id: Q9P2K2 gene_symbol: TXNDC16 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- 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. existing_annotations: - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: 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. action: KEEP_AS_NON_CORE reason: >- Secretion is genuine but secondary; the protein's primary site is the ER lumen. supported_by: - reference_id: file:human/TXNDC16/TXNDC16-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Secreted' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: 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. action: ACCEPT reason: >- Correct primary localization; TXNDC16/ERp90 is a soluble ER-luminal glycoprotein. supported_by: - reference_id: file:human/TXNDC16/TXNDC16-uniprot.txt supporting_text: Endoplasmic reticulum lumen - term: id: GO:0005576 label: extracellular region evidence_type: EXP original_reference_id: PMID:25122923 qualifier: located_in review: 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. action: KEEP_AS_NON_CORE reason: >- Genuine secretion arising from the masked KDEL motif, but secondary to the primary ER-lumen localization. supported_by: - reference_id: PMID:25122923 supporting_text: >- We were able to show TXNDC16 secretion in different human cell lines due to masked and therefore nonfunctional ER retrieval motif. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: EXP original_reference_id: PMID:25122923 qualifier: located_in review: summary: >- Experimental confirmation of the ER-luminal glycoprotein localization of TXNDC16. action: ACCEPT reason: >- Correct primary localization, consistent with the IDA and electronic annotations. supported_by: - reference_id: PMID:25122923 supporting_text: >- TXNDC16 was previously found to be an endoplasmic reticulum (ER)-luminal glycoprotein. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21359175 qualifier: enables review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: PMID:21359175 supporting_text: >- ERp90 co-immunoprecipitates with ERFAD, a flavoprotein involved in ER-associated degradation (ERAD), through what is most likely a direct interaction. - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IDA original_reference_id: PMID:21359175 qualifier: located_in review: summary: >- Direct evidence that ERp90/TXNDC16 is a soluble ER-luminal glycoprotein. action: ACCEPT reason: >- Experimentally supported primary localization. supported_by: - reference_id: PMID:21359175 supporting_text: >- we find ERp90 to be a soluble ER-luminal glycoprotein that comprises five potential thioredoxin (Trx)-like domains. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19199708 qualifier: located_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: PMID:25122923 supporting_text: >- A previously indicated exosomal TXNDC16 secretion could not be confirmed in HEK293 cells. core_functions: - description: >- ER-luminal PDI-family glycoprotein that lacks a canonical CXXC redox motif and acts as a direct interaction partner of the ERAD flavoprotein ERFAD (FOXRED2), proposed to function in recruitment or delivery of substrates to the ERAD retrotranslocation machinery. locations: - id: GO:0005788 label: endoplasmic reticulum lumen supported_by: - reference_id: PMID:21359175 supporting_text: >- We propose that the function of ERp90 is related to substrate recruitment or delivery to the ERAD retrotranslocation machinery by ERFAD. knowledge_gaps: - gap_statement: >- 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. boundary: >- 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. gap_kind: - BIOLOGY - ONTOLOGY dark_aspect: MF_DARK status: OPEN 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. resolution: >- 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: - reference_id: PMID:21359175 supporting_text: >- While none of the Trx domains contain a canonical Cys-Xaa-Xaa-Cys active-site motif, other conserved cysteines could endow the protein with redox activity. reference_section_type: ABSTRACT - reference_id: PMID:21359175 supporting_text: >- Finally, ERp90 could perform a CXXC-independent redox function, conceivably in collaboration with the redox-active ERFAD, through the conserved C664 or even the CX9C motif in the Trx2. reference_section_type: DISCUSSION - gap_statement: >- 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. boundary: >- 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. gap_kind: - BIOLOGY dark_aspect: BP_DARK status: OPEN 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. resolution: >- 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: - reference_id: PMID:21359175 supporting_text: >- Since we did not succeed in performing siRNA-mediated knockdown experiments of ERp90 to study an involvement of ERp90 in ERAD, we can presently only speculate about the function of ERp90 in relation to ERFAD. reference_section_type: DISCUSSION - reference_id: PMID:21359175 supporting_text: >- Future work should allow us to distinguish between these various possibilities. reference_section_type: DISCUSSION - gap_statement: >- 