Thioredoxin-1 (Trx1) is a small (~12 kDa) ubiquitous oxidoreductase that plays a central role in cellular redox homeostasis. The protein contains the conserved active site motif CGPC (Cys32-Gly-Pro-Cys35) within a canonical thioredoxin fold, enabling it to catalyze dithiol-disulfide exchange reactions. The catalytic mechanism involves nucleophilic attack by Cys32 on substrate disulfide bonds, forming a mixed disulfide intermediate that is resolved by Cys35, releasing the reduced substrate while forming an intramolecular disulfide in Trx1. The oxidized Trx1 is regenerated by thioredoxin reductase (TrxR1) using NADPH. Major physiological substrates include peroxiredoxins (for H2O2 detoxification), ribonucleotide reductase (for deoxyribonucleotide synthesis), and oxidized protein tyrosine phosphatases. Beyond its catalytic function, Trx1 regulates transcription factors including AP-1 and NF-kB via interaction with APE1/Ref-1, and modulates apoptosis by binding ASK1 in its reduced state. Trx1 also serves as a nitrosothiol carrier, with Cys73 capable of S-nitrosylation and transnitrosation of target proteins like caspase-3. The protein is predominantly cytosolic but translocates to the nucleus upon cellular stress, and is also secreted via a leaderless pathway where it exhibits cytokine-like properties and can modulate cell surface receptors like CD30.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location. Thioredoxin is secreted via a leaderless secretory pathway and has documented extracellular functions [PMID:1332947]. Reason: This annotation is well-supported by experimental evidence showing Trx1 secretion. PMID:1332947 demonstrated that thioredoxin is actively secreted by various cell types through a non-classical secretory pathway. Supporting Evidence: PMID:1332947 Thioredoxin, despite its function as an intracellular disulfide reducing enzyme and its lack of a signal sequence, has been found to play some roles extracellularly. Here we show that thioredoxin is actively secreted by a variety of normal and transformed cells file:human/TXN/TXN-deep-research-falcon.md See deep research file for comprehensive analysis |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation supported by experimental evidence showing nuclear translocation of Trx1 in response to cellular stress [PMID:9108029, PMID:11118054]. Reason: Nuclear localization is well-established. Trx1 translocates to the nucleus where it interacts with Ref-1/APE1 to regulate AP-1 transcription factor activity. Supporting Evidence: PMID:9108029 Phorbol 12-myristate 13 acetate efficiently translocated TRX into the HeLa cell nucleus where Ref-1 preexists. PMID:11118054 After exposure to IR, nuclear levels of immunoreactive TRX increased, accompanied by an increase in AP-1 DNA binding activity. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation consistent with Trx1 being predominantly cytoplasmic [PMID:9108029, PMID:11118054]. Reason: Cytoplasmic localization is the primary location for Trx1 in unstressed cells, where it performs its major redox functions. Supporting Evidence: PMID:11118054 Thioredoxin (TRX) is a cytoplasmic, redox-sensitive signaling factor believed to participate in the regulation of nuclear transcription factors mediating cellular responses to environmental stress. |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | MODIFY | Summary: IEA annotation based on UniProt keyword mapping. Trx1 does not directly participate in transcription but regulates transcription factor DNA-binding activity. Reason: This term is too direct - Trx1 does not function as a transcription factor or directly in the transcription machinery. Instead, it regulates transcription factor activity through redox mechanisms. A more appropriate term would be GO:0043388 (positive regulation of DNA binding) or GO:0006357 (regulation of transcription by RNA polymerase II). Proposed replacements: positive regulation of DNA binding |
