{"gene":"TXNL1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1998,"finding":"TRP32 (TXNL1) was purified from human thymoma cells co-purifying with a catalytic fragment of MST kinase (a STE20 family kinase proteolytically activated by caspase). The protein contains an N-terminal thioredoxin domain with a conserved active site and exhibits thioredoxin-like reducing activity, capable of reducing interchain disulfide bridges of insulin in vitro. The thioredoxin domain of TRP32 is more sensitive to oxidation than human thioredoxin. Subcellular fractionation and immunostaining established cytoplasmic localization.","method":"Protein purification (co-purification), molecular cloning, in vitro insulin disulfide reduction assay, subcellular fractionation, immunostaining","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with direct biochemical purification and subcellular fractionation, replicated across multiple cell lines","pmids":["9668102"],"is_preprint":false},{"year":2009,"finding":"TXNL1/TRP32 binds to Rpn11, a subunit of the 19S regulatory complex of the human 26S proteasome, establishing it as a redox-active cofactor of the proteasome. TXNL1 has thioredoxin activity with a redox potential of approximately -250 mV. A Cys-to-Ser active site mutant of TXNL1 formed disulfide bonds with eEF1A1 (a substrate-recruiting factor of the 26S proteasome), identifying eEF1A1 as a likely physiological substrate. Knockdown of TXNL1 resulted in moderate stabilization of ubiquitin-protein conjugates.","method":"Co-purification with 26S proteasome, active-site mutagenesis (Cys-to-Ser), in vitro redox assay, siRNA knockdown with ubiquitin-conjugate accumulation readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical interaction with mutagenesis, redox potential measurement, and functional knockdown phenotype in single rigorous study","pmids":["19349277"],"is_preprint":false},{"year":2007,"finding":"TXNL1 is a component of a high-molecular-weight complex that includes p38MAPK, and plays a selective regulatory role in fluid-phase endocytosis by controlling GDI capacity to capture Rab5. TXNL1 is proposed to act as a redox sensor converting oxidative signals into changes in GDI-mediated Rab5 capture, thereby modulating fluid-phase endocytosis.","method":"Biochemical co-purification of a p38MAPK-containing complex, functional endocytosis assays, Rab5 capture assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-purification and functional endocytosis assays in single lab, mechanistic link between TXNL1 redox activity and GDI/Rab5 is proposed but not fully reconstituted","pmids":["17987124"],"is_preprint":false},{"year":2013,"finding":"TRP32 (TXNL1) specifically reduces oxidized PRL (phosphatase of regenerating liver) phosphatases. In vitro reduction assays showed that only TRP32, among tested TRX-related proteins, potently reduces oxidized PRL, while other thioredoxin-related proteins show little or no activity. The unique C-terminal domain of TRP32 is required and sufficient for direct interaction with PRL. TRP32 knockdown significantly prolongs H2O2-induced oxidation of PRL in cells.","method":"In vitro reduction assay, binding domain analysis with truncation mutants, siRNA knockdown with H2O2-induced PRL oxidation as readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstituted reduction assay, domain-mapping of interaction, and cellular knockdown validation with multiple orthogonal methods in single study","pmids":["23362275"],"is_preprint":false},{"year":2014,"finding":"TXNL1 downregulates XRCC1 (a base excision repair protein) via the ubiquitin-proteasome pathway, establishing a TXNL1-XRCC1 regulatory axis that contributes to cisplatin resistance in gastric cancer cells. TXNL1 was identified as a cofactor of the 26S proteasome in this context.","method":"Proteomic analysis, Western blotting, cisplatin resistance assays in sensitive vs. resistant gastric cancer cell lines","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteomic identification with functional cell-based validation, single lab, mechanism of ubiquitin-proteasome pathway inferred but not fully reconstituted","pmids":["24525731"],"is_preprint":false},{"year":2015,"finding":"TXNL1 regulates cisplatin-induced apoptosis in gastric cancer cells through a pathway associated with Bcl-2-mediated mitochondrial apoptosis. Knockdown of TXNL1 in sensitive cell lines increased cisplatin resistance, whereas overexpression of TXNL1 in resistant cell lines restored cisplatin-induced apoptosis and cell death.","method":"siRNA knockdown, overexpression, TUNEL assay, clonogenic assay, Western blotting for Bcl-2/apoptosis pathway components","journal":"Current cancer drug targets","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function and gain-of-function experiments with defined apoptotic phenotype, single lab, pathway placement by protein expression changes","pmids":["25348020"],"is_preprint":false},{"year":2018,"finding":"Newcastle disease virus V protein interacts with TXNL1 (identified by yeast two-hybrid and verified by co-immunolocalization in DF-1 cells). Overexpression of TXNL1 