{"gene":"PDIA6","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":1995,"finding":"The cDNA encoding human P5 (PDIA6) was cloned and sequenced. The predicted 440-amino-acid sequence contains two thioredoxin-like domains characteristic of the protein disulfide isomerase superfamily.","method":"cDNA cloning and sequence analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — foundational cloning and structural characterization, single study","pmids":["7590364"],"is_preprint":false},{"year":2007,"finding":"PDIA6 (ERp5/P5) is present on the surface of tumor cells and associates with membrane-anchored MICA via transitory mixed disulfide complexes. Reduction of the alpha3 domain disulfide bond of MICA by cell-surface PDIA6 is required for proteolytic MICA shedding, promoting tumor immune evasion. Pharmacological inhibition of thioreductase activity and PDIA6 gene silencing both abolished MICA shedding.","method":"Co-immunoprecipitation, gene silencing (siRNA), pharmacological inhibition, cell-surface biochemistry","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic knockdown, and pharmacological inhibition with specific mechanistic readout; high citation count","pmids":["17495932"],"is_preprint":false},{"year":2009,"finding":"P5 (PDIA6) forms a non-covalent complex with BiP (immunoglobulin heavy chain binding protein) and shows substrate specificity towards BiP client proteins, distinguishing it functionally from other PDI family members such as ERp57 and ERp46.","method":"Co-immunoprecipitation, substrate specificity trapping assays","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with substrate specificity profiling across multiple PDI family members; high citation count","pmids":["19887585"],"is_preprint":false},{"year":2008,"finding":"P5 (PDIA6) is present in mitochondria, in addition to its known ER localization. Identification was achieved via affinity chromatography using a phage antibody recognizing the CGHC motif, confirmed by Western blot, mass spectrometry, cell fractionation, proteinase protection assays, and immuno-electron microscopy.","method":"Affinity chromatography, Western blot, mass spectrometry, cell fractionation, proteinase protection, immuno-electron microscopy","journal":"Journal of Biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal localization methods including immuno-EM","pmids":["18424807"],"is_preprint":false},{"year":2010,"finding":"Pig PDI-P5 (PDIA6 ortholog) exhibits anti-chaperone activity in vitro: while showing thiol-dependent disulfide reductase activity, it inhibits oxidative refolding of reduced denatured lysozyme by catalyzing formation of disulfide cross-linked, non-productively folded lysozyme, contrasting with PDIA3 which promotes refolding. PDI-P5 is down-regulated from epididymal corpus to cauda sperm.","method":"In vitro insulin turbidity reductase assay, oxidative refolding assay with lysozyme, SDS-PAGE/Western blot, 2D gel electrophoresis, peptide mass fingerprinting","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic assays with ortholog; single study","pmids":["20152940"],"is_preprint":false},{"year":2014,"finding":"PDIA6 physically interacts with IRE1α and enhances IRE1α activity (monitored by IRE1α phosphorylation and XBP1 mRNA splicing) selectively in response to ER Ca2+ depletion, but does not substantially affect PERK or ATF6 pathways. miR-322 suppresses PDIA6 mRNA stability; ER Ca2+ depletion reduces miR-322 abundance, increasing PDIA6 expression and consequently IRE1α activity. In vivo mouse and C. elegans experiments confirmed this feedback loop.","method":"Co-immunoprecipitation, phosphorylation assays, XBP1 mRNA splicing assay, miRNA manipulation, in vivo mouse/worm ER stress models","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 2 — Co-IP of PDIA6-IRE1α, multiple orthogonal methods, in vivo validation in two organisms","pmids":["24917591"],"is_preprint":false},{"year":2015,"finding":"PDIA6 interacts with both PERK and IRE1α and inhibits their UPR signaling. In insulin-producing beta cells, PDIA6 knockdown selectively enhances RIDD (regulated IRE1-dependent decay) activity toward insulin transcripts up to 4-fold at physiological glucose concentrations, reducing insulin production and glucose-stimulated insulin secretion, without affecting XBP1 splicing. This demonstrates that PDIA6 attenuates IRE1 enzymatic activities to maintain physiological signaling.","method":"shRNA silencing, RT-PCR/molecular assays, fluorescent RIDD reporter in intact islets, PERK inhibitor experiments","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 2 — genetic knockdown with multiple molecular readouts, fluorescent reporter in intact tissue, pharmacological controls","pmids":["26487694"],"is_preprint":false},{"year":2016,"finding":"PDIA6 co-immunoprecipitates with wild-type proinsulin and preferentially associates (~10-fold more) with misfolded Akita mutant proinsulin (Cys96Tyr) compared to other PDI