| GO:0015035 protein-disulfide reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for the core molecular function of thioredoxin. This is the primary enzymatic activity of Trx1. Reason: This is the defining enzymatic activity of thioredoxin - reducing disulfide bonds in target proteins via its CGPC active site. Well-established by multiple experimental studies. Supporting Evidence: PMID:2176490 HTR was as efficient as E. coli or plant and algal thioredoxins when assayed with E. coli ribonucleotide reductase or for the reduction of insulin. |
| GO:0019725 cellular homeostasis | IEA GO_REF:0000117 | MODIFY | Summary: IEA annotation that is overly general. Trx1 specifically maintains cellular redox homeostasis. Reason: While Trx1 does contribute to cellular homeostasis, the more specific and accurate term is GO:0045454 (cell redox homeostasis), which precisely describes the function of the thioredoxin system. Proposed replacements: cell redox homeostasis |
| GO:0005515 protein binding | IPI PMID:10814541 A possible interaction of thioredoxin with VDUP1 in HeLa cel... | MODIFY | Summary: This study identified VDUP1/TXNIP as a thioredoxin-binding protein using yeast two-hybrid screening in HeLa cells [PMID:10814541]. Reason: The generic protein binding term should be replaced with a more specific term. TXNIP is a physiologically important negative regulator of Trx1 that binds through the redox-active site cysteines. Proposed replacements: scaffold protein binding Supporting Evidence: PMID:10814541 Loss of interaction between VDUP1 and hTrx was observed either when two cysteines (Cys 32 and 35) in hTrx were substituted by serines |
| GO:0005515 protein binding | IPI PMID:15480426 Thioredoxin modulates activator protein 1 (AP-1) activity an... | ACCEPT | Summary: This study demonstrated direct interaction between Trx and Jab1 (COPS5), showing that Trx negatively regulates Jab1-controlled signaling pathways [PMID:15480426]. Reason: While protein binding is generic, this represents a specific functional interaction where Trx modulates AP-1 activity and p27Kip1 degradation through Jab1 binding. The interaction is validated by FRET and co-immunoprecipitation. Supporting Evidence: PMID:15480426 Fluorescence resonance energy transfer and co-immunoprecipitation studies revealed that Trx and Jab1 colocalize and directly interact with each other. |
| GO:0005515 protein binding | IPI PMID:15657067 Phosphotyrosine signaling networks in epidermal growth facto... | KEEP AS NON CORE | Summary: High-throughput proteomics study identifying TXN in phosphotyrosine signaling networks. Reason: This is from a large-scale proteomics study without specific mechanistic validation for Trx1. The interaction may be indirect or represent a broader signaling network context rather than a direct functional interaction. Supporting Evidence: PMID:15657067 Epub 2005 Jan 17. Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells. |
| GO:0005515 protein binding | IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by... | KEEP AS NON CORE | Summary: Large-scale protein-protein interaction mapping study by mass spectrometry. Reason: High-throughput study without specific mechanistic validation. Protein binding is too generic for annotation purposes without functional context. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry. |
| GO:0005515 protein binding | IPI PMID:17557078 Selective redox regulation of cytokine receptor signaling by... | ACCEPT | Summary: This study identified CD30 (TNFRSF8) as a specific extracellular target of Trx1 through kinetic trapping and demonstrated functional regulation of CD30 signaling [PMID:17557078]. Reason: This represents a well-characterized, specific protein-protein interaction with functional consequences. Trx1 catalytically interacts with CD30 on the cell surface to regulate receptor-ligand interactions. Supporting Evidence: PMID:17557078 Using a mechanism-based kinetic trapping technique to identify disulfide exchange interactions on the intact surface of living lymphocytes, we found that Trx1 catalytically interacts with a single principal target protein. This target protein was identified as the tumor necrosis factor receptor superfamily member 8 (TNFRSF8/CD30). |
