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.
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.
Supporting Evidence:
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).
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | 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. Reason: Correct primary localization, matching the UniProt curated subcellular location and the protein's documented role as an ER-resident oxidoreductase. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu... | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Q6PKC3; P42858: HTT; NbExp=7; IntAct=EBI-749812, EBI-466029; |
| GO:0005515 protein binding | IPI PMID:18985028 Hepatitis C virus infection protein network. | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Q6PKC3; PRO_0000037551 [Q9WMX2]; Xeno; NbExp=2; IntAct=EBI-749812, EBI-6863748; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Q6PKC3; Q2WGJ6: KLHL38; NbExp=3; IntAct=EBI-749812, EBI-6426443; |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: IntAct capture from a neurodegenerative-disease interactome screen (HTT among partners). Uninformative bare protein binding. 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. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Q6PKC3; P42858: HTT; NbExp=7; IntAct=EBI-749812, EBI-466029; |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | 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. Reason: Peripheral localization tied to the DUOX/thyroid context; not the core ER site of action. Retained as non-core as an experimental annotation. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Interacts with the cytoplasmic part of DUOX1 and DUOX2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-209815 | KEEP AS NON CORE | Summary: Reactome plasma-membrane annotation derived from the thyroxine-biosynthesis reaction context (EFP1/DUOX thyroid H2O2 system at the follicular apical membrane). Reason: Legacy thyroid reaction-context localization; not the protein's primary ER location. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Interacts with the cytoplasmic part of DUOX1 and DUOX2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-209840 | KEEP AS NON CORE | Summary: Reactome plasma-membrane annotation from the thyroxine-biosynthesis (DUOX) reaction context. Reason: Legacy thyroid reaction-context localization; not the protein's primary ER location. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Interacts with the cytoplasmic part of DUOX1 and DUOX2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-209925 | KEEP AS NON CORE | Summary: Reactome plasma-membrane annotation from the thyroxine-biosynthesis (DUOX) reaction context. Reason: Legacy thyroid reaction-context localization; not the protein's primary ER location. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Interacts with the cytoplasmic part of DUOX1 and DUOX2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-209973 | KEEP AS NON CORE | Summary: Reactome plasma-membrane annotation from the thyroxine-biosynthesis (DUOX) reaction context. Reason: Legacy thyroid reaction-context localization; not the protein's primary ER location. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Interacts with the cytoplasmic part of DUOX1 and DUOX2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-350901 | KEEP AS NON CORE | Summary: Reactome plasma-membrane annotation from the thyroxine-biosynthesis (DUOX) reaction context. Reason: Legacy thyroid reaction-context localization; not the protein's primary ER location. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Interacts with the cytoplasmic part of DUOX1 and DUOX2. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5693681 | KEEP AS NON CORE | Summary: Reactome plasma-membrane annotation from the DUOX1 H2O2-generating reaction context. Reason: Legacy thyroid reaction-context localization; not the protein's primary ER location. Supporting Evidence: file:human/TXNDC11/TXNDC11-uniprot.txt Interacts with the cytoplasmic part of DUOX1 and DUOX2. |
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Download this section (compressed HTML)Q: 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?
Q: Beyond EDEM2, does the Trx5 reductase activity of TXNDC11 act on other ER substrates or redox partners during oxidative protein folding?
Experiment: 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.
Experiment: 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.
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