family members, suggesting a specific role as a reductase targeting misfolded proinsulin to the ER degradation pathway.","method":"Co-immunoprecipitation of FLAG-tagged proinsulin constructs, mass spectrometry interactome analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with MS confirmation, replicated in second beta cell line; single lab","pmids":["26947243"],"is_preprint":false},{"year":2016,"finding":"PDIA6 knockdown in bladder cancer cells reduces β-catenin, cyclin D1, and c-Myc protein expression, suppressing Wnt/β-catenin signaling, and decreases cell proliferation and invasion both in vitro and in vivo in xenograft models.","method":"siRNA knockdown, Western blot, proliferation/invasion assays, xenograft tumor model","journal":"Oncology Research","confidence":"Medium","confidence_rationale":"Tier 3 — loss-of-function with defined pathway readout; single lab, single approach per method","pmids":["27760590"],"is_preprint":false},{"year":2016,"finding":"PDIA6 overexpression in HeLa cells promotes proliferation by suppressing phosphorylation of β-catenin at Ser45 and Ser33/Ser37/Thr41, thereby inhibiting ubiquitin-proteasome-mediated β-catenin degradation and increasing nuclear β-catenin accumulation with upregulation of Wnt target genes cyclin D1 and c-Myc. The effect was abolished by the proteasome inhibitor MG132.","method":"Ectopic overexpression, Western blot, cell cycle analysis, ubiquitin-proteasome inhibitor rescue experiment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression with pathway rescue, mechanistic follow-up; single lab","pmids":["27462866"],"is_preprint":false},{"year":2016,"finding":"PDIA6 knockdown in U87MG glioblastoma cells increases ADAM17 sheddase activity and activates EGFR signaling (elevated pEGFR, pFAK, HB-EGF), enhancing MMP-2 activation and cell migration/invasion. Simultaneous double-knockdown of PDIA6 and ADAM17 reduced pEGFR and invasion, placing PDIA6 as a negative regulator of the ADAM17/EGFR signaling axis in glioblastoma.","method":"siRNA knockdown, Western blot, wound-healing assay, Matrigel invasion assay, organotypic culture, zymography","journal":"Journal of Neurosurgery","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic epistasis via double knockdown, multiple functional readouts; single lab","pmids":["27540907"],"is_preprint":false},{"year":2019,"finding":"PDIA6 interacts with MAP4K1 (HPK1) and inhibits its phosphorylation, leading to suppression of the JNK/c-Jun signaling pathway. PDIA6 knockdown increases cisplatin-induced apoptosis and autophagy in NSCLC cells, while overexpression has the opposite effect, positioning PDIA6 as an inhibitor of the MAP4K1/JNK/c-Jun apoptotic axis.","method":"Phospho-kinase array, co-immunoprecipitation, gain- and loss-of-function, in vitro and in vivo xenograft experiments","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of PDIA6-MAP4K1, phospho-kinase array, in vivo validation; single lab","pmids":["30922965"],"is_preprint":false},{"year":2020,"finding":"In a forward genetic ENU screen, a hypomorphic Pdia6 mutation in mice causes lymphoid and myeloid hypoplasia. Bone marrow transplantation experiments showed the immune deficiency is cell-extrinsic: PDIA6-deficient bone marrow reconstituted wild-type hosts normally, but wild-type bone marrow failed to reconstitute PDIA6-deficient hosts. PDIA6 was shown to be required for proper folding/secretion of hematopoietic niche factors Wnt3a, BAFF, and IL-7 by extra-hematopoietic stromal cells.","method":"ENU forward genetic screen, bone marrow transplantation (competitive and non-competitive), Western blot for Wnt3a/BAFF/IL-7","journal":"Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 — rigorous in vivo genetic epistasis via bone marrow transplantation, multiple client proteins identified","pmids":["31985756"],"is_preprint":false},{"year":2021,"finding":"PDIA6 (P5) forms a dimer via a unique leucine-valine adhesive motif in the N-terminal thioredoxin-like domain, featuring periodic repeats of Leu/Val at the 3rd or 4th position on 15-residue anti-parallel α-helices stabilized by salt bridges and C-capping interactions. A monomeric P5 mutant with disrupted adhesive motif shows structural instability and induces ER stress. Dimerization is required for PDIA6 to inactivate IRE1α via intermolecular disulfide bond reduction and for Ca2+-dependent chaperone function regulation in vitro.","method":"X-ray crystallography/structure determination, mutagenesis, in vitro IRE1α disulfide reduction assay, ER stress reporter assay","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — structural determination with mutagenesis validation and in vitro functional assays","pmids":["33857433"],"is_preprint":false},{"year":2021,"finding":"PDIA6 overexpression in pancreatic cancer cells promotes deubiquitination of β-catenin and PD-L1 through interaction with CSN5 (COP9 signalosome subunit 5), upregulating their expression and promoting