induced apoptosis and inhibited NDV replication, while knockdown had opposite effects. TXNL1-induced apoptosis operates through a Bcl-2/Bax and Caspase-3 pathway.","method":"Yeast two-hybrid, immunofluorescence co-localization, overexpression/knockdown with flow cytometry apoptosis assay, Western blotting, qRT-PCR, plaque assay","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — interaction validated by co-localization, functional assays with overexpression and knockdown, single lab with multiple readouts","pmids":["30290847"],"is_preprint":false},{"year":2023,"finding":"TXNL1 has dual functions: (1) a TrxR1 (TXNRD1)-coupled redox activity that reduces disulfides in insulin, cystine, and GSSG, although with at least one order of magnitude higher Km for TrxR1 compared to Trx1; and (2) an ATP-independent chaperone activity that prevents protein aggregation and keeps reduced insulin in solution. The chaperone activity does not require the redox-active cysteines, as Cys-to-Ser substituted variants and conditions lacking TrxR1/NADPH retained chaperone function.","method":"Recombinant protein expression and purification, Cys-to-Ser active-site mutagenesis, in vitro disulfide reduction assays, chaperone aggregation assays, kinetic measurements (Km determination)","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution, mutagenesis, and in vitro functional assays for both enzymatic and chaperone activities with rigorous controls in single study","pmids":["37804695"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of human TXNL1 bound to the 19S regulatory particle of the 26S proteasome reveals interactions with PSMD1 (Rpn2), PSMD4 (Rpn10), and PSMD14 (Rpn11). Proteasome binding is necessary for ubiquitin-independent degradation of TXNL1 upon cellular exposure to metal- or metalloid-containing oxidative agents.","method":"Cryo-EM structure determination, cellular oxidative stress experiments with metal/metalloid agents, functional degradation assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with identified binding interfaces and functional validation of stress-induced degradation requiring proteasome binding","pmids":["40770113"],"is_preprint":false},{"year":2025,"finding":"High-resolution cryo-EM structures of TXNL1 bound to the human 26S proteasome reveal conformation-specific binding modes dependent on the proteasome's ATPase motor state. The resting-state proteasome binds TXNL1 with low affinity above Rpn11, while the actively degrading proteasome shows high-affinity TXNL1 binding whereby TXNL1's C-terminal tail covers the catalytic groove of Rpn11 and coordinates the active-site Zn2+, suggesting TXNL1 can modulate Rpn11 deubiquitinase activity.","method":"Time-resolved cryo-EM at saturating and sub-stoichiometric TXNL1 concentrations, biophysical binding assays, biochemical experiments","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM with multiple conformational states, biophysical validation of binding affinity differences, single rigorous study with multiple orthogonal methods","pmids":["41198955"],"is_preprint":false},{"year":2025,"finding":"TXNL1 expression is specifically downregulated by arsenic through a DNMT1-USP10 axis: arsenic upregulates DNMT1, which hypermethylates the USP10 promoter to repress USP10 transcription, leading to decreased deubiquitination of TXNL1 by USP10, increased TXNL1 ubiquitination, and proteasomal degradation of TXNL1. Restoration of TXNL1 expression suppresses arsenic-induced ROS production, DNA oxidative damage, and malignant transformation.","method":"siRNA knockdown, overexpression, USP10 promoter methylation analysis, ubiquitination assays, ROS measurement, DNA damage assays, malignant transformation assays in vitro and in vivo","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissected with multiple intervention points and orthogonal methods (methylation, ubiquitination, functional ROS/transformation), single lab","pmids":["41275040"],"is_preprint":false},{"year":2025,"finding":"PhIX-MS (photo-induced in situ crosslinking mass spectrometry) combined with cryo-EM placed TXNL1's PITH domain above the Rpn11 deubiquitinase of the proteasome regulatory particle, with the dynamic thioredoxin domain positioned near RPN2/PSMD1 and RPN13/ADRM1 — a location consistent with reducing substrates prior to proteolysis.","method":"PhIX-MS (UV crosslinking in intact cells combined with mass spectrometry), cryo-EM, AlphaFold modeling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — novel structural proteomics method with cryo-EM validation, preprint without full peer review, consistent with published structures","pmids":["bio_10.1101_2025.07.31.667872"],"is_preprint":true}],"current_model":"TXNL1 (TRP32) is a cytoplasmic thioredoxin-fold protein that acts as a redox-active cofactor of the 26S proteasome by binding the 19S regulatory particle at Rpn11/PSMD14, Rpn2/PSMD1, and Rpn10/PSMD4 in a conformation-dependent manner — with its C-terminal PITH domain anchoring it above Rpn11 and its C-terminal tail covering Rpn11's catalytic groove and coordinating its active-site Zn2+ during active substrate degradation — while also functioning as an ATP-independent chaperone; it specifically reduces oxidized PRL phosphatases via its C-terminal domain, targets eEF1A1 for proteasomal processing, downregulates XRCC1 via the ubiquitin-proteasome pathway, regulates fluid-phase endocytosis through GDI-mediated Rab5 capture, and is itself subject to ubiquitin-independent proteasomal degradation upon oxidative stress, with its stability controlled by the deubiquitinase USP10."