| GO:0005515 protein binding | IPI PMID:17606900 Thioredoxin is required for S-nitrosation of procaspase-3 an... | MODIFY | Summary: This study demonstrated specific transnitrosation between Trx1 and procaspase-3, showing Trx participation in anti-apoptotic signaling [PMID:17606900]. Reason: This represents a specific functional interaction where Trx1 transfers nitrosyl groups to caspase-3, inhibiting apoptosis. A more specific term describing this regulatory interaction would be appropriate. Proposed replacements: cysteine-type endopeptidase inhibitor activity Supporting Evidence: PMID:17606900 Here we show that a specific transnitrosation reaction between procaspase-3 and thioredoxin-1 (Trx) occurs in cultured human T cells and prevents apoptosis. |
| GO:0005515 protein binding | IPI PMID:19690162 Salmonella type III secretion effector SlrP is an E3 ubiquit... | ACCEPT | Summary: This study identified Trx1 as a target of Salmonella effector SlrP, which acts as an E3 ubiquitin ligase for thioredoxin [PMID:19690162]. Reason: While this represents a pathogen-host interaction rather than normal physiology, the interaction is specific and has been validated by multiple methods including coimmunoprecipitation. Supporting Evidence: PMID:19690162 Using a genetic screen, we identified the small, reduction/oxidation-regulatory protein thioredoxin as a mammalian binding partner of the Salmonella effector SlrP. The interaction was confirmed by affinity chromatography and coimmunoprecipitation. |
| GO:0005515 protein binding | IPI PMID:19805025 CIB1 functions as a Ca(2+)-sensitive modulator of stress-ind... | KEEP AS NON CORE | Summary: This study focused on CIB1-ASK1 interaction rather than direct Trx-protein binding. Reason: The paper's main focus is on CIB1 as a modulator of ASK1 signaling. While Trx1 is mentioned in the context of ASK1 regulation, the specific protein binding evidence for Trx1 is indirect in this study. Supporting Evidence: PMID:19805025 CIB1 functions as a Ca(2+)-sensitive modulator of stress-induced signaling by targeting ASK1. |
| GO:0005515 protein binding | IPI PMID:20029029 Regulation of epidermal growth factor receptor trafficking b... | UNDECIDED | Summary: Study on HDAC6 regulation of EGFR trafficking. Reason: Unable to verify the specific Trx1 protein binding context in this study without access to the full publication. Supporting Evidence: PMID:20029029 Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. |
| GO:0005515 protein binding | IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by... | KEEP AS NON CORE | Summary: Large-scale quantitative proteomics study on cullin-RING ubiquitin ligase networks [PMID:21145461]. Reason: This is a high-throughput proteomics study focused on CRL network dynamics. Any Trx1 interactions identified would be incidental to the main focus and lack specific mechanistic validation. Supporting Evidence: PMID:21145461 Here, we report the development of a quantitative proteomics platform centered on multiplex absolute quantification (AQUA) technology to elucidate the architecture of the cullin-RING ubiquitin ligase (CRL) network |
| GO:0005515 protein binding | IPI PMID:21771788 Positive regulation of apoptosis signal-regulating kinase 1 ... | ACCEPT | Summary: This study focuses on ZPR9 as a positive regulator of ASK1 and mentions Trx as a negative regulator that competes with ZPR9 [PMID:21771788]. Reason: The study validates the Trx-ASK1 interaction in the context of understanding ASK1 regulation, showing that ZPR9 destabilizes the Trx-ASK1 complex. Supporting Evidence: PMID:21771788 Ectopic expression of wild-type ZPR9, but not an S314A/T318A mutant, stimulated ASK1 kinase activity and positively regulated ASK1-mediated signaling to both JNK and p38 kinases by destabilizing complex formation between ASK1 and its negative regulators, Trx and 14-3-3 |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | KEEP AS NON CORE | Summary: Protein interaction network study of human liver. Reason: High-throughput interactome study without specific mechanistic validation for Trx1 interactions. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver. |
| GO:0005515 protein binding | IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ... | UNDECIDED | Summary: Mammalian membrane two-hybrid assay study. Reason: Unable to verify the specific Trx1 interaction context without access to the full publication. Supporting Evidence: PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells. |
