.40.30.10","chopping":"97-215","consensus_level":"medium","plddt":92.6541,"start":97,"end":215},{"cath_id":"3.40.30.10","chopping":"219-255_289-354","consensus_level":"medium","plddt":84.6953,"start":219,"end":354},{"cath_id":"3.40.30.10","chopping":"357-410_598-678","consensus_level":"medium","plddt":86.245,"start":357,"end":678},{"cath_id":"-","chopping":"451-478_494-541","consensus_level":"high","plddt":55.9026,"start":451,"end":541},{"cath_id":"3.40.30.10","chopping":"694-786","consensus_level":"high","plddt":87.7878,"start":694,"end":786},{"cath_id":"1.20.5","chopping":"819-905","consensus_level":"high","plddt":89.6359,"start":819,"end":905}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PKC3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PKC3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PKC3-F1-predicted_aligned_error_v6.png","plddt_mean":70.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TXNDC11","jax_strain_url":"https://www.jax.org/strain/search?query=TXNDC11"},"sequence":{"accession":"Q6PKC3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PKC3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PKC3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PKC3"}},"corpus_meta":[{"pmid":"7961976","id":"PMC_7961976","title":"Characterization of the regulatory elements in the promoter of the human elongation factor-1 alpha gene.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7961976","citation_count":67,"is_preprint":false},{"pmid":"15561711","id":"PMC_15561711","title":"Identification of a novel partner of duox: EFP1, a thioredoxin-related protein.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15561711","citation_count":59,"is_preprint":false},{"pmid":"27283361","id":"PMC_27283361","title":"Genetic dissection of mammalian ERAD through comparative haploid and CRISPR forward genetic screens.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27283361","citation_count":58,"is_preprint":false},{"pmid":"30374462","id":"PMC_30374462","title":"Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates.","date":"2018","source":"Communications 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EFP1 belongs to the thioredoxin-related protein family with conserved active site and folding structures. Co-immunoprecipitation confirmed interaction in transfected COS cells and primary human thyrocytes. EFP1 also interacts with TPO but not thyroglobulin. Immunofluorescence showed co-localization of EFP1 and Duox inside transfected cells. EFP1 was not sufficient to induce Duox plasma membrane expression or H2O2 production.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence co-localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP in two cell systems (COS cells and primary thyrocytes) plus yeast two-hybrid, single lab\",\n      \"pmids\": [\"15561711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TXNDC11 was identified through parallel genome-wide CRISPR/Cas9 and haploid gene-trap forward genetic screens as required for ERAD of MHC class I molecules. The gene encodes an EDEM2/3-associated disulfide reductase functioning in the canonical glycoprotein ERAD pathway.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 forward genetic screen, haploid gene-trap mutagenesis screen\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent genome-wide genetic screens with >70% concordance, but mechanistic characterization is limited to the brief description of disulfide reductase activity without in vitro reconstitution\",\n      \"pmids\": [\"27283361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TXNDC11 associates with EDEM1 and EDEM2 and enhances their mannosidase activity on glycoprotein substrates (but not on free N-glycans). The EDEMs associate with oxidoreductases including protein disulfide isomerase and especially TXNDC11 to enhance glycoprotein mannosidase activity, which is further stimulated when the substrate glycoprotein is in an unfolded/denatured state.\",\n      \"method\": \"In vitro mannosidase activity assay, co-immunoprecipitation, denatured vs. native glycoprotein substrate comparison\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with denatured substrates, single lab, multiple orthogonal conditions tested\",\n      \"pmids\": [\"30374462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EDEM2 forms a stable disulfide bond with TXNDC11 via C558 on EDEM2 (outside the mannosidase homology domain) linked to C692 in the Trx5 domain of TXNDC11 (the sole CXXC motif-containing domain). This covalent disulfide bond is essential for EDEM2 mannosidase activity (Man9GlcNAc2 → Man8GlcNAc2 isomer B) and subsequent gpERAD in HCT116 cells. The purified EDEM2-TXNDC11 complex exhibited α1,2-mannosidase activity in vitro, converting Man9 to Man8B.