},"narrative":{"mechanistic_narrative":"TXNL1 (TRP32) is a cytoplasmic thioredoxin-fold protein that couples redox chemistry to protein quality control by serving as a redox-active cofactor of the 26S proteasome [PMID:19349277, PMID:40770113]. Its N-terminal thioredoxin domain carries a conserved active site and reduces interchain disulfides in vitro, functioning in a TrxR1 (TXNRD1)-coupled cycle to reduce insulin, cystine, and GSSG, while a distinct ATP-independent chaperone activity that prevents protein aggregation operates independently of the redox-active cysteines [PMID:9668102, PMID:37804695]. TXNL1 docks onto the 19S regulatory particle through contacts with Rpn2/PSMD1, Rpn10/PSMD4, and Rpn11/PSMD14, with its PITH domain anchored above the Rpn11 deubiquitinase; binding is conformation-dependent, and in the actively degrading proteasome the C-terminal tail covers Rpn11's catalytic groove and coordinates its active-site Zn2+, positioning TXNL1 to reduce substrates prior to proteolysis and to modulate Rpn11 activity [PMID:40770113, PMID:41198955, PMID:bio_10.1101_2025.07.31.667872]. The protein engages substrate-handling and target factors of this system, forming a disulfide-linked intermediate with eEF1A1 and driving downregulation of XRCC1 through the ubiquitin-proteasome pathway, and its C-terminal domain selectively reduces oxidized PRL phosphatases [PMID:19349277, PMID:23362275, PMID:24525731]. TXNL1 is itself a proteasome substrate, undergoing ubiquitin-independent degradation upon exposure to metal/metalloid oxidative agents, with arsenic repressing TXNL1 via a DNMT1-USP10 axis that increases its ubiquitination and proteasomal turnover [PMID:40770113, PMID:41275040]. Beyond these roles, TXNL1 has been linked to fluid-phase endocytosis through GDI-mediated Rab5 capture and to cisplatin-induced apoptosis in gastric cancer cells [PMID:17987124, PMID:25348020].","teleology":[{"year":1998,"claim":"Established TXNL1/TRP32 as a bona fide thioredoxin-family reductase, defining its core biochemical activity before any cellular role was known.","evidence":"Co-purification from thymoma cells, molecular cloning, and in vitro insulin disulfide reduction with cytoplasmic localization by fractionation/immunostaining","pmids":["9668102"],"confidence":"High","gaps":["No physiological substrate identified","Significance of co-purification with MST kinase fragment not resolved","Reason for greater oxidation sensitivity than Trx1 unexplained"]},{"year":2007,"claim":"Linked TXNL1 redox activity to a cellular trafficking output, proposing it as a redox sensor for fluid-phase endocytosis.","evidence":"Biochemical co-purification of a p38MAPK-containing complex with Rab5 capture and endocytosis assays","pmids":["17987124"],"confidence":"Medium","gaps":["GDI/Rab5 redox link proposed but not reconstituted","Direct substrate of TXNL1 in this pathway unknown","Composition of the p38MAPK complex not fully defined"]},{"year":2009,"claim":"Identified TXNL1 as a redox cofactor physically bound to the proteasome 19S particle and nominated eEF1A1 as a substrate, connecting its thioredoxin chemistry to protein degradation.","evidence":"Co-purification with 26S proteasome, Cys-to-Ser trapping mutant forming a disulfide with eEF1A1, redox potential measurement, and siRNA knockdown stabilizing ubiquitin conjugates","pmids":["19349277"],"confidence":"High","gaps":["Functional consequence of eEF1A1 reduction not established","Only moderate ubiquitin-conjugate stabilization on knockdown","Binding interface on the proteasome not mapped structurally"]},{"year":2013,"claim":"Defined a substrate-specific reductase function, showing TXNL1's unique C-terminal domain selectively reduces oxidized PRL phosphatases.","evidence":"In vitro reduction assays comparing Trx-related proteins, truncation mapping of the PRL-interacting domain, and knockdown prolonging H2O2-induced PRL oxidation","pmids":["23362275"],"confidence":"High","gaps":["Downstream signaling consequence of PRL reduction not addressed","Whether PRL reduction requires proteasome binding unknown"]},{"year":2014,"claim":"Connected TXNL1's proteasome-cofactor role to a disease-relevant target, the BER protein XRCC1, in chemoresistance.","evidence":"Proteomics, Western blotting, and cisplatin resistance assays in sensitive vs. resistant gastric cancer lines","pmids":["24525731"],"confidence":"Medium","gaps":["Direct vs. indirect control of XRCC1 turnover not resolved","Ubiquitin-proteasome step inferred, not reconstituted"]},{"year":2015,"claim":"Placed TXNL1 upstream of mitochondrial apoptosis, showing it sensitizes gastric cancer cells to cisplatin.","evidence":"siRNA