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. boundary: >- 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. gap_kind: - BIOLOGY - CURATION dark_aspect: RESIDUAL_SUBGAP status: OPEN 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. resolution: >- 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: - reference_id: PMID:25122923 supporting_text: >- We were able to show TXNDC16 secretion in different human cell lines due to masked and therefore nonfunctional ER retrieval motif. reference_section_type: ABSTRACT - reference_id: PMID:25122923 supporting_text: >- The secreted serum protein TXNDC16 is bound in circulating immune complexes, which were found both in meningioma and healthy blood donor sera. reference_section_type: ABSTRACT - reference_id: PMID:25122923 supporting_text: >- A previously indicated exosomal TXNDC16 secretion could not be confirmed in HEK293 cells. reference_section_type: ABSTRACT proposed_new_terms: [] 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: PMID:19199708 title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: >- High-throughput exosome proteomics; source of the extracellular exosome annotation, which a later study could not reproduce. Not informative for TXNDC16's molecular function. - id: PMID:21359175 title: Identification of the PDI-family member ERp90 as an interaction partner of ERFAD. findings: - statement: >- ERp90/TXNDC16 is a soluble ER-luminal glycoprotein with about five potential thioredoxin domains, none of which contain a canonical CXXC active-site motif; it directly interacts with the ERAD flavoprotein ERFAD (FOXRED2), suggesting a role in substrate recruitment/delivery to the ERAD retrotranslocation machinery. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full-text cached; the defining functional characterization of TXNDC16/ERp90, establishing ER- lumen localization, the absence of a canonical CXXC motif, and the ERFAD/ERAD interaction. - id: PMID:25122923 title: Secretion and immunogenicity of the meningioma-associated antigen TXNDC16. findings: - statement: >- TXNDC16 is an ER-luminal glycoprotein that is secreted from human cell lines because its KDEL ER-retrieval motif is masked and non-functional; it is a meningioma-associated antigen, and a previously reported exosomal secretion could not be confirmed. reference_section_type: ABSTRACT full_text_unavailable: true reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- Cached entry is abstract-only; supports the ER-lumen localization, the masked-KDEL-driven secretion, and casts doubt on the exosomal localization. - id: PMID:32971745 title: Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD. findings: - statement: >- Authoritative review that classifies ERp90/TXNDC16 as a non-catalytic PDI-family member whose thioredoxin-like domains carry non-canonical motifs (CX8C, CX9C, CX6C) rather than active CXXC, and places it within the ERAD retrotranslocation network alongside factors such as OS-9 and SEL1L. reference_section_type: LITERATURE_REVIEW reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: >- PubMed-verified (PMID:32971745, DOI:10.3390/cells9092138). Review-level synthesis that corroborates the primary finding (PMID:21359175) that TXNDC16/ERp90 lacks a canonical CXXC and is likely non-catalytic, and frames it within ERAD glycoprotein quality control. The specific non-canonical motif assignments and OS-9/SEL1L associations are review/family-level inferences, not gene-specific primary data, so no new annotations are derived from them. - id: PMID:38673779 title: Innovation in Non-Invasive Diagnosis and Disease Monitoring for Meningiomas. findings: - statement: >- Review of meningioma liquid-biopsy approaches that summarizes prior work on TXNDC16 as a meningioma-associated antigen, noting a five-epitope autoantibody panel discriminating meningioma from healthy sera with ~90% sensitivity and ~83.7% specificity as a proof-of-concept serology biomarker. reference_section_type: LITERATURE_REVIEW reference_review: relevance: LOW correctness: VERIFIED review_notes: >- PubMed-verified (PMID:38673779, DOI:10.3390/ijms25084195). Secondary review that restates the Harz 2014 (PMID:25122923) TXNDC16 meningioma autoantibody/biomarker findings; contextual disease/biomarker relevance only, not new mechanistic evidence for the gene's molecular function. - id: file:human/TXNDC16/TXNDC16-uniprot.txt title: UniProt entry Q9P2K2 (TXD16_HUMAN), Thioredoxin domain-containing protein 16 findings: - statement: >- Large PDI-family ER-luminal glycoprotein (ERp90) with a thioredoxin domain and a masked, non-functional KDEL ER-retention motif; interacts with FOXRED2 (ERFAD); secreted. reference_section_type: OTHER suggested_questions: - question: >- 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? - question: >- Is the proposed ERAD substrate-recruitment/delivery role (via ERFAD/FOXRED2) borne out by identifying endogenous ERAD substrates whose degradation depends on TXNDC16? suggested_experiments: - description: >- 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. - description: >- 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.