TXNDC16 (Thioredoxin domain-containing protein 16; also called ERp90 or KIAA1344) is a large (825 aa precursor) soluble glycoprotein of the protein disulfide isomerase (PDI) family resident in the endoplasmic reticulum lumen. After signal-peptide cleavage it comprises several (about five) thioredoxin (Trx)-like domains and is N-glycosylated, with at least some of its cysteines forming intramolecular disulfides. Notably, none of its Trx domains contains a canonical Cys-Xaa-Xaa-Cys redox active-site motif, so it is likely a redox-inactive or non-catalytic PDI-family member whose precise enzymatic activity remains uncharacterized. Its best-supported molecular role is as a direct interaction partner of the ER-associated degradation (ERAD) flavoprotein ERFAD (FOXRED2), suggesting a function in recruitment or delivery of substrates to the ERAD retrotranslocation machinery. TXNDC16 carries a masked, non-functional KDEL-type ER-retrieval motif and is therefore partly secreted into the extracellular space; it has been described as a meningioma-associated antigen against which patient autoantibodies arise.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic (UniProt SubCell "Secreted") assignment of extracellular localization. TXNDC16 is partly secreted because its KDEL-type ER-retrieval motif is masked and non-functional. This is a real but secondary localization relative to its primary ER-lumen residence. Reason: Secretion is genuine but secondary; the protein's primary site is the ER lumen. Supporting Evidence: file:human/TXNDC16/TXNDC16-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic assignment of ER-lumen localization, consistent with the experimental IDA/EXP annotations and the curated subcellular location. This is the primary site of TXNDC16. Reason: Correct primary localization; TXNDC16/ERp90 is a soluble ER-luminal glycoprotein. Supporting Evidence: file:human/TXNDC16/TXNDC16-uniprot.txt Endoplasmic reticulum lumen |
| GO:0005576 extracellular region | EXP PMID:25122923 Secretion and immunogenicity of the meningioma-associated an... | KEEP AS NON CORE | Summary: Experimental demonstration that TXNDC16 is secreted from human cell lines because its ER retrieval motif is masked and non-functional. A real but secondary localization. Reason: Genuine secretion arising from the masked KDEL motif, but secondary to the primary ER-lumen localization. Supporting Evidence: PMID:25122923 We were able to show TXNDC16 secretion in different human cell lines due to masked and therefore nonfunctional ER retrieval motif. |
| GO:0005788 endoplasmic reticulum lumen | EXP PMID:25122923 Secretion and immunogenicity of the meningioma-associated an... | ACCEPT | Summary: Experimental confirmation of the ER-luminal glycoprotein localization of TXNDC16. Reason: Correct primary localization, consistent with the IDA and electronic annotations. Supporting Evidence: PMID:25122923 TXNDC16 was previously found to be an endoplasmic reticulum (ER)-luminal glycoprotein. |
| GO:0005515 protein binding | IPI PMID:21359175 Identification of the PDI-family member ERp90 as an interact... | KEEP AS NON CORE | Summary: Co-immunoprecipitation showing TXNDC16/ERp90 directly interacts with ERFAD (FOXRED2), an ER flavoprotein involved in ERAD. This is the functionally most informative interaction for TXNDC16, suggesting an ERAD substrate-recruitment/delivery role, but the bare protein binding term itself is uninformative. Reason: Records a genuine, functionally meaningful ERAD-related interaction, but per guidelines bare protein binding is not elevated to a core molecular function; a more specific adapter/ERAD term would be preferable if the role is confirmed. Supporting Evidence: PMID:21359175 ERp90 co-immunoprecipitates with ERFAD, a flavoprotein involved in ER-associated degradation (ERAD), through what is most likely a direct interaction. |
| GO:0005788 endoplasmic reticulum lumen | IDA PMID:21359175 Identification of the PDI-family member ERp90 as an interact... | ACCEPT | Summary: Direct evidence that ERp90/TXNDC16 is a soluble ER-luminal glycoprotein. Reason: Experimentally supported primary localization. Supporting Evidence: PMID:21359175 we find ERp90 to be a soluble ER-luminal glycoprotein that comprises five potential thioredoxin (Trx)-like domains. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: High-throughput proteomic detection of TXNDC16 in parotid-gland exosomes. A later study could not confirm exosomal secretion in HEK293 cells, so this localization is uncertain; retained as non-core rather than removed since it is a proteomics-based experimental detection. Reason: Proteomic detection in exosomes that was not reproduced in a subsequent study (PMID:25122923); uncertain and non-core, but not removed on weak grounds. Supporting Evidence: PMID:25122923 A previously indicated exosomal TXNDC16 secretion could not be confirmed in HEK293 cells. |
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Download this section (compressed HTML)Q: Does TXNDC16/ERp90 possess any thiol-disulfide redox activity despite lacking a canonical CXXC motif, using its other conserved cysteines, or is it a purely non-catalytic scaffold/adapter?