knockdown and overexpression with TUNEL, clonogenic assays, and Bcl-2 pathway Western blotting","pmids":["25348020"],"confidence":"Medium","gaps":["Molecular mechanism linking TXNL1 to Bcl-2 not defined","Pathway placement based on expression changes only"]},{"year":2018,"claim":"Implicated TXNL1 in antiviral apoptotic signaling through interaction with Newcastle disease virus V protein.","evidence":"Yeast two-hybrid, co-localization, and overexpression/knockdown with apoptosis and replication readouts in DF-1 cells","pmids":["30290847"],"confidence":"Medium","gaps":["Interaction not validated by reciprocal biochemical methods","Mechanism by which V protein modulates TXNL1 unclear"]},{"year":2023,"claim":"Resolved TXNL1 as a dual-function protein, separating its TrxR1-coupled reductase activity from a cysteine-independent chaperone activity.","evidence":"Recombinant reconstitution, Cys-to-Ser mutagenesis, disulfide reduction and chaperone aggregation assays, and Km determination","pmids":["37804695"],"confidence":"High","gaps":["High Km for TrxR1 raises question of physiological reductant","Substrate specificity of chaperone activity not defined"]},{"year":2025,"claim":"Provided the structural basis for proteasome engagement, mapping TXNL1 contacts to PSMD1, PSMD4, and PSMD14 and showing proteasome binding is required for its stress-induced ubiquitin-independent degradation.","evidence":"Cryo-EM structure of TXNL1 on the 19S particle plus oxidative-stress degradation assays with metal/metalloid agents","pmids":["40770113"],"confidence":"High","gaps":["Trigger converting binding into degradation not defined","Identity of substrates reduced at this site unconfirmed"]},{"year":2025,"claim":"Demonstrated conformation-dependent binding tied to the proteasome ATPase motor state, with the TXNL1 C-terminal tail capping Rpn11 and coordinating its Zn2+ during active degradation.","evidence":"Time-resolved cryo-EM at varying TXNL1 concentrations with biophysical and biochemical binding assays","pmids":["41198955"],"confidence":"High","gaps":["Net effect on Rpn11 deubiquitinase output during degradation not quantified","Coupling between substrate reduction and degradation timing unclear"]},{"year":2025,"claim":"Defined a regulatory circuit controlling TXNL1 abundance, in which arsenic represses USP10 via DNMT1-driven promoter methylation to promote TXNL1 ubiquitination and turnover.","evidence":"Knockdown/overexpression, promoter methylation and ubiquitination assays, and ROS/DNA damage/transformation readouts in vitro and in vivo","pmids":["41275040"],"confidence":"Medium","gaps":["Direct USP10-TXNL1 deubiquitination not biochemically reconstituted","Relationship to ubiquitin-independent degradation pathway unresolved"]},{"year":null,"claim":"How TXNL1's redox/chaperone activities are functionally coupled to substrate reduction at the proteasome catalytic site, and which endogenous substrates this serves, remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No comprehensive census of proteasome substrates reduced by TXNL1","Physiological reductant given high TrxR1 Km undetermined","In vivo consequence of modulating Rpn11 during degradation not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,3,7]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,8,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8,10]}],"complexes":["26S proteasome (19S regulatory particle cofactor)"],"partners":["PSMD14","PSMD1","PSMD4","ADRM1","EEF1A1","USP10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43396","full_name":"Thioredoxin-like protein 1","aliases":["32 kDa thioredoxin-related protein"],"length_aa":289,"mass_kda":32.3,"function":"Active thioredoxin with a redox potential of about -250 mV","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O43396/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TXNL1","classification":"Not Classified","n_dependent_lines":51,"n_total_lines":1208,"dependency_fraction":0.042218543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMC4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TXNL1","total_profiled":1310},"omim":[{"mim_id":"618784","title":"PITH DOMAIN-CONTAINING PROTEIN 1; PITHD1","url":"https://www.omim.org/entry/618784"},{"mim_id":"603049","title":"THIOREDOXIN-LIKE 1; TXNL1","url":"https://www.omim.org/entry/603049"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TXNL1"},"hgnc":{"alias_symbol":["Txl","TRP32"],"prev_symbol":["TXNL"]},"alphafold":{"accession":"O43396","domains":[{"cath_id":"3.40.30.10","chopping":"4-106","consensus_level":"high","plddt":95.8931,"start":4,"end":106},{"cath_id":"2.60.120.470","chopping":"123-268","consensus_level":"high","plddt":96.5797,"start":123,"end":268}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43396","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43396-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43396-F1-predicted_aligned_error_v6.png","plddt_mean":91.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TXNL1","jax_strain_url":"https://www.jax.org/strain/search?query=TXNL1"},"sequence":{"accession":"O43396","fasta_url":"https://rest.uniprot.org/uniprotkb/O43396.