cancer progression and NK cell evasion. CSN5 shRNA partially reversed these effects.","method":"Co-immunoprecipitation of PDIA6-CSN5, gain- and loss-of-function, ubiquitination assays, xenograft models, NK cell cytotoxicity assays","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional rescue by CSN5 knockdown; single lab","pmids":["34325342"],"is_preprint":false},{"year":2022,"finding":"PDIA6 displays a novel RNA-binding activity identified by RNA interactome capture (RIC) in melanoma cells. Mapping revealed an RNA-binding domain within PDIA6, and this RNA-binding activity is required for its tumorigenic properties in metastatic progression assays.","method":"RNA interactome capture (RIC), domain mapping, loss-of-function with in vitro metastasis assays","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 — RIC with domain mapping and functional validation; single lab","pmids":["35848924"],"is_preprint":false}],"current_model":"PDIA6 is an ER-resident oxidoreductase with two thioredoxin-like domains that dimerizes via a unique leucine-valine adhesive motif; it selectively interacts with and attenuates IRE1α (via intermolecular disulfide bond reduction) and PERK to modulate the UPR, associates with BiP to process client proteins including misfolded proinsulin, promotes MICA shedding on tumor cell surfaces via disulfide exchange, contributes to hematopoiesis by folding niche-secreted factors (Wnt3a, BAFF, IL-7), regulates cancer cell proliferation and signaling through the Wnt/β-catenin and MAP4K1/JNK pathways, and possesses an unconventional RNA-binding activity required for its tumorigenic properties."},"narrative":{"teleology":[{"year":1995,"claim":"Cloning of PDIA6 established it as a PDI family member with two thioredoxin-like domains, placing it within the oxidoreductase superfamily but leaving its specific substrates and cellular roles unknown.","evidence":"cDNA cloning and sequence analysis of human P5","pmids":["7590364"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated","No substrates identified","No cellular function assigned"]},{"year":2007,"claim":"Discovery that cell-surface PDIA6 reduces the α3-domain disulfide bond of MICA to enable its proteolytic shedding revealed the first specific substrate and an extracellular function in tumor immune evasion, expanding its role beyond the ER lumen.","evidence":"Co-IP, siRNA knockdown, and pharmacological inhibition of thioreductase activity on tumor cell lines","pmids":["17495932"],"confidence":"High","gaps":["Identity of the sheddase protease activated by MICA reduction not determined","Whether PDIA6 acts on other NKG2D ligands unknown"]},{"year":2008,"claim":"Detection of PDIA6 in mitochondria by multiple orthogonal methods indicated dual ER–mitochondrial localization, raising the question of organelle-specific functions.","evidence":"Affinity chromatography, Western blot, mass spectrometry, cell fractionation, proteinase protection, and immuno-electron microscopy","pmids":["18424807"],"confidence":"High","gaps":["No mitochondrial substrate or function identified","Mechanism of mitochondrial targeting unknown"]},{"year":2009,"claim":"Identification of a non-covalent PDIA6–BiP complex with distinct client specificity compared to ERp57 and ERp46 established PDIA6 as a functionally specialized ER chaperone partner rather than a redundant PDI family member.","evidence":"Co-IP and substrate specificity trapping assays comparing PDI family members","pmids":["19887585"],"confidence":"High","gaps":["Identity of endogenous BiP clients processed by PDIA6 not comprehensively defined","Structural basis of PDIA6–BiP interaction not resolved"]},{"year":2014,"claim":"Demonstration that PDIA6 physically interacts with IRE1α and enhances its signaling selectively during ER Ca²⁺ depletion—regulated by miR-322—revealed PDIA6 as a UPR modulator and introduced a feedback circuit connecting calcium homeostasis to UPR branch selection.","evidence":"Co-IP of PDIA6–IRE1α, miRNA manipulation, XBP1 splicing assay, in vivo mouse and C. elegans ER stress models","pmids":["24917591"],"confidence":"High","gaps":["Whether PDIA6 acts on IRE1α via disulfide exchange or allosteric mechanism not resolved at this stage","Effect on ATF6 and PERK disputed between studies"]},{"year":2015,"claim":"Functional dissection in β-cells showed PDIA6 attenuates IRE1α RIDD activity toward insulin mRNA without affecting XBP1 splicing, and also interacts with PERK, demonstrating selective modulation of distinct IRE1α outputs and a broader UPR regulatory role than initially appreciated.","evidence":"shRNA silencing, fluorescent RIDD reporter in intact islets, PERK inhibitor experiments","pmids":["26487694"],"confidence":"High","gaps":["How PDIA6 differentially controls RIDD vs. XBP1 splicing mechanistically is unresolved","Stoichiometry and dynamics of PDIA6–IRE1α vs. PDIA6–PERK complexes not determined"]},{"year":2016,"claim":"Multiple studies converged to