Q: Is the proposed ERAD substrate-recruitment/delivery role (via ERFAD/FOXRED2) borne out by identifying endogenous ERAD substrates whose degradation depends on TXNDC16?
Experiment: Knock out TXNDC16 in human cells and assay the degradation kinetics of model ERAD substrates, with and without ERFAD/FOXRED2, to test the proposed substrate-delivery function.
Experiment: Perform in vitro redox assays (e.g., insulin turbidimetric reduction, RNase refolding) with purified TXNDC16 and active-site cysteine mutants to determine whether it has any catalytic oxidoreductase activity in the absence of a canonical CXXC motif.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: It is unresolved whether TXNDC16/ERp90 is a purely non-catalytic PDI-family scaffold/adaptor or whether it performs a CXXC-independent redox activity using conserved noncanonical cysteines.
OPEN BIOLOGYONTOLOGY MF_DARK
What is known: ERp90 is a soluble ER-luminal PDI-family glycoprotein with five Trx-like domains and no canonical Cys-Xaa-Xaa-Cys active-site motif; some cysteines form intramolecular disulfides. The open question is whether those noncanonical cysteines are structural only or contribute directly to redox chemistry.
Significance: The molecular function cannot be curated more specifically than ER-lumen localization and ERFAD binding until this distinction is resolved; a catalytic oxidoreductase role and a non-catalytic substrate-adaptor role imply different GO molecular functions.
What would resolve it: Purify full-length ERp90 and cysteine mutants for redox assays, disulfide-state mapping, and ERFAD-dependent substrate handoff assays in parallel with cellular rescue experiments.
Provenance (the field's own admissions):
Gap: The ERAD substrate set and pathway step that depend on TXNDC16 remain unknown. ERp90 is proposed to help ERFAD recruit or deliver substrates to the retrotranslocation machinery, but no endogenous substrates or loss-of-function ERAD defects have been demonstrated.
OPEN BIOLOGY BP_DARK
What is known: TXNDC16/ERp90 physically associates with ERFAD/FOXRED2 and is positioned in the ERAD luminal network. What is missing is functional evidence that specific glycoprotein or disulfide-containing ERAD clients require TXNDC16 for recognition, reduction, handoff to SEL1L/OS-9, retrotranslocation, or degradation.
Significance: This gap separates an interaction-based ERAD hypothesis from a process annotation. Resolving it would define whether TXNDC16 is a core ERAD factor, a client-specific cofactor, or a bystander in an ERFAD-containing complex.
What would resolve it: Generate TXNDC16 knockout/rescue cells and measure degradation, disulfide status, and retrotranslocation of model and proteome-wide ERAD substrates, including ERFAD-dependent and ERFAD-independent contexts.
Provenance (the field's own admissions):
Gap: The biological significance of TXNDC16 secretion and meningioma-associated autoantibodies is unclear. TXNDC16 is secreted because its ER-retrieval motif is masked, and antibodies can distinguish meningioma sera, but it is not known whether extracellular TXNDC16 has a function or is mainly a biomarker/immunogenic byproduct of leakage from the ER-lumen pool.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: Secretion from multiple human cell lines and circulating immune complexes are documented, while exosomal secretion was not confirmed in HEK293 cells. The unresolved part is whether secreted TXNDC16 participates in disease biology, antigen presentation, or immune-complex formation beyond diagnostic association.
Significance: This limits curation of extracellular annotations: secretion is real and should be retained, but disease-associated immunogenicity should not be interpreted as a normal extracellular molecular function without mechanistic evidence.
What would resolve it: Determine the source and form of serum TXNDC16 in meningioma and controls, test whether immune complexes contain intact secreted protein or fragments, and assess any extracellular effects on immune or tumor cells.
Provenance (the field's own admissions):
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