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43396/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43396"}},"corpus_meta":[{"pmid":"24525731","id":"PMC_24525731","title":"TXNL1-XRCC1 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membranes.","date":"1997","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/9130254","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.31.667872","title":"Structures of dynamic interactors at native proteasomes by PhIX-MS and cryoelectron microscopy","date":"2025-08-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.31.667872","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16124,"output_tokens":3629,"usd":0.051403,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11192,"output_tokens":3767,"usd":0.075067,"stage2_stop_reason":"end_turn"},"total_usd":0.12647,"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\": 1998,\n      \"finding\": \"TRP32 (TXNL1) was purified from human thymoma cells co-purifying with a catalytic fragment of MST kinase (a STE20 family kinase proteolytically activated by caspase). The protein contains an N-terminal thioredoxin domain with a conserved active site and exhibits thioredoxin-like reducing activity, capable of reducing interchain disulfide bridges of insulin in vitro. The thioredoxin domain of TRP32 is more sensitive to oxidation than human thioredoxin. Subcellular fractionation and immunostaining established cytoplasmic localization.\",\n      \"method\": \"Protein purification (co-purification), molecular cloning, in vitro insulin disulfide reduction assay, subcellular fractionation, immunostaining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with direct biochemical purification and subcellular fractionation, replicated across multiple cell lines\",\n      \"pmids\": [\"9668102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TXNL1/TRP32 binds to Rpn11, a subunit of the 19S regulatory complex of the human 26S proteasome, establishing it as a redox-active cofactor of the proteasome. TXNL1 has thioredoxin activity with a redox potential of approximately -250 mV. A Cys-to-Ser active site mutant of TXNL1 formed disulfide bonds with eEF1A1 (a substrate-recruiting factor of the 26S proteasome), identifying eEF1A1 as a likely physiological substrate. Knockdown of TXNL1 resulted in moderate stabilization of ubiquitin-protein conjugates.\",\n      \"method\": \"Co-purification with 26S proteasome, active-site mutagenesis (Cys-to-Ser), in vitro redox assay, siRNA knockdown with ubiquitin-conjugate accumulation readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical interaction with mutagenesis, redox potential measurement, and functional knockdown phenotype in single rigorous study\",\n      \"pmids\": [\"19349277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TXNL1 is a component of a high-molecular-weight complex that includes p38MAPK, and plays a selective regulatory role in fluid-phase endocytosis by controlling GDI capacity to capture Rab5. TXNL1 is proposed to act as a redox sensor converting oxidative signals into changes in GDI-mediated Rab5 capture, thereby modulating fluid-phase endocytosis.\",\n      \"method\": \"Biochemical co-purification of a p38MAPK-containing complex, functional endocytosis assays, Rab5 capture assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-purification and functional endocytosis assays in single lab, mechanistic link between TXNL1 redox activity and GDI/Rab5 is proposed but not fully reconstituted\",\n      \"pmids\": [\"17987124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRP32 (TXNL1) specifically reduces oxidized PRL (phosphatase of regenerating liver) phosphatases. In vitro reduction assays showed that only TRP32, among tested TRX-related proteins, potently reduces oxidized PRL, while other thioredoxin-related proteins show little or no activity. The unique C-terminal domain of TRP32 is required and sufficient for direct interaction with PRL. TRP32 knockdown significantly prolongs H2O2-induced oxidation of PRL in cells.\",\n      \"method\": \"In vitro reduction assay, binding domain analysis with truncation mutants, siRNA knockdown with H2O2-induced PRL oxidation as readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstituted reduction assay, domain-mapping of interaction, and cellular knockdown validation with multiple orthogonal methods in single study\",\n      \"pmids\": [\"23362275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TXNL1 downregulates XRCC1 (a base excision repair protein) via the ubiquitin-proteasome pathway, establishing a TXNL1-XRCC1 regulatory axis that contributes to cisplatin resistance in gastric cancer cells. TXNL1 was identified as a cofactor of the 26S proteasome in this context.