show PDIA6 stabilizes β-catenin by suppressing its phosphorylation and proteasomal degradation, promoting Wnt target gene expression, while also preferentially associating with misfolded proinsulin and negatively regulating the ADAM17/EGFR axis—broadening its known substrates and signaling roles in both cancer and ER quality control.","evidence":"Overexpression and siRNA knockdown in cancer and β-cell lines, Western blot for β-catenin phosphorylation, MG132 rescue, Co-IP of proinsulin variants, epistasis via PDIA6/ADAM17 double knockdown, in vivo xenografts","pmids":["27462866","27760590","26947243","27540907"],"confidence":"Medium","gaps":["Whether β-catenin stabilization is a direct disulfide-dependent mechanism or indirect is unknown","ADAM17 regulation mechanism (direct disulfide exchange or indirect) not resolved","Cancer pathway findings each from single labs"]},{"year":2019,"claim":"PDIA6 was shown to interact with MAP4K1 and inhibit its phosphorylation, suppressing JNK/c-Jun signaling and cisplatin-induced apoptosis in NSCLC, establishing a new cytosolic signaling axis through which PDIA6 promotes chemoresistance.","evidence":"Phospho-kinase array, Co-IP of PDIA6–MAP4K1, gain- and loss-of-function, in vivo xenografts","pmids":["30922965"],"confidence":"Medium","gaps":["Whether the PDIA6–MAP4K1 interaction is direct and disulfide-dependent not determined","Subcellular site of interaction (ER, cytosol, or surface) not established","Single lab finding"]},{"year":2020,"claim":"A forward genetic screen in mice revealed that PDIA6 is essential for hematopoiesis in a cell-extrinsic manner: it is required in stromal cells for proper folding and secretion of Wnt3a, BAFF, and IL-7, linking its ER chaperone function to immune system development.","evidence":"ENU mutagenesis screen, competitive and non-competitive bone marrow transplantation, Western blot for niche factors","pmids":["31985756"],"confidence":"High","gaps":["Full spectrum of niche-secreted PDIA6 client proteins not defined","Whether other hematopoietic cytokines are also PDIA6-dependent not tested"]},{"year":2021,"claim":"Crystal structure determination resolved PDIA6 dimerization via a leucine-valine adhesive motif, and mutagenesis proved that the dimer is required for IRE1α inactivation through intermolecular disulfide reduction and for ER proteostasis, providing the first structural explanation for its signaling and chaperone functions.","evidence":"X-ray crystallography, site-directed mutagenesis of adhesive motif, in vitro IRE1α disulfide reduction assay, ER stress reporter","pmids":["33857433"],"confidence":"High","gaps":["Structure of PDIA6 in complex with IRE1α or BiP not available","Whether dimerization is regulated in vivo by redox or calcium signals unknown"]},{"year":2022,"claim":"Identification of PDIA6 as an RNA-binding protein with a mapped RNA-binding domain that is required for metastatic progression uncovered an unexpected non-canonical activity, suggesting functional roles beyond its oxidoreductase and chaperone activities.","evidence":"RNA interactome capture in melanoma cells, domain mapping, loss-of-function in metastasis assays","pmids":["35848924"],"confidence":"Medium","gaps":["RNA targets of PDIA6 not identified","Whether RNA binding is linked to or independent of its disulfide isomerase activity unknown","Single lab, single cancer type"]},{"year":null,"claim":"Major unresolved questions include the identity of PDIA6's RNA targets, the structural basis of its interaction with IRE1α and PERK in the dimeric state, whether its effects on β-catenin and MAP4K1 involve direct disulfide exchange, and the functional significance of its mitochondrial localization.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No PDIA6–IRE1α or PDIA6–PERK co-crystal structure","RNA targets uncharacterized","Mitochondrial function undefined","Direct vs. indirect mechanism for β-catenin stabilization unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,1,4,13]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,4,13]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[2,7,12]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,3,5,6,7,13]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,4,7,12,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,6,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,10,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,9,14,15]}],"complexes":["PDIA6 homodimer"],"partners":["HSPA5","ERN1","EIF2AK3","MICA","MAP4K1","COPS5","INS"],"other_free_text":[]},"mechanistic_narrative":"PDIA6 is an ER-resident protein disulfide isomerase that functions as an oxidoreductase, chaperone, and signaling modulator across multiple cellular contexts. It dimerizes via a leucine-valine adhesive motif in its N-terminal thioredoxin-like domain, and this dimer is required for structural stability, Ca²⁺-dependent chaperone activity, and inactivation of IRE1α through intermolecular disulfide