\",\n      \"method\": \"Gene knockout (HCT116 cells), site-directed mutagenesis of cysteine residues, purification of EDEM2-TXNDC11 complex from transfected cells, in vitro mannosidase activity assay with pyridylamine-labeled substrates\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified complex, mutagenesis identifying specific disulfide-bonded cysteines, KO cell validation, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32065582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EDEM2 stably disulfide-bonded to TXNDC11 is responsible for the first step of sequential N-glycan mannose trimming (M9→M8B) in gpERAD; EDEM3 and EDEM1 are responsible for the subsequent step (M8B→M7/M6/M5). This places TXNDC11-EDEM2 complex as the initiator of the gpERAD oligosaccharide processing route.\",\n      \"method\": \"Genetic epistasis via gene knockout, in vitro mannosidase assay with purified proteins, pyridylamine-labeled oligosaccharide substrates\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified proteins, pathway placement by KO epistasis, replicates and extends findings from prior study by same group\",\n      \"pmids\": [\"34698634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TXNDC11 is an ER stress-inducible gene regulated by the IRE1-sXBP1 pathway: its promoter contains a functional unfolded protein response element (UPRE), and ER stress increases TXNDC11 mRNA and luciferase reporter activity via this UPRE. TXNDC11 deficiency in HEK293 cells increased full-length protein levels and delayed degradation of ER-resident stress sensors ATF6α, CREB3, and CREB3L2, indicating TXNDC11 promotes their turnover.\",\n      \"method\": \"RT-PCR, Western blot, luciferase reporter assay with UPRE, cycloheximide chase in TXNDC11-deficient vs. wild-type HEK293 cells\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with defined phenotypic readout (protein stability), reporter assay confirming UPRE functionality, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36152228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TXNDC11 deficiency (unlike SEL1L or Hrd1 deficiency) did not increase NFE2L1 protein expression in HEK293 cells, indicating TXNDC11-mediated ERAD is not required for NFE2L1 degradation, in contrast to CREB3/ATF6 family members whose stability is regulated by TXNDC11.\",\n      \"method\": \"ERAD-deficient HEK293 cell lines, Western blot, proteasome inhibitor treatments\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (Western blot), negative finding for NFE2L1 but informative for substrate specificity\",\n      \"pmids\": [\"41656087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LOX protein was not increased in EDEM2- or TXNDC11-deficient HEK293 cells (in contrast to SEL1L- or Hrd1-deficient cells), indicating that the EDEM2-TXNDC11 mannose trimming arm of ERAD is not required for LOX protein regulation.\",\n      \"method\": \"ERAD-deficient HEK293 cell lines (EDEM2 KO, TXNDC11 KO), Western blot, comparison with SEL1L/Hrd1 KO\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method, negative finding informative for substrate specificity of TXNDC11-EDEM2 complex\",\n      \"pmids\": [\"41518417\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TXNDC11 is an ER-resident, thioredoxin domain-containing protein that forms a stable disulfide bond between its Trx5 domain (C692) and EDEM2 (C558), constituting the EDEM2-TXNDC11 complex that catalyzes the first step of N-glycan mannose trimming (Man9GlcNAc2 → Man8GlcNAc2 isomer B) required to initiate glycoprotein ERAD; its expression is induced by ER stress via the IRE1-sXBP1/UPRE pathway, it interacts with Duox proteins in thyroid tissue, and it promotes the turnover of ER-resident transcription factors ATF6α, CREB3, and CREB3L2, though its ERAD activity is substrate-selective.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TXNDC11 is an ER-resident, thioredoxin domain-containing protein that initiates the N-glycan mannose-trimming step required to commit misfolded glycoproteins to ER-associated degradation (ERAD) [#1, #4]. It functions as an obligate partner of the mannosidase EDEM2, forming a stable intermolecular disulfide bond between C692 in its Trx5 domain (its sole CXXC-containing domain) and C558 of EDEM2; this covalent linkage is essential for the complex's α1,2-mannosidase activity, which converts Man9GlcNAc2 to the Man8GlcNAc2 isomer B [#3]. The purified EDEM2-TXNDC11 complex catalyzes this first trimming step, while subsequent trimming is carried out by EDEM3 and EDEM1, placing the TXNDC11-EDEM2 complex at the entry point of the gpERAD oligosaccharide-processing route [#4]; TXNDC11 also associates with and stimulates the glycoprotein mannosidase activity of EDEM1 and EDEM2, particularly toward unfolded substrates [#2]. TXNDC11 is itself an ER stress-inducible gene, transcriptionally upregulated through a functional UPRE in its promoter via the IRE1-sXBP1 pathway, and it promotes turnover of the ER-resident transcription factors ATF6α, CREB3, and CREB3L2, with substrate selectivity that excludes NFE2L1 and LOX [#5, #6, #7]. An earlier identification described TXNDC11 (EFP1) as a thioredoxin-related interactor of the thyroid oxidases Duox1/Duox2 and TPO in thyrocytes [#0].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Before any ERAD role was known, the question was what protein TXNDC11 (EFP1) physically engages; identifying it as a thioredoxin-related binding partner of thyroid oxidases established it as a redox-active interactor in the ER/thyroid context.