\",\n      \"method\": \"Proteomic analysis, Western blotting, cisplatin resistance assays in sensitive vs. resistant gastric cancer cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteomic identification with functional cell-based validation, single lab, mechanism of ubiquitin-proteasome pathway inferred but not fully reconstituted\",\n      \"pmids\": [\"24525731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TXNL1 regulates cisplatin-induced apoptosis in gastric cancer cells through a pathway associated with Bcl-2-mediated mitochondrial apoptosis. Knockdown of TXNL1 in sensitive cell lines increased cisplatin resistance, whereas overexpression of TXNL1 in resistant cell lines restored cisplatin-induced apoptosis and cell death.\",\n      \"method\": \"siRNA knockdown, overexpression, TUNEL assay, clonogenic assay, Western blotting for Bcl-2/apoptosis pathway components\",\n      \"journal\": \"Current cancer drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function and gain-of-function experiments with defined apoptotic phenotype, single lab, pathway placement by protein expression changes\",\n      \"pmids\": [\"25348020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Newcastle disease virus V protein interacts with TXNL1 (identified by yeast two-hybrid and verified by co-immunolocalization in DF-1 cells). Overexpression of TXNL1 induced apoptosis and inhibited NDV replication, while knockdown had opposite effects. TXNL1-induced apoptosis operates through a Bcl-2/Bax and Caspase-3 pathway.\",\n      \"method\": \"Yeast two-hybrid, immunofluorescence co-localization, overexpression/knockdown with flow cytometry apoptosis assay, Western blotting, qRT-PCR, plaque assay\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — interaction validated by co-localization, functional assays with overexpression and knockdown, single lab with multiple readouts\",\n      \"pmids\": [\"30290847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TXNL1 has dual functions: (1) a TrxR1 (TXNRD1)-coupled redox activity that reduces disulfides in insulin, cystine, and GSSG, although with at least one order of magnitude higher Km for TrxR1 compared to Trx1; and (2) an ATP-independent chaperone activity that prevents protein aggregation and keeps reduced insulin in solution. The chaperone activity does not require the redox-active cysteines, as Cys-to-Ser substituted variants and conditions lacking TrxR1/NADPH retained chaperone function.\",\n      \"method\": \"Recombinant protein expression and purification, Cys-to-Ser active-site mutagenesis, in vitro disulfide reduction assays, chaperone aggregation assays, kinetic measurements (Km determination)\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution, mutagenesis, and in vitro functional assays for both enzymatic and chaperone activities with rigorous controls in single study\",\n      \"pmids\": [\"37804695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of human TXNL1 bound to the 19S regulatory particle of the 26S proteasome reveals interactions with PSMD1 (Rpn2), PSMD4 (Rpn10), and PSMD14 (Rpn11). Proteasome binding is necessary for ubiquitin-independent degradation of TXNL1 upon cellular exposure to metal- or metalloid-containing oxidative agents.\",\n      \"method\": \"Cryo-EM structure determination, cellular oxidative stress experiments with metal/metalloid agents, functional degradation assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with identified binding interfaces and functional validation of stress-induced degradation requiring proteasome binding\",\n      \"pmids\": [\"40770113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"High-resolution cryo-EM structures of TXNL1 bound to the human 26S proteasome reveal conformation-specific binding modes dependent on the proteasome's ATPase motor state. The resting-state proteasome binds TXNL1 with low affinity above Rpn11, while the actively degrading proteasome shows high-affinity TXNL1 binding whereby TXNL1's C-terminal tail covers the catalytic groove of Rpn11 and coordinates the active-site Zn2+, suggesting TXNL1 can modulate Rpn11 deubiquitinase activity.\",\n      \"method\": \"Time-resolved cryo-EM at saturating and sub-stoichiometric TXNL1 concentrations, biophysical binding assays, biochemical experiments\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM with multiple conformational states, biophysical validation of binding affinity differences, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"41198955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TXNL1 expression is specifically downregulated by arsenic through a DNMT1-USP10 axis: arsenic upregulates DNMT1, which hypermethylates the USP10 promoter to repress USP10 transcription, leading to decreased deubiquitination of TXNL1 by USP10, increased TXNL1 ubiquitination, and proteasomal degradation of TXNL1. Restoration of TXNL1 expression suppresses arsenic-induced ROS production, DNA oxidative damage, and malignant transformation.\",\n      \"method\": \"siRNA knockdown, overexpression, USP10 promoter methylation analysis, ubiquitination assays, ROS measurement, DNA damage assays, malignant transformation assays in vitro and in vivo\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissected with multiple intervention points and orthogonal methods (methylation, ubiquitination, functional ROS/transformation), single lab\",\n      \"pmids\": [\"41275040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PhIX-MS (photo-induced in situ crosslinking mass spectrometry) combined with cryo-EM placed TXNL1's PITH domain above the Rpn11 deubiquitinase of the proteasome regulatory particle, with the dynamic thioredoxin domain positioned near RPN2/PSMD1 and RPN13/ADRM1 — a location consistent with reducing substrates prior to proteolysis.