bond reduction [PMID:33857433]. PDIA6 forms a complex with BiP to process client proteins, preferentially associates with misfolded proinsulin, and is essential for folding and secretion of hematopoietic niche factors (Wnt3a, BAFF, IL-7) by stromal cells, such that its loss causes cell-extrinsic immune deficiency in mice [PMID:19887585, PMID:26947243, PMID:31985756]. Beyond the ER, PDIA6 acts at the cell surface to promote MICA shedding through disulfide exchange-mediated immune evasion [PMID:17495932], negatively regulates the ADAM17/EGFR axis [PMID:27540907], stabilizes β-catenin by preventing its phosphorylation-dependent degradation [PMID:27462866], and possesses an unconventional RNA-binding activity required for its tumorigenic properties [PMID:35848924]."},"prefetch_data":{"uniprot":{"accession":"Q15084","full_name":"Protein disulfide-isomerase A6","aliases":["Endoplasmic reticulum protein 5","ER protein 5","ERp5","Protein disulfide isomerase P5","Thioredoxin domain-containing protein 7"],"length_aa":440,"mass_kda":48.1,"function":"May function as a chaperone that inhibits aggregation of misfolded proteins (PubMed:12204115). Negatively regulates the unfolded protein response (UPR) through binding to UPR sensors such as ERN1, which in turn inactivates ERN1 signaling (PubMed:24508390). May also regulate the UPR via the EIF2AK3 UPR sensor (PubMed:24508390). Plays a role in platelet aggregation and activation by agonists such as convulxin, collagen and thrombin (PubMed:15466936)","subcellular_location":"Endoplasmic reticulum lumen; Cell membrane; Melanosome","url":"https://www.uniprot.org/uniprotkb/Q15084/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDIA6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PDIA6","total_profiled":1310},"omim":[{"mim_id":"616942","title":"PROTEIN DISULFIDE ISOMERASE, FAMILY A, MEMBER 5; PDIA5","url":"https://www.omim.org/entry/616942"},{"mim_id":"611099","title":"PROTEIN DISULFIDE ISOMERASE, FAMILY A, MEMBER 6; PDIA6","url":"https://www.omim.org/entry/611099"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PDIA6"},"hgnc":{"alias_symbol":["P5","ERp5"],"prev_symbol":["TXNDC7"]},"alphafold":{"accession":"Q15084","domains":[{"cath_id":"3.40.30.10","chopping":"27-139","consensus_level":"high","plddt":91.9544,"start":27,"end":139},{"cath_id":"3.40.30.10","chopping":"162-271","consensus_level":"high","plddt":92.1157,"start":162,"end":271},{"cath_id":"3.40.30.10","chopping":"278-396","consensus_level":"high","plddt":93.7439,"start":278,"end":396}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15084","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15084-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15084-F1-predicted_aligned_error_v6.png","plddt_mean":86.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDIA6","jax_strain_url":"https://www.jax.org/strain/search?query=PDIA6"},"sequence":{"accession":"Q15084","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15084.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15084/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15084"}},"corpus_meta":[{"pmid":"365352","id":"PMC_365352","title":"Structural 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\"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDIA6 interacts with IRE1α and enhances IRE1α activity (monitored by IRE1α phosphorylation and XBP1 mRNA splicing) in response to ER Ca2+ depletion; this interaction selectively promotes the IRE1α arm of the UPR but does not substantially affect other UPR pathways. PDIA6 abundance is regulated post-transcriptionally by miR-322, which targets PDIA6 mRNA stability.\",\n      \"method\": \"Co-immunoprecipitation, XBP1 splicing assays, phosphorylation assays, miRNA manipulation, in vivo mouse and C. elegans models\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, splicing assay, phosphorylation, miRNA knockdown/overexpression) in cell culture and in vivo models\",\n      \"pmids\": [\"24917591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDIA6 interacts with both PERK and IRE1α, inhibiting their UPR signaling; specifically, PDIA6 selectively inhibits the RIDD (regulated IRE1-dependent decay) activity of IRE1α at physiological glucose concentrations in pancreatic beta cells, thereby maintaining insulin mRNA levels and insulin secretion.\",\n      \"method\": \"shRNA silencing of PDIA6, measurement of insulin secretion (ELISA), RIDD reporter assay in intact islets, molecular assays in cultured cells, PERK inhibitor experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including fluorescent reporter in intact islets, epistasis with PERK inhibitor, and shRNA knockdown with defined secretion phenotype\",\n      \"pmids\": [\"26487694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 preferentially associates with misfolded (Akita) proinsulin compared to wild-type proinsulin (~10-fold enrichment), while other PDI family members do not show this selectivity, suggesting PDIA6 acts as a key reductase targeting misfolded proinsulin to the ER degradation pathway.