| GO:0005515 protein binding | IPI PMID:24976139 Reactivation of oxidized PTP1B and PTEN by thioredoxin 1 | ACCEPT | Summary: This study demonstrated that Trx1 reactivates oxidized PTP1B and PTEN phosphatases through direct thiol-disulfide exchange [PMID:24976139]. Reason: This represents a mechanistically validated interaction where Trx1 reduces oxidized phosphatases, returning them to their active state. The interaction was confirmed by kinetic trapping. Supporting Evidence: PMID:24976139 Finally, using a mechanism-based trapping approach, we demonstrate direct thiol disulphide exchange between the active sites of thioredoxin and either phosphatase. |
| GO:0005515 protein binding | IPI PMID:25402766 Peroxiredoxin-2 and STAT3 form a redox relay for H2O2 signal... | ACCEPT | Summary: This study describes a Prx2-STAT3 redox relay but validates that Trx1 is the physiological reductant of Prx2 [PMID:25402766]. Reason: The study confirms the Trx1-Prx2 interaction as part of the cellular redox signaling system. Prx2 is a well-established Trx1 substrate. Supporting Evidence: PMID:25402766 Prx2 forms a redox relay with the transcription factor STAT3 in which oxidative equivalents flow from Prx2 to STAT3. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Large-scale human interactome mapping study. Reason: High-throughput interactome study. Protein binding annotations from such studies require additional validation for functional significance. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | UNDECIDED | Summary: Study on EGFR network rewiring in colorectal cancer cells. Reason: Unable to verify the specific Trx1 protein binding context without access to the full publication. Supporting Evidence: PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Reference map of human binary protein interactome. Reason: High-throughput binary interactome study. Requires additional validation for specific Trx1 interactions. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | UNDECIDED | Summary: Interactome mapping study on neurodegenerative disease proteins. Reason: Unable to verify the specific Trx1 interaction context without access to the full publication. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: IDA annotation based on immunofluorescence data showing nucleoplasm localization. Reason: Consistent with nuclear translocation of Trx1 upon cellular stress as demonstrated in multiple studies [PMID:9108029, PMID:11118054]. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA annotation based on immunofluorescence data showing cytosolic localization. Reason: The cytosol is the primary location for Trx1 in unstressed cells, consistent with its function in maintaining cytosolic protein redox state. |
| GO:0004791 thioredoxin-disulfide reductase (NADPH) activity | TAS Reactome:R-NUL-9617742 | REMOVE | Summary: Reactome annotation. Note that this GO term describes the activity of thioredoxin reductase, not thioredoxin itself. Reason: This is incorrect - GO:0004791 describes the activity of thioredoxin reductase (TrxR), which reduces oxidized thioredoxin using NADPH. Thioredoxin itself does not have this activity; it is the substrate of this reaction, not the enzyme. The correct term for thioredoxin is GO:0015035 (protein-disulfide reductase activity). |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:22492997 DJ-1 induces thioredoxin 1 expression through the Nrf2 pathw... | ACCEPT | Summary: This study shows that DJ-1 induces Trx1 expression through Nrf2, and Trx1 is required for DJ-1-dependent AKT activation in response to H2O2 [PMID:22492997]. Reason: The study demonstrates that Trx1 knockdown abrogates DJ-1-dependent, H2O2-induced AKT activation, supporting a role in PI3K/AKT signaling regulation. Supporting Evidence: PMID:22492997 Additionally, knockdown of Trx1 significantly abrogates DJ-1-dependent, hydrogen peroxide-induced activation of the pro-survival factor AKT. |
| GO:0061692 cellular detoxification of hydrogen peroxide | IGI PMID:22492997 DJ-1 induces thioredoxin 1 expression through the Nrf2 pathw... | ACCEPT | Summary: The study shows that Trx1 is induced by DJ-1 and provides cytoprotection against H2O2 [PMID:22492997]. Reason: Trx1 functions in H2O2 detoxification by reducing peroxiredoxins, which directly detoxify H2O2. This is a core function of the thioredoxin system. Supporting Evidence: PMID:22492997 Further, Nrf2 knockdown abolishes DJ-1-mediated Trx1 induction and cytoprotection against hydrogen peroxide |
| GO:0005654 nucleoplasm | TAS Reactome:R-NUL-9617742 | ACCEPT | Summary: Reactome TAS annotation for nucleoplasm localization. Reason: Consistent with documented nuclear translocation of Trx1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-111751 | ACCEPT | Summary: Reactome annotation for Trx1 participation in ribonucleotide reductase reaction. Reason: Trx1 is a well-established electron donor for ribonucleotide reductase in the cytosol, supporting deoxyribonucleotide synthesis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-111804 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with primary cytosolic localization of Trx1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1250280 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with cytosolic function of Trx1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3225851 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3341343 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3697882 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5676917 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5676940 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-73646 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with cytosolic localization. |
| GO:0005515 protein binding | IPI PMID:15246877 S-nitrosation of thioredoxin in the nitrogen monoxide/supero... | ACCEPT | Summary: This study demonstrates that S-nitrosation of Trx leads to dissociation from ASK1, activating the kinase [PMID:15246877]. Reason: The study validates the functional Trx-ASK1 interaction and shows that redox modification of Trx regulates ASK1 activity. Supporting Evidence: PMID:15246877 N2O3-dependent S-nitrosation of Trx at approximately 2-fold of NO excess compared to the superoxide amount resulted in dissociation and activation of apoptosis signal regulating kinase 1 (ASK1). |
| GO:0005515 protein binding | IPI PMID:17260951 Buried S-nitrosocysteine revealed in crystal structures of h... | ACCEPT | Summary: Crystal structure study of S-nitrosylated human thioredoxin showing homodimer formation [PMID:17260951]. Reason: The study provides structural evidence for Trx1 homodimerization and S-nitrosylation at Cys62 and Cys69, important for understanding Trx1 regulation. Supporting Evidence: PMID:17260951 S-Nitroso modifications of cysteines 62 and 69 are clearly visible in the structure and display planar cis geometries, whereas cysteines 32, 35, and 73 form intra- and intermolecular disulfide bonds. |
| GO:0005515 protein binding | IPI PMID:9108029 AP-1 transcriptional activity is regulated by a direct assoc... | ACCEPT | Summary: Foundational study demonstrating direct association between Trx and Ref-1/APE1 to regulate AP-1 transcriptional activity [PMID:9108029]. Reason: This is a key study establishing the Trx-Ref-1 interaction and its role in redox regulation of transcription factors. The interaction requires the Trx catalytic cysteines. Supporting Evidence: PMID:9108029 To prove the direct active site-mediated association between TRX and Ref-1, we generated a series of substitution-mutant cysteine residues of TRX. In both an in vitro diamide-induced cross-linking study and an in vivo mammalian two-hybrid assay we proved that TRX can associate directly with Ref-1 in the nucleus |
| GO:0005576 extracellular region | IDA PMID:1332947 Secretion of thioredoxin by normal and neoplastic cells thro... | ACCEPT | Summary: Key study demonstrating secretion of thioredoxin through a leaderless pathway [PMID:1332947]. Reason: This study established that Trx1 is secreted by various cell types through a non-classical secretory pathway, independent of the ER-Golgi route. Supporting Evidence: PMID:1332947 thioredoxin is actively secreted by a variety of normal and transformed cells, including fibroblasts, airway epithelial cells, and activated B and T lymphocytes. Neither brefeldin A nor dinitrophenol, two drugs that block transport through the exocytic pathway, inhibit secretion of thioredoxin |