\",\n      \"method\": \"PhIX-MS (UV crosslinking in intact cells combined with mass spectrometry), cryo-EM, AlphaFold modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — novel structural proteomics method with cryo-EM validation, preprint without full peer review, consistent with published structures\",\n      \"pmids\": [\"bio_10.1101_2025.07.31.667872\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TXNL1 (TRP32) is a cytoplasmic thioredoxin-fold protein that acts as a redox-active cofactor of the 26S proteasome by binding the 19S regulatory particle at Rpn11/PSMD14, Rpn2/PSMD1, and Rpn10/PSMD4 in a conformation-dependent manner — with its C-terminal PITH domain anchoring it above Rpn11 and its C-terminal tail covering Rpn11's catalytic groove and coordinating its active-site Zn2+ during active substrate degradation — while also functioning as an ATP-independent chaperone; it specifically reduces oxidized PRL phosphatases via its C-terminal domain, targets eEF1A1 for proteasomal processing, downregulates XRCC1 via the ubiquitin-proteasome pathway, regulates fluid-phase endocytosis through GDI-mediated Rab5 capture, and is itself subject to ubiquitin-independent proteasomal degradation upon oxidative stress, with its stability controlled by the deubiquitinase USP10.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TXNL1 (TRP32) is a cytoplasmic thioredoxin-fold protein that couples redox chemistry to protein quality control by serving as a redox-active cofactor of the 26S proteasome [#1, #8]. Its N-terminal thioredoxin domain carries a conserved active site and reduces interchain disulfides in vitro, functioning in a TrxR1 (TXNRD1)-coupled cycle to reduce insulin, cystine, and GSSG, while a distinct ATP-independent chaperone activity that prevents protein aggregation operates independently of the redox-active cysteines [#0, #7]. TXNL1 docks onto the 19S regulatory particle through contacts with Rpn2/PSMD1, Rpn10/PSMD4, and Rpn11/PSMD14, with its PITH domain anchored above the Rpn11 deubiquitinase; binding is conformation-dependent, and in the actively degrading proteasome the C-terminal tail covers Rpn11's catalytic groove and coordinates its active-site Zn2+, positioning TXNL1 to reduce substrates prior to proteolysis and to modulate Rpn11 activity [#8, #9, #11]. The protein engages substrate-handling and target factors of this system, forming a disulfide-linked intermediate with eEF1A1 and driving downregulation of XRCC1 through the ubiquitin-proteasome pathway, and its C-terminal domain selectively reduces oxidized PRL phosphatases [#1, #3, #4]. TXNL1 is itself a proteasome substrate, undergoing ubiquitin-independent degradation upon exposure to metal/metalloid oxidative agents, with arsenic repressing TXNL1 via a DNMT1-USP10 axis that increases its ubiquitination and proteasomal turnover [#8, #10]. Beyond these roles, TXNL1 has been linked to fluid-phase endocytosis through GDI-mediated Rab5 capture and to cisplatin-induced apoptosis in gastric cancer cells [#2, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established TXNL1/TRP32 as a bona fide thioredoxin-family reductase, defining its core biochemical activity before any cellular role was known.\",\n      \"evidence\": \"Co-purification from thymoma cells, molecular cloning, and in vitro insulin disulfide reduction with cytoplasmic localization by fractionation/immunostaining\",\n      \"pmids\": [\"9668102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified\", \"Significance of co-purification with MST kinase fragment not resolved\", \"Reason for greater oxidation sensitivity than Trx1 unexplained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked TXNL1 redox activity to a cellular trafficking output, proposing it as a redox sensor for fluid-phase endocytosis.\",\n      \"evidence\": \"Biochemical co-purification of a p38MAPK-containing complex with Rab5 capture and endocytosis assays\",\n      \"pmids\": [\"17987124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GDI/Rab5 redox link proposed but not reconstituted\", \"Direct substrate of TXNL1 in this pathway unknown\", \"Composition of the p38MAPK complex not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified TXNL1 as a redox cofactor physically bound to the proteasome 19S particle and nominated eEF1A1 as a substrate, connecting its thioredoxin chemistry to protein degradation.\",\n      \"evidence\": \"Co-purification with 26S proteasome, Cys-to-Ser trapping mutant forming a disulfide with eEF1A1, redox potential measurement, and siRNA knockdown stabilizing ubiquitin conjugates\",\n      \"pmids\": [\"19349277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of eEF1A1 reduction not established\", \"Only moderate ubiquitin-conjugate stabilization on knockdown\", \"Binding interface on the proteasome not mapped structurally\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a substrate-specific reductase function, showing TXNL1's unique C-terminal domain selectively reduces oxidized PRL phosphatases.\",\n      \"evidence\": \"In vitro reduction assays comparing Trx-related proteins, truncation mapping of the PRL-interacting domain, and knockdown prolonging H2O2-induced PRL oxidation\",\n      \"pmids\": [\"23362275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling consequence of PRL reduction not addressed\", \"Whether PRL reduction requires proteasome binding unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected TXNL1's proteasome-cofactor role to a disease-relevant target, the BER protein XRCC1, in chemoresistance.\",\n      \"evidence\": \"Proteomics, Western blotting, and cisplatin resistance assays in sensitive vs. resistant gastric cancer lines\",\n      \"pmids\": [\"24525731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect control of XRCC1 turnover not resolved\", \"Ubiquitin-proteasome step inferred, not reconstituted\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed TXNL1 upstream of mitochondrial apoptosis, showing it sensitizes gastric cancer cells to cisplatin.\",\n      \"evidence\": \"siRNA knockdown and overexpression with TUNEL, clonogenic assays, and Bcl-2 pathway Western blotting\",\n      \"pmids\": [\"25348020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking TXNL1 to Bcl-2 not defined\", \"Pathway placement based on expression changes only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated TXNL1 in antiviral apoptotic signaling through interaction with Newcastle disease virus V protein.\",\n      \"evidence\": \"Yeast two-hybrid, co-localization, and overexpression/knockdown with apoptosis and replication readouts in DF-1 cells\",\n      \"pmids\": [\"30290847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction not validated by reciprocal biochemical methods\", \"Mechanism by which V protein modulates TXNL1 unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved TXNL1 as a dual-function protein, separating its TrxR1-coupled reductase activity from a cysteine-independent chaperone activity.\",\n      \"evidence\": \"Recombinant reconstitution, Cys-to-Ser mutagenesis, disulfide reduction and chaperone aggregation assays, and Km determination\",\n      \"pmids\": [\"37804695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High Km for TrxR1 raises question of physiological reductant\", \"Substrate specificity of chaperone activity not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural basis for proteasome engagement, mapping TXNL1 contacts to PSMD1, PSMD4, and PSMD14 and showing proteasome binding is required for its stress-induced ubiquitin-independent degradation.\",\n      \"evidence\": \"Cryo-EM structure of TXNL1 on the 19S particle plus oxidative-stress degradation assays with metal/metalloid agents\",\n      \"pmids\": [\"40770113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger converting binding into degradation not defined\", \"Identity of substrates reduced at this site unconfirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated conformation-dependent binding tied to the proteasome ATPase motor state, with the TXNL1 C-terminal tail capping Rpn11 and coordinating its Zn2+ during active degradation.\",\n      \"evidence\": \"Time-resolved cryo-EM at varying TXNL1 concentrations with biophysical and biochemical binding assays\",\n      \"pmids\": [\"41198955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Net effect on Rpn11 deubiquitinase output during degradation not quantified\", \"Coupling between substrate reduction and degradation timing unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a regulatory circuit controlling TXNL1 abundance, in which arsenic represses USP10 via DNMT1-driven promoter methylation to promote TXNL1 ubiquitination and turnover.\",\n      \"evidence\": \"Knockdown/overexpression, promoter methylation and ubiquitination assays, and ROS/DNA damage/transformation readouts in vitro and in vivo\",\n      \"pmids\": [\"41275040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct USP10-TXNL1 deubiquitination not biochemically reconstituted\", \"Relationship to ubiquitin-independent degradation pathway unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TXNL1's redox/chaperone activities are functionally coupled to substrate reduction at the proteasome catalytic site, and which endogenous substrates this serves, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No comprehensive census of proteasome substrates reduced by TXNL1\", \"Physiological reductant given high TrxR1 Km undetermined\", \"In vivo consequence of modulating Rpn11 during degradation not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 3, 7]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [\"26S proteasome (19S regulatory particle cofactor)\"],\n    \"partners\": [\"PSMD14\", \"PSMD1\", \"PSMD4\", \"ADRM1\", \"EEF1A1\", \"USP10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}