\",\n      \"method\": \"Co-immunoprecipitation of FLAG-tagged wild-type and Akita proinsulin from pancreatic beta cell lines, mass spectrometry identification of interactors\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with quantitative comparison and confirmed in two independent beta cell lines\",\n      \"pmids\": [\"26947243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDIA6 (P5) dimerizes via a unique leucine-valine adhesive motif in its N-terminal thioredoxin-like domain; the dimer interface is stabilized by reciprocal salt bridges and C-capping interactions. A monomeric mutant with impaired adhesive motif shows structural instability and induces ER stress, and is unable to inactivate IRE1α via intermolecular disulfide bond reduction or to exert Ca2+-dependent chaperone regulation.\",\n      \"method\": \"Crystal/structural analysis, mutagenesis of the adhesive motif, IRE1α disulfide reduction assay in vitro, ER stress reporter assays, in vitro chaperone activity assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure determination combined with mutagenesis and in vitro functional assays for IRE1α regulation\",\n      \"pmids\": [\"33857433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDIA6 loss-of-function in mice (hypomorphic ENU allele) causes severe lymphoid and myeloid hypoplasia; bone marrow transplant experiments show the immune defect is cell-extrinsic, and PDIA6 is required for proper folding of extracellular factors (Wnt3a, BAFF, IL-7) produced by the non-hematopoietic compartment that support hematopoietic development.\",\n      \"method\": \"ENU forward genetic screen, bone marrow transplantation rescue experiments, Western blot for Wnt3a/BAFF/IL-7 protein levels\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via bone marrow transplant rescue, identifying cell-extrinsic mechanism with specific cytokine substrates\",\n      \"pmids\": [\"31985756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDIA6 interacts with MAP4K1 and inhibits its phosphorylation, thereby suppressing the JNK/c-Jun signaling pathway and reducing cisplatin-induced apoptosis and autophagy in non-small cell lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, human phospho-kinase array, gain- and loss-of-function experiments in vitro and in vivo\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus phospho-kinase array and functional readouts, but single lab study\",\n      \"pmids\": [\"30922965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 knockdown in glioblastoma (U87MG) cells increases migration and invasion by activating ADAM17 sheddase activity, leading to enhanced EGFR signaling (increased pEGFR, pFAK, MMP-2, MT1-MMP, HB-EGF); simultaneous knockdown of PDIA6 and ADAM17 reverses these effects, placing PDIA6 upstream of ADAM17 in EGFR-mediated invasion.\",\n      \"method\": \"siRNA knockdown, Western blotting, zymography, wound-healing assay, Matrigel invasion assay, organotypic culture, EGFR inhibitor epistasis\",\n      \"journal\": \"Journal of neurosurgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with double knockdown and pharmacological inhibitors, but single lab study\",\n      \"pmids\": [\"27540907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 overexpression promotes HeLa cell proliferation by suppressing phosphorylation of β-catenin at Ser45 and Ser33/Ser37/Thr41, inhibiting β-catenin ubiquitin-proteasome degradation and increasing nuclear β-catenin accumulation and downstream targets cyclin D1 and c-Myc.\",\n      \"method\": \"Ectopic overexpression, Western blotting for phospho-β-catenin, ubiquitin-proteasome inhibitor (MG132) rescue experiment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with pharmacological rescue, but pathway placement indirect, single lab\",\n      \"pmids\": [\"27462866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P5 (PDIA6) is present in mitochondria in addition to the ER; identified in bovine liver mitochondrial extract by affinity chromatography with anti-CGHC phage antibody, confirmed by Western blot with anti-P5 antibody, mass spectrometry, proteinase protection assay, and immuno-electron microscopy.\",\n      \"method\": \"Organelle fractionation, affinity chromatography, Western blot, mass spectrometry, proteinase sensitivity assay, immuno-electron microscopy\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal localization methods, but functional consequence in mitochondria not fully established\",\n      \"pmids\": [\"18424807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Recombinant pig PDI-P5 (PDIA6 homolog) exhibits anti-chaperone activity in oxidative refolding of reduced denatured lysozyme: it catalyzes formation of non-native intermolecular disulfide bonds and inhibits productive refolding at equimolar ratios, in contrast to PDIA3 which promotes refolding.