Mouse thioredoxin-1 (Trx1/Txn1) 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 using NADPH. Major physiological substrates include peroxiredoxins (for H2O2 detoxification), ribonucleotide reductase (for deoxyribonucleotide synthesis), and oxidized proteins. Mouse Txn1 interacts with TXNIP through its redox-active site, and also interacts with MAP3K5 (ASK1) and CASP3. Trx1 regulates transcription factors AP-1 and NF-kB via interaction with APEX1/Ref-1 and modulates apoptosis. The protein is predominantly cytosolic but translocates to the nucleus upon cellular stress, and is also secreted via a leaderless pathway.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation based on subcellular location. Thioredoxin is secreted via a leaderless secretory pathway. Reason: Extracellular localization is well-established for thioredoxin across mammalian species. UniProt annotation confirms secretion via a leaderless pathway. Supporting Evidence: UniProtKB:P10639 Secreted by a leaderless secretory pathway file:mouse/Txn1/Txn1-deep-research-falcon.md it can also associate with membranes and be **secreted via a leaderless secretory pathway**, with extracellular roles including signaling/chemotaxis |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation supported by evidence showing nuclear translocation of Trx1 in response to cellular stress. Reason: Nuclear localization is well-established. Trx1 translocates to the nucleus where it interacts with Ref-1/APEX1 to regulate AP-1 transcription factor activity. Supporting Evidence: UniProtKB:P10639 Note=Translocates from the cytoplasm into the nucleus after phorbol 12-myristate 13-acetate induction (PMA) file:mouse/Txn1/Txn1-deep-research-falcon.md Trx1 is described as **mainly cytoplasmic**, but capable of **nuclear translocation** under oxidative/nitrosative stress |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation consistent with Trx1 being predominantly cytoplasmic. Reason: Cytoplasmic localization is the primary location for Trx1 in unstressed cells, where it performs its major redox functions. Supporting Evidence: UniProtKB:P10639 Predominantly in the cytoplasm in non irradiated cells |
| 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 via interaction with APEX1/Ref-1. 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. Supporting Evidence: UniProtKB:P10639 -!- FUNCTION: Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions (By similarity) file:mouse/Txn1/Txn1-deep-research-perplexity.md The thioredoxin 1 protein encoded by the Txn gene is a small, highly conserved oxidoreductase with a molecular weight of approximately 12 kilodaltons[11]. file:mouse/Txn1/Txn1-deep-research-falcon.md Trx1 catalyzes the **reduction of oxidized cysteine residues and protein disulfide bonds** in target proteins (i.e., converting a disulfide to two thiols), via its **Cys32/Cys35** catalytic pair |
| 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:0005654 nucleoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation based on subcellular location data. Reason: Consistent with nuclear translocation of Trx1 upon cellular stress as demonstrated in multiple studies. Supporting Evidence: UniProtKB:P10639 Nucleus {ECO:0000250|UniProtKB:P10599}. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation 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. Supporting Evidence: UniProtKB:P10639 Predominantly in the cytoplasm in non irradiated cells file:mouse/Txn1/Txn1-deep-research-falcon.md Trx1 is described as **mainly cytoplasmic** |
| GO:0009314 response to radiation | IEA GO_REF:0000107 | ACCEPT | Summary: Annotation transferred from human ortholog showing Trx1 responds to ionizing radiation. Reason: Trx1 translocates to the nucleus in response to ionizing radiation and activates AP-1, as documented in human studies with conserved function in mouse. Supporting Evidence: UniProtKB:P10639 Radiation induces translocation of TRX from the cytoplasm to the nucleus |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: Annotation transferred from human ortholog based on structural evidence. Reason: Thioredoxin forms homodimers through Cys73 disulfide bonds, as demonstrated in structural studies of human Trx1 with conserved residues in mouse. Supporting Evidence: UniProtKB:P10639 Homodimer; disulfide-linked |
| GO:0045454 cell redox homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: Core function annotation for thioredoxin's role in maintaining cellular redox balance. Reason: This is a core function of thioredoxin - maintaining cellular redox homeostasis through its disulfide reductase activity. Supporting Evidence: file:mouse/Txn1/Txn1-deep-research-falcon.md Thioredoxin-1 is a conserved **thiol-disulfide oxidoreductase** that maintains proteins in the reduced state and participates in antioxidant defense and redox signaling |
| GO:0047134 protein-disulfide reductase [NAD(P)H] activity | IEA GO_REF:0000107 | REMOVE | Summary: Annotation transferred from human ortholog. 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). |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Annotation transferred from human ortholog. Reason: This represents a downstream signaling effect of Trx1 rather than a core function. The evidence from human studies shows Trx1 is required for H2O2-induced AKT activation. |
| GO:0061692 cellular detoxification of hydrogen peroxide | IEA GO_REF:0000107 | ACCEPT | Summary: Annotation transferred from human ortholog. Reason: Trx1 functions in H2O2 detoxification by reducing peroxiredoxins, which directly detoxify H2O2. This is a core function of the thioredoxin system. Falcon notes Trx1 has low intrinsic affinity for H2O2 itself, so the detoxification is via redox relay through peroxiredoxin regeneration rather than direct peroxidase activity. Supporting Evidence: file:mouse/Txn1/Txn1-deep-research-falcon.md it is also described as reducing oxidized **peroxiredoxins** (i.e., supporting peroxide detox/redox cycling indirectly through peroxiredoxin regeneration) file:mouse/Txn1/Txn1-deep-research-falcon.md Trx1 is also noted to have low affinity for H2O2 itself, supporting the view that its antioxidant effect is largely via redox relay/partner proteins rather than acting as a direct peroxidase |
| GO:0071731 response to nitric oxide | IEA GO_REF:0000107 | ACCEPT | Summary: Annotation transferred from human ortholog. Reason: Trx1 responds to NO by becoming S-nitrosylated at Cys73 and subsequently mediating transnitrosation of target proteins like caspase-3. Supporting Evidence: UniProtKB:P10639 Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide |
| GO:0005829 cytosol | TAS Reactome:R-MMU-1250256 | ACCEPT | Summary: Reactome annotation for TXNIP release from oxidized thioredoxin in cytosol. Reason: The TXNIP-Trx1 interaction occurs in the cytosol and is well-established. |
| GO:0009314 response to radiation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity to human TXN. Reason: Conserved function based on high sequence similarity to human thioredoxin. |
| GO:0043388 positive regulation of DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation showing Trx1 positively regulates AP-1 DNA binding activity. Reason: Trx1 regulates AP-1 DNA binding through its interaction with Ref-1/APEX1, a function conserved between human and mouse. Falcon deep research adds that thioredoxin is also required for NF-kB DNA binding, consistent with a broader role in keeping transcription-factor cysteines in a reduced, DNA-binding-competent state. Supporting Evidence: UniProtKB:P10639 Induces the FOS/JUN AP-1 DNA binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity (By similarity) file:mouse/Txn1/Txn1-deep-research-falcon.md thioredoxin is also noted as required for **NF-ΞΊB binding to DNA**, pointing to a mechanistic role in transcriptional redox regulation |
| GO:0043066 negative regulation of apoptotic process | ISS GO_REF:0000024 | NEW | Summary: Trx1 inhibits apoptosis by S-nitrosylating caspase-3, and by binding/ inhibiting the apoptosis signal-regulating kinase ASK1 (MAP3K5) under basal conditions. Reason: Trx1 inhibits caspase-3 activity through S-nitrosylation, thereby preventing apoptosis. This function is conserved from human ortholog. Falcon deep research additionally documents the ASK1/TXNIP axis, in which thioredoxin binds and suppresses ASK1 basally; displacement by TXNIP promotes oxidative-stress and apoptotic signaling. Supporting Evidence: UniProtKB:P10639 Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity file:mouse/Txn1/Txn1-deep-research-falcon.md Thioredoxin is described as binding and inhibiting **ASK1** under basal conditions; displacement or inactivation of thioredoxin (e.g., by TXNIP) promotes oxidative stress signaling and downstream outcomes (e.g., apoptosis/inflammasome-linked signaling) |
| GO:0035605 peptidyl-cysteine S-nitrosylase activity | ISS GO_REF:0000024 | NEW | Summary: Trx1 acts as a transnitrosylase, transferring an NO group from its Cys-nitrosylated active center to a cysteine of target proteins such as caspase-3. Reason: UniProt documents that Trx1 nitrosylates the active-site Cys of CASP3 in response to NO, which is precisely a peptidyl-cysteine S-nitrosylase (transnitrosylase) molecular function. This is the MF underlying the third core function and is conserved from the human ortholog. Added with ISS evidence on GO_REF:0000024 (manual ortholog transfer) rather than as a deep-research-only annotation. Supporting Evidence: UniProtKB:P10639 Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity |
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Download this section (compressed HTML)Q: What is the relative contribution of cytosolic vs nuclear Trx1 to cellular redox homeostasis in mouse tissues?
Q: How is Trx1 secretion regulated in mouse and what are the primary extracellular functions?
Experiment: Quantitative proteomics to identify the complete Trx1 substrate repertoire under different stress conditions in mouse cells
Hypothesis: Trx1 has condition-specific substrates that change depending on the type of cellular stress.
Type: Quantitative proteomics
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