id: Q6PKC3 gene_symbol: TXNDC11 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- TXNDC11 (Thioredoxin domain-containing protein 11; also called EFP1) is a large (985 aa) single-pass endoplasmic reticulum membrane glycoprotein of the protein disulfide isomerase (PDI) family. It contains a single N-terminal transmembrane helix and a luminal region with five thioredoxin (Trx)-like domains followed by a C-terminal coiled coil. Only one of its Trx domains carries a canonical redox-active CXXC motif; the other Trx folds are degenerate/redox-inactive, and biochemically the catalytic center behaves as a thiol-disulfide reductase rather than an oxidase. TXNDC11 forms a stable, disulfide-linked complex with the ER mannosidase-like protein EDEM2, and this covalent partnership is required for the initial mannose-trimming step (Man9 to Man8) that commits misfolded N-glycoproteins to ER-associated degradation (glycoprotein ERAD). TXNDC11 was originally identified through its interaction with the cytoplasmic regions of the dual oxidases DUOX1 and DUOX2 and with thyroid peroxidase, suggesting a redox-regulatory role linked to the thyroid hydrogen-peroxide-generating system, though TXNDC11 alone is not sufficient to support DUOX-mediated H2O2 generation. It is widely but weakly expressed, with higher expression in thyroid and prostate. alternative_products: - name: '1' id: Q6PKC3-1 - name: '2' id: Q6PKC3-2 sequence_note: VSP_014335 - name: '3' id: Q6PKC3-3 sequence_note: VSP_014336, VSP_014337 existing_annotations: - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: >- TXNDC11 is a single-pass ER membrane protein; the ER membrane localization is its primary subcellular location and is consistent with its luminal thioredoxin-domain redox/chaperone function and its partnership with the ER mannosidase EDEM2. action: ACCEPT reason: >- Correct primary localization, matching the UniProt curated subcellular location and the protein's documented role as an ER-resident oxidoreductase. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17500595 qualifier: enables review: summary: >- IntAct capture of a TXNDC11-HTT (huntingtin) interaction from a huntingtin-interacting protein screen. Bare protein binding is uninformative and this partner does not reflect TXNDC11's core ER redox/ERAD function. action: KEEP_AS_NON_CORE reason: >- Records a real but high-throughput interaction; per guidelines, bare protein binding is not elevated to a core function and the partner is unrelated to the EDEM2/ERAD activity. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: 'Q6PKC3; P42858: HTT; NbExp=7; IntAct=EBI-749812, EBI-466029;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18985028 qualifier: enables review: summary: >- IntAct capture of a TXNDC11-HCV (hepatitis C virus) protein interaction from a virus-host interactome screen. Uninformative bare protein binding, unrelated to the core function. action: KEEP_AS_NON_CORE reason: >- Real but high-throughput xeno interaction; per guidelines not elevated to core, and the partner does not reflect TXNDC11's ER oxidoreductase/ERAD role. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: 'Q6PKC3; PRO_0000037551 [Q9WMX2]; Xeno; NbExp=2; IntAct=EBI-749812, EBI-6863748;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: >- IntAct captures from the HuRI binary interactome (partners including KLHL38, MKRN3, PRPF18, RAB2B, ZNF417). Uninformative bare protein binding from a systematic two-hybrid screen. action: KEEP_AS_NON_CORE reason: >- High-throughput binary interactome data; bare protein binding is not a core function and these partners do not reflect the EDEM2/ERAD or DUOX redox roles. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: 'Q6PKC3; Q2WGJ6: KLHL38; NbExp=3; IntAct=EBI-749812, EBI-6426443;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: >- IntAct capture from a neurodegenerative-disease interactome screen (HTT among partners). Uninformative bare protein binding. action: KEEP_AS_NON_CORE reason: >- High-throughput interactome data; bare protein binding is not elevated to core and the partner does not reflect TXNDC11's core ER redox/ERAD function. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: 'Q6PKC3; P42858: HTT; NbExp=7; IntAct=EBI-749812, EBI-466029;' - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- HPA immunofluorescence-based cytosol annotation. TXNDC11 is a single-pass ER membrane protein with luminal thioredoxin domains; a primary cytosolic localization is not supported by its biology, and HPA reticular staining can be scored loosely. Retained as non-core rather than removed since it is an experimental (IDA) localization. action: KEEP_AS_NON_CORE reason: >- Conflicts with the curated ER membrane localization and the protein's topology; kept as non-core per the rule against removing experimental annotations on weak grounds. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: >- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: >- HPA immunofluorescence plasma-membrane annotation. This is consistent with the legacy EFP1/DUOX thyroid-system context (DUOX1/2 are plasma/apical-membrane oxidases) but is not TXNDC11's primary ER localization. action: KEEP_AS_NON_CORE reason: >- Peripheral localization tied to the DUOX/thyroid context; not the core ER site of action. Retained as non-core as an experimental annotation. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: Interacts with the cytoplasmic part of DUOX1 and DUOX2. - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-209815 qualifier: located_in review: summary: >- Reactome plasma-membrane annotation derived from the thyroxine-biosynthesis reaction context (EFP1/DUOX thyroid H2O2 system at the follicular apical membrane). action: KEEP_AS_NON_CORE reason: >- Legacy thyroid reaction-context localization; not the protein's primary ER location. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: Interacts with the cytoplasmic part of DUOX1 and DUOX2. - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-209840 qualifier: located_in review: summary: >- Reactome plasma-membrane annotation from the thyroxine-biosynthesis (DUOX) reaction context. action: KEEP_AS_NON_CORE reason: >- Legacy thyroid reaction-context localization; not the protein's primary ER location. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: Interacts with the cytoplasmic part of DUOX1 and DUOX2. - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-209925 qualifier: located_in review: summary: >- Reactome plasma-membrane annotation from the thyroxine-biosynthesis (DUOX) reaction context. action: KEEP_AS_NON_CORE reason: >- Legacy thyroid reaction-context localization; not the protein's primary ER location. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: Interacts with the cytoplasmic part of DUOX1 and DUOX2. - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-209973 qualifier: located_in review: summary: >- Reactome plasma-membrane annotation from the thyroxine-biosynthesis (DUOX) reaction context. action: KEEP_AS_NON_CORE reason: >- Legacy thyroid reaction-context localization; not the protein's primary ER location. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: Interacts with the cytoplasmic part of DUOX1 and DUOX2. - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-350901 qualifier: located_in review: summary: >- Reactome plasma-membrane annotation from the thyroxine-biosynthesis (DUOX) reaction context. action: KEEP_AS_NON_CORE reason: >- Legacy thyroid reaction-context localization; not the protein's primary ER location. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: Interacts with the cytoplasmic part of DUOX1 and DUOX2. - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5693681 qualifier: located_in review: summary: >- Reactome plasma-membrane annotation from the DUOX1 H2O2-generating reaction context. action: KEEP_AS_NON_CORE reason: >- Legacy thyroid reaction-context localization; not the protein's primary ER location. supported_by: - reference_id: file:human/TXNDC11/TXNDC11-uniprot.txt supporting_text: Interacts with the cytoplasmic part of DUOX1 and DUOX2. core_functions: - description: >- ER thiol-disulfide oxidoreductase (reductase) that, via the single redox-active CXXC motif in its Trx5 domain, forms a covalent disulfide-linked complex with EDEM2 required for EDEM2-mediated mannose trimming that initiates glycoprotein ERAD. molecular_function: id: GO:0015035 label: protein-disulfide reductase activity locations: - id: GO:0005789 label: endoplasmic reticulum membrane supported_by: - reference_id: PMID:32065582 supporting_text: >- C558 present outside of the mannosidase homology domain of EDEM2 was linked to C692 in Trx5, which solely contains the CXXC motif in TXNDC11 proposed_new_terms: - proposed_name: protein-disulfide reductase activity (Trx5 CXXC) proposed_definition: >- Molecular function: TXNDC11 Trx5 domain CXXC (C692-C695) exhibits thiol-disulfide reductase activity and forms a covalent disulfide with EDEM2; recommend annotating GO:0015035 protein-disulfide reductase activity (or GO:0003756 protein disulfide isomerase activity). justification: >- Experimentally established core molecular function (PMID:32065582) that is absent from the current GOA, which lists only protein binding for the MF aspect. supported_by: - reference_id: PMID:32065582 supporting_text: >- The Trx5 domain expressed and purified from cells exhibited reductase activity in vitro. full_text_unavailable: true - proposed_name: ERAD pathway / glycoprotein mannose trimming initiation proposed_definition: >- Biological process: TXNDC11 is required, via its disulfide-linked EDEM2 complex, for the first mannose-trimming step of glycoprotein ERAD; recommend annotating GO:0036503 (ERAD pathway) or glycoprotein catabolic process terms. justification: >- Well-supported biological role absent from current GOA (PMID:32065582; PMID:30374462). supported_by: - reference_id: PMID:32065582 supporting_text: >- This covalent bonding was essential for mannose trimming and subsequent gpERAD in HCT116 cells. references: - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: Reactome:R-HSA-209815 title: Tyrosine is monoiodinated findings: [] - id: Reactome:R-HSA-209840 title: Two DITs combine to form thyroxine findings: [] - id: Reactome:R-HSA-209925 title: DIT and MIT combine to form triiodothyronine findings: [] - id: Reactome:R-HSA-209973 title: Tyrosine is diiodinated findings: [] - id: Reactome:R-HSA-350901 title: Iodide is organified findings: [] - id: Reactome:R-HSA-5693681 title: DUOX1 reduces O2 to H2O2 findings: [] - id: PMID:17500595 title: Huntingtin interacting proteins are genetic modifiers of neurodegeneration. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: >- High-throughput huntingtin-interactome screen; source of the TXNDC11-HTT IntAct protein binding capture. Not relevant to TXNDC11's core ER redox/ERAD function. - id: PMID:18985028 title: Hepatitis C virus infection protein network. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: >- Virus-host interactome screen; source of a xeno HCV interaction. Not relevant to the core function. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: >- HuRI binary interactome; source of several systematic two-hybrid protein binding captures. - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: >- Neurodegenerative-disease interactome screen; source of a protein binding capture. - id: PMID:15561711 title: 'Identification of a novel partner of duox: EFP1, a thioredoxin-related protein.' findings: - statement: >- TXNDC11/EFP1 interacts with the cytoplasmic regions of DUOX1 and DUOX2 and with thyroid peroxidase, implicating it as a redox regulator in the thyroid H2O2-generating system, though it is not sufficient for DUOX-mediated H2O2 generation. reference_section_type: ABSTRACT full_text_unavailable: true reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Original identification of EFP1/TXNDC11 as a DUOX partner; basis of the UniProt FUNCTION and SUBUNIT statements and the Reactome thyroid/plasma-membrane annotations. Cached full text unavailable; verified via the UniProt entry which cites this paper for the DUOX/TPO/CYBA interactions and tissue specificity. - id: PMID:32065582 title: >- EDEM2 stably disulfide-bonded to TXNDC11 catalyzes the first mannose trimming step in mammalian glycoprotein ERAD. findings: - statement: >- EDEM2 is stably disulfide-bonded to TXNDC11 (C558 of EDEM2 to C692 in the Trx5 domain, the only CXXC-containing Trx domain of TXNDC11); this covalent bond is essential for mannose trimming and subsequent glycoprotein ERAD. reference_section_type: ABSTRACT - statement: >- The Trx5 domain of TXNDC11 exhibits reductase activity in vitro; TXNDC11 functions as a reductase rather than an oxidase in this complex. reference_section_type: RESULTS full_text_unavailable: true reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Definitive study establishing TXNDC11's core function as the disulfide-linked EDEM2 partner required for the first mannose-trimming step of glycoprotein ERAD, with Trx5 CXXC reductase activity. Not in the current GOA; basis for the proposed new MF/BP terms. Cached full text unavailable; quotes verified against the gene notes deep-research summary. - id: PMID:30374462 title: >- Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates. findings: - statement: >- EDEMs associate with oxidoreductases including TXNDC11, enhancing mannosidase activity on glycoproteins. reference_section_type: ABSTRACT full_text_unavailable: true reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Corroborates the EDEM-TXNDC11 oxidoreductase association supporting mannose trimming. Cached full text unavailable. - id: PMID:37686174 title: >- High Thioredoxin Domain-Containing Protein 11 Expression Is Associated with Tumour Progression in Glioma. findings: - statement: >- High TXNDC11 protein expression is associated with WHO high-grade tumour classification and poor prognosis in glioma and is an independent prognostic factor; TXNDC11 silencing inhibits proliferation, migration and invasion and induces apoptosis in GBM cells, while overexpression has the opposite effect. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (PMID:37686174, DOI:10.3390/ijms241713367). Gene-specific translational study proposing TXNDC11 as an oncogene/prognostic biomarker and candidate therapeutic target in glioblastoma. Disease-association evidence, not core ER redox/ERAD function; informs a non-core disease role. - id: PMID:37528230 title: >- Mechanisms of substrate processing during ER-associated protein degradation. findings: - statement: >- Authoritative 2023 review placing TXNDC11 among mammalian ERAD factors that coordinate recognition, processing, ubiquitylation, extraction and proteasomal targeting of ER substrates. reference_section_type: LITERATURE_REVIEW reference_review: relevance: LOW correctness: VERIFIED review_notes: >- PubMed-verified (PMID:37528230, DOI:10.1038/s41580-023-00633-8). Expert review providing consensus framing of TXNDC11 within ER quality control/ERAD networks; contextual/background rather than primary evidence for this gene. - id: DOI:10.1248/bpbreports.6.6_193 title: >- Regulation of the ER-Resident Mannosidase EDEM2 in HEK293 Cells. findings: - statement: >- TXNDC11 deficiency markedly decreases EDEM2 protein without a corresponding decrease in EDEM2 mRNA, indicating that TXNDC11 post-transcriptionally stabilizes EDEM2; reductive stress (DTT) destabilizes both EDEM2 and TXNDC11 protein, and the destabilized EDEM2 can become an SEL1L-dependent ERAD substrate. reference_section_type: RESULTS full_text_unavailable: true reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: >- Identifier resolved to BPB Reports 6:193-199 (2023) via DOI:10.1248/bpbreports.6.6_193; journal is not indexed in PubMed so no PMID is available and full text is not cached. Falcon deep-research reports it shows TXNDC11 is required for EDEM2 protein stability, extending the EDEM2-TXNDC11 partnership; topic/title confirmed but findings not independently verified against cached full text. - id: file:human/TXNDC11/TXNDC11-uniprot.txt title: UniProt entry Q6PKC3 (TXD11_HUMAN), Thioredoxin domain-containing protein 11 findings: - statement: >- Single-pass ER membrane protein of the protein disulfide isomerase family with thioredoxin domains and redox-active CXXC; identified as a DUOX1/DUOX2/TPO/CYBA-interacting redox regulator (EFP1); higher expression in thyroid and prostate. reference_section_type: OTHER suggested_questions: - question: >- Is the legacy EFP1/DUOX thyroid-system role a genuine in vivo function of TXNDC11, or an incidental interaction superseded by the EDEM2/ERAD role? - question: >- Beyond EDEM2, does the Trx5 reductase activity of TXNDC11 act on other ER substrates or redox partners during oxidative protein folding? suggested_experiments: - description: >- Reconstitute the purified EDEM2-TXNDC11 complex and assay mannose trimming (Man9 to Man8) with and without Trx5 CXXC (C692/C695) mutations to confirm the redox requirement. - description: >- Quantitative proteomics of glycoprotein ERAD substrates stabilized upon TXNDC11 knockout in human cells to define the endogenous substrate repertoire dependent on the EDEM2-TXNDC11 step.