| GO:0005634 nucleus | IDA PMID:9108029 AP-1 transcriptional activity is regulated by a direct assoc... | ACCEPT | Summary: Study demonstrating nuclear translocation of Trx in response to PMA treatment [PMID:9108029]. Reason: The study clearly shows Trx translocation to the nucleus where it interacts with Ref-1 to regulate AP-1 activity. Supporting Evidence: PMID:9108029 Phorbol 12-myristate 13 acetate efficiently translocated TRX into the HeLa cell nucleus where Ref-1 preexists. |
| GO:0005737 cytoplasm | IDA PMID:9108029 AP-1 transcriptional activity is regulated by a direct assoc... | ACCEPT | Summary: Study confirming cytoplasmic localization of Trx in unstimulated cells [PMID:9108029]. Reason: The cytoplasm is the primary location for Trx1 before nuclear translocation upon stimulation. Supporting Evidence: PMID:9108029 AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. |
| GO:0009314 response to radiation | IDA PMID:9108029 AP-1 transcriptional activity is regulated by a direct assoc... | KEEP AS NON CORE | Summary: While the study discusses Trx function, the primary radiation response data is in PMID:11118054. Reason: The study mentions radiation context but is primarily focused on PMA-induced nuclear translocation. The radiation response is better documented in PMID:11118054. Supporting Evidence: PMID:9108029 AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:17182577 Cross-reactivity and 1.4-A crystal structure of Malassezia s... | ACCEPT | Summary: This study primarily focuses on thioredoxin as an allergen and cross-reactivity between fungal and human thioredoxins [PMID:17182577]. Reason: Although focused on allergenic properties, the study confirms the disulfide reductase activity is conserved across thioredoxins from different species. Supporting Evidence: PMID:17182577 We have identified thioredoxins (Trx) of Malassezia sympodialis, a yeast involved in the pathogenesis of atopic eczema, and of Aspergillus fumigatus, a fungus involved in pulmonary complications, as novel IgE-binding proteins. We show that these Trx, including the human enzyme, represent cross-reactive structures |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:19032234 Auto- and cross-reactivity to thioredoxin allergens in aller... | ACCEPT | Summary: Study on thioredoxin allergenicity in allergic bronchopulmonary aspergillosis [PMID:19032234]. Reason: The study confirms functional conservation of thioredoxin activity across species. Supporting Evidence: PMID:19032234 All thioredoxins, including the human enzyme, bind IgE from patients with allergic bronchopulmonary aspergillosis and induce allergen-specific proliferation |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:2176490 Human thioredoxin reactivity-structure/function relationship | ACCEPT | Summary: Foundational study characterizing human thioredoxin reactivity and structure-function relationships [PMID:2176490]. Reason: This is a key study demonstrating the protein-disulfide reductase activity of human thioredoxin using ribonucleotide reductase and insulin reduction assays. Supporting Evidence: PMID:2176490 HTR was as efficient as E. coli or plant and algal thioredoxins when assayed with E. coli ribonucleotide reductase or for the reduction of insulin. |
| GO:0042803 protein homodimerization activity | IDA PMID:17260951 Buried S-nitrosocysteine revealed in crystal structures of h... | ACCEPT | Summary: Crystal structure study revealing disulfide-linked homodimer formation in human thioredoxin [PMID:17260951]. Reason: The study provides high-resolution structural evidence for Trx1 homodimerization through Cys73 disulfide bond. Supporting Evidence: PMID:17260951 cysteines 32, 35, and 73 form intra- and intermolecular disulfide bonds |
| GO:0042803 protein homodimerization activity | IDA PMID:9369469 Human thioredoxin homodimers: regulation by pH, role of aspa... | ACCEPT | Summary: Detailed biochemical and structural study of human thioredoxin homodimerization and its pH regulation [PMID:9369469]. Reason: The study provides comprehensive biochemical characterization of Trx1 dimerization, including pH dependence and the role of Asp60. Supporting Evidence: PMID:9369469 A recent crystal structure determination of human thioredoxin revealed an inactive dimeric form of the protein covalently linked through a disulfide bond involving Cys 73 from each monomer |
| GO:0045454 cell redox homeostasis | IDA PMID:2176490 Human thioredoxin reactivity-structure/function relationship | ACCEPT | Summary: Foundational study establishing human thioredoxin function in redox reactions [PMID:2176490]. Reason: This is a core function of thioredoxin - maintaining cellular redox homeostasis through its disulfide reductase activity. Supporting Evidence: PMID:2176490 The reactivity of human thioredoxin (HTR) was tested in several reactions. HTR was as efficient as E. coli or plant and algal thioredoxins when assayed with E. coli ribonucleotide reductase or for the reduction of insulin. |
| GO:0045454 cell redox homeostasis | IMP PMID:9108029 AP-1 transcriptional activity is regulated by a direct assoc... | ACCEPT | Summary: Study demonstrating Trx function in redox regulation of transcription factor activity [PMID:9108029]. Reason: The study demonstrates that Trx redox status is critical for its function in regulating AP-1 activity, supporting its role in cellular redox homeostasis. Supporting Evidence: PMID:9108029 Thioredoxin (TRX) is a pleiotropic cellular factor that has thiol-mediated redox activity and is important in regulation of cellular processes |
| GO:0047134 protein-disulfide reductase [NAD(P)H] activity | IDA PMID:17182577 Cross-reactivity and 1.4-A crystal structure of Malassezia s... | REMOVE | Summary: Study on thioredoxin allergenicity that confirms enzymatic activity. Reason: This GO term describes an enzyme that directly uses NAD(P)H to reduce protein disulfides. However, Trx1 itself does not directly use NADPH - it is reduced by thioredoxin reductase which uses NADPH. The correct term is GO:0015035 (protein-disulfide reductase activity), which does not specify the electron donor. Supporting Evidence: PMID:17182577 Cross-reactivity and 1.4-A crystal structure of Malassezia sympodialis thioredoxin (Mala s 13), a member of a new pan-allergen family. |
| GO:0071731 response to nitric oxide | IMP PMID:16408020 Thioredoxin catalyzes the S-nitrosation of the caspase-3 act... | ACCEPT | Summary: This study demonstrates that Trx1 catalyzes S-nitrosation of caspase-3 in response to NO [PMID:16408020]. Reason: Trx1 responds to NO by becoming S-nitrosylated at Cys73 and subsequently transferring the nitrosyl group to caspase-3, representing a specific cellular response to NO. Supporting Evidence: PMID:16408020 We demonstrated that a single cysteine in thioredoxin (Trx) is capable of a targeted, reversible transnitrosation reaction with Cys163 of Casp-3. |
| GO:0071731 response to nitric oxide | IMP PMID:17606900 Thioredoxin is required for S-nitrosation of procaspase-3 an... | ACCEPT | Summary: Study demonstrating Trx requirement for S-nitrosation of procaspase-3 and inhibition of apoptosis [PMID:17606900]. Reason: Confirms that Trx1 is essential for NO-mediated S-nitrosation of caspase-3 and consequent anti-apoptotic signaling. Supporting Evidence: PMID:17606900 Here we show that a specific transnitrosation reaction between procaspase-3 and thioredoxin-1 (Trx) occurs in cultured human T cells and prevents apoptosis. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: High-throughput proteomics study of exosomes from prostatic secretions. Reason: High-throughput proteomic identification of Trx1 in exosomes. While consistent with extracellular localization, this is likely a secondary observation rather than a core function. Supporting Evidence: PMID:23533145 2013 Apr 23. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: High-throughput RNA interactome capture study. Reason: RNA binding is not a characterized function of thioredoxin. This may represent indirect association or false positive from high-throughput screening. Trx1 is not known to have specific RNA binding activity. Supporting Evidence: PMID:22658674 May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | MARK AS OVER ANNOTATED | Summary: mRNA-bound proteome study. Reason: Same as above - RNA binding is not a characterized function of thioredoxin and likely represents high-throughput screen artifact. Supporting Evidence: PMID:22681889 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Proteomics study of urinary exosomes. Reason: Consistent with Trx1 secretion, but exosomal localization is not a core function. Supporting Evidence: PMID:19056867 2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Study of MHC class II-associated proteins in B-cell exosomes. Reason: Consistent with extracellular presence of Trx1 but not a core function. Supporting Evidence: PMID:20458337 2010 May 11. MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1250264 | ACCEPT | Summary: Reactome annotation for TXNIP binding to reduced thioredoxin in cytosol. Reason: The TXNIP-Trx1 interaction occurs in the cytosol and is well-established. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796045 | ACCEPT | Summary: Reactome annotation for cytosolic localization. Reason: Consistent with cytosolic localization. |
| GO:0005515 protein binding | IPI PMID:11118054 Thioredoxin nuclear translocation and interaction with redox... | ACCEPT | Summary: Study demonstrating Trx interaction with Ref-1 in the nucleus following ionizing radiation [PMID:11118054]. Reason: The study validates the Trx-Ref-1 interaction and shows it occurs in the nucleus after radiation exposure. Supporting Evidence: PMID:11118054 It was shown that a physical interaction between Ref-1 and TRX occurs within the nucleus and is enhanced after exposure to IR. |
| GO:0009314 response to radiation | IDA PMID:11118054 Thioredoxin nuclear translocation and interaction with redox... | ACCEPT | Summary: Study demonstrating Trx nuclear translocation and AP-1 activation in response to ionizing radiation [PMID:11118054]. Reason: The study clearly demonstrates that Trx responds to ionizing radiation by translocating to the nucleus and activating AP-1. Supporting Evidence: PMID:11118054 After exposure to IR, nuclear levels of immunoreactive TRX increased, accompanied by an increase in AP-1 DNA binding activity. |
| GO:0043388 positive regulation of DNA binding | IDA PMID:11118054 Thioredoxin nuclear translocation and interaction with redox... | ACCEPT | Summary: Study demonstrating that Trx from irradiated cells activates AP-1 DNA binding activity [PMID:11118054]. Reason: The study directly demonstrates that Trx positively regulates AP-1 DNA binding activity through its redox function. Supporting Evidence: PMID:11118054 Furthermore, TRX immunoprecipitated from irradiated cells was capable of activating AP-1 DNA binding activity in nonirradiated nuclear extracts. |
| GO:0043066 negative regulation of apoptotic process | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:16408020 We demonstrated that a single cysteine in thioredoxin (Trx) is capable of a targeted, reversible transnitrosation reaction with Cys163 of Casp-3. PMID:17606900 Here we show that a specific transnitrosation reaction between procaspase-3 and thioredoxin-1 (Trx) occurs in cultured human T cells and prevents apoptosis. |
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Download this section (compressed HTML)Q: What is the relative contribution of cytosolic vs nuclear Trx1 to cellular redox homeostasis?
Q: How is Trx1 secretion regulated and what are the primary extracellular functions?
Q: What determines substrate specificity among the various Trx1 targets?
Experiment: Quantitative proteomics to identify the complete Trx1 substrate repertoire under different stress conditions
Hypothesis: Trx1 has condition-specific substrates that change depending on the type of cellular stress.
Type: Quantitative proteomics
Experiment: Live cell imaging to monitor Trx1 nuclear translocation dynamics
Hypothesis: Trx1 nuclear translocation follows specific kinetics that correlate with AP-1 activation.
Type: Live cell imaging
Experiment: Structural studies of Trx1-ASK1 complex to understand regulatory mechanism
Hypothesis: Reduced Trx1 binds ASK1 in a specific conformation that prevents kinase activation.
Type: Structural biology (cryo-EM or X-ray crystallography)
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