\",\n      \"evidence\": \"Yeast two-hybrid with Duox1 EF-hand bait, reciprocal Co-IP in COS cells and primary thyrocytes, immunofluorescence co-localization\",\n      \"pmids\": [\"15561711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic activity or redox mechanism demonstrated\", \"Functional consequence of Duox/TPO binding not established\", \"ER glycoprotein role not yet recognized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Unbiased forward genetics asked which genes are required for glycoprotein ERAD and identified TXNDC11 as an EDEM2/3-associated factor needed to degrade MHC class I, linking it to the canonical gpERAD pathway.\",\n      \"evidence\": \"Parallel genome-wide CRISPR/Cas9 and haploid gene-trap screens for ERAD of MHC class I\",\n      \"pmids\": [\"27283361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Disulfide reductase activity asserted but not reconstituted in vitro\", \"Direct biochemical partnership with EDEM2 not yet mapped\", \"Substrate scope undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"To define what TXNDC11 contributes biochemically, this work showed it associates with EDEM1/EDEM2 and enhances their mannosidase activity on glycoprotein (not free-glycan) substrates, identifying it as a functional oxidoreductase cofactor of the EDEMs.\",\n      \"evidence\": \"In vitro mannosidase assays with native vs. denatured glycoprotein substrates, Co-IP\",\n      \"pmids\": [\"30374462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The molecular nature of the EDEM-TXNDC11 linkage not resolved\", \"Specific cysteines and bond not identified\", \"Step in the trimming cascade not assigned\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The mechanistic basis of the partnership was resolved by showing a stable intermolecular disulfide bond (EDEM2 C558–TXNDC11 Trx5 C692) is required for mannosidase activity, converting an associative cofactor model into a defined covalent catalytic complex.\",\n      \"evidence\": \"HCT116 knockouts, cysteine site-directed mutagenesis, purification of the EDEM2-TXNDC11 complex, in vitro α1,2-mannosidase assay with pyridylamine-labeled substrates\",\n      \"pmids\": [\"32065582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the disulfide bond activates EDEM2 catalysis not structurally defined\", \"Whether TXNDC11 redox chemistry actively forms/maintains the bond not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"To place the complex in the pathway, epistasis showed EDEM2-TXNDC11 performs the first trimming step (M9→M8B) while EDEM3/EDEM1 act subsequently, identifying TXNDC11 as the initiator of the gpERAD oligosaccharide route.\",\n      \"evidence\": \"Knockout epistasis and in vitro mannosidase assays with purified proteins and pyridylamine-labeled oligosaccharides\",\n      \"pmids\": [\"34698634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of substrate selection at the first step unknown\", \"How trimming output is handed to downstream lectins/ERAD machinery not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"This work asked how TXNDC11 is regulated and what it degrades, showing it is an IRE1-sXBP1/UPRE-induced gene that promotes turnover of ER-resident transcription factors ATF6α, CREB3, and CREB3L2, embedding it in UPR feedback.\",\n      \"evidence\": \"RT-PCR, Western blot, UPRE luciferase reporter, cycloheximide chase in TXNDC11-deficient vs. WT HEK293 cells\",\n      \"pmids\": [\"36152228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these substrates are degraded via the EDEM2 mannose-trimming arm specifically not separated\", \"Direct physical engagement with the transcription factors not shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"To test the breadth of TXNDC11-dependent ERAD, two studies showed NFE2L1 and LOX are NOT stabilized by TXNDC11 (or EDEM2) loss, unlike SEL1L/Hrd1 loss, establishing that the EDEM2-TXNDC11 arm is substrate-selective rather than a general ERAD requirement.\",\n      \"evidence\": \"Western blot of NFE2L1 and LOX in TXNDC11/EDEM2 KO vs. SEL1L/Hrd1 KO HEK293 cells with proteasome inhibitor controls\",\n      \"pmids\": [\"41656087\", \"41518417\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method (Western blot) negative findings without orthogonal confirmation\", \"Rules governing which substrates require the mannose-trimming arm undefined\", \"Mechanistic basis of selectivity not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TXNDC11's thioredoxin/CXXC redox chemistry mechanistically activates EDEM2 mannosidase catalysis, what determines substrate selectivity of the trimming arm, and how its earlier Duox/TPO association relates to its ERAD function remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the EDEM2-TXNDC11 complex\", \"Catalytic redox cycle of TXNDC11 not demonstrated\", \"Connection between thyroid oxidase binding and gpERAD role unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"EDEM2-TXNDC11 complex\"],\n    \"partners\": [\"EDEM2\", \"EDEM1\", \"DUOX1\", \"DUOX2\", \"TPO\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}