\",\n      \"method\": \"In vitro insulin turbidity reductase assay, oxidative refolding assay with lysozyme, SDS-PAGE and Western blot analysis of disulfide-crosslinked products\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution assay with biochemical characterization, but single lab and limited to porcine homolog\",\n      \"pmids\": [\"20152940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The cDNA encoding human P5 (PDIA6) was cloned; the predicted 440-amino-acid sequence contains two thioredoxin-like domains characteristic of the protein disulfide isomerase superfamily.\",\n      \"method\": \"cDNA cloning and sequencing, sequence homology analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — foundational cloning paper establishing domain architecture, single method\",\n      \"pmids\": [\"7590364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"P5 (PDIA6) protein is co-localized with tau in neurofibrillary tangles in Alzheimer's disease brain; S-nitrosylated PDIA6 is present in AD brains at reduced expression levels, and siRNA knockdown of P5 reduces viability of SH-SY5Y neuronal cells under ER stress.\",\n      \"method\": \"Immunohistochemistry, co-localization analysis, siRNA knockdown, cell viability assay, Western blot for S-nitrosylation\",\n      \"journal\": \"Journal of Alzheimer's disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization and siRNA knockdown with limited mechanistic depth, single lab\",\n      \"pmids\": [\"24037032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDIA6 displays an unconventional RNA-binding activity identified by RNA interactome capture (RIC) in melanoma cells; its RNA-binding domain was mapped and RNA binding is required for PDIA6 tumorigenic (metastatic) properties in melanoma.\",\n      \"method\": \"RNA interactome capture (RIC), domain mapping, functional in vitro assays for migration/invasion/metastasis with RNA-binding mutants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIC plus domain mapping and functional validation with RNA-binding mutants, single lab\",\n      \"pmids\": [\"35848924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDIA6 overexpression in pancreatic cancer cells promotes deubiquitination of β-catenin and PD-L1 via interaction with CSN5 (COP9 signalosome subunit 5), upregulating their protein levels; CSN5 shRNA partially reverses these effects.\",\n      \"method\": \"Co-immunoprecipitation, gain- and loss-of-function experiments, ubiquitination assays, CSN5 shRNA epistasis\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitination assay and epistasis with CSN5 knockdown, single lab\",\n      \"pmids\": [\"34325342\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDIA6 is an ER-resident oxidoreductase with two thioredoxin-like domains that functions as a dimer (via a leucine-valine adhesive motif) to regulate ER homeostasis: it physically interacts with and modulates the activity of UPR sensors IRE1α (selectively inhibiting RIDD activity and XBP1 splicing) and PERK, forms a non-covalent complex with BiP to process BiP client substrates, preferentially targets misfolded proinsulin for ER-associated degradation, and also supports hematopoiesis cell-extrinsically by folding secreted factors (Wnt3a, BAFF, IL-7); additionally, PDIA6 modulates cancer cell signaling through MAP4K1/JNK, ADAM17/EGFR, and β-catenin pathways, and possesses an unconventional RNA-binding activity required for its pro-metastatic function.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"The cDNA encoding human P5 (PDIA6) was cloned and sequenced. The predicted 440-amino-acid sequence contains two thioredoxin-like domains characteristic of the protein disulfide isomerase superfamily.\",\n      \"method\": \"cDNA cloning and sequence analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — foundational cloning and structural characterization, single study\",\n      \"pmids\": [\"7590364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PDIA6 (ERp5/P5) is present on the surface of tumor cells and associates with membrane-anchored MICA via transitory mixed disulfide complexes. Reduction of the alpha3 domain disulfide bond of MICA by cell-surface PDIA6 is required for proteolytic MICA shedding, promoting tumor immune evasion. Pharmacological inhibition of thioreductase activity and PDIA6 gene silencing both abolished MICA shedding.\",\n      \"method\": \"Co-immunoprecipitation, gene silencing (siRNA), pharmacological inhibition, cell-surface biochemistry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic knockdown, and pharmacological inhibition with specific mechanistic readout; high citation count\",\n      \"pmids\": [\"17495932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"P5 (PDIA6) forms a non-covalent complex with BiP (immunoglobulin heavy chain binding protein) and shows substrate specificity towards BiP client proteins, distinguishing it functionally from other PDI family members such as ERp57 and ERp46.\",\n      \"method\": \"Co-immunoprecipitation, substrate specificity trapping assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with substrate specificity profiling across multiple PDI family members; high citation count\",\n      \"pmids\": [\"19887585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"P5 (PDIA6) is present in mitochondria, in addition to its known ER localization. Identification was achieved via affinity chromatography using a phage antibody recognizing the CGHC motif, confirmed by Western blot, mass spectrometry, cell fractionation, proteinase protection assays, and immuno-electron microscopy.\",\n      \"method\": \"Affinity chromatography, Western blot, mass spectrometry, cell fractionation, proteinase protection, immuno-electron microscopy\",\n      \"journal\": \"Journal of Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal localization methods including immuno-EM\",\n      \"pmids\": [\"18424807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pig PDI-P5 (PDIA6 ortholog) exhibits anti-chaperone activity in vitro: while showing thiol-dependent disulfide reductase activity, it inhibits oxidative refolding of reduced denatured lysozyme by catalyzing formation of disulfide cross-linked, non-productively folded lysozyme, contrasting with PDIA3 which promotes refolding. PDI-P5 is down-regulated from epididymal corpus to cauda sperm.\",\n      \"method\": \"In vitro insulin turbidity reductase assay, oxidative refolding assay with lysozyme, SDS-PAGE/Western blot, 2D gel electrophoresis, peptide mass fingerprinting\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assays with ortholog; single study\",\n      \"pmids\": [\"20152940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDIA6 physically interacts with IRE1α and enhances IRE1α activity (monitored by IRE1α phosphorylation and XBP1 mRNA splicing) selectively in response to ER Ca2+ depletion, but does not substantially affect PERK or ATF6 pathways. miR-322 suppresses PDIA6 mRNA stability; ER Ca2+ depletion reduces miR-322 abundance, increasing PDIA6 expression and consequently IRE1α activity. In vivo mouse and C. elegans experiments confirmed this feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, XBP1 mRNA splicing assay, miRNA manipulation, in vivo mouse/worm ER stress models\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of PDIA6-IRE1α, multiple orthogonal methods, in vivo validation in two organisms\",\n      \"pmids\": [\"24917591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDIA6 interacts with both PERK and IRE1α and inhibits their UPR signaling. In insulin-producing beta cells, PDIA6 knockdown selectively enhances RIDD (regulated IRE1-dependent decay) activity toward insulin transcripts up to 4-fold at physiological glucose concentrations, reducing insulin production and glucose-stimulated insulin secretion, without affecting XBP1 splicing. This demonstrates that PDIA6 attenuates IRE1 enzymatic activities to maintain physiological signaling.\",\n      \"method\": \"shRNA silencing, RT-PCR/molecular assays, fluorescent RIDD reporter in intact islets, PERK inhibitor experiments\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with multiple molecular readouts, fluorescent reporter in intact tissue, pharmacological controls\",\n      \"pmids\": [\"26487694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 co-immunoprecipitates with wild-type proinsulin and preferentially associates (~10-fold more) with misfolded Akita mutant proinsulin (Cys96Tyr) compared to other PDI family members, suggesting a specific role as a reductase targeting misfolded proinsulin to the ER degradation pathway.\",\n      \"method\": \"Co-immunoprecipitation of FLAG-tagged proinsulin constructs, mass spectrometry interactome analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with MS confirmation, replicated in second beta cell line; single lab\",\n      \"pmids\": [\"26947243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 knockdown in bladder cancer cells reduces β-catenin, cyclin D1, and c-Myc protein expression, suppressing Wnt/β-catenin signaling, and decreases cell proliferation and invasion both in vitro and in vivo in xenograft models.\",\n      \"method\": \"siRNA knockdown, Western blot, proliferation/invasion assays, xenograft tumor model\",\n      \"journal\": \"Oncology Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with defined pathway readout; single lab, single approach per method\",\n      \"pmids\": [\"27760590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 overexpression in HeLa cells promotes proliferation by suppressing phosphorylation of β-catenin at Ser45 and Ser33/Ser37/Thr41, thereby inhibiting ubiquitin-proteasome-mediated β-catenin degradation and increasing nuclear β-catenin accumulation with upregulation of Wnt target genes cyclin D1 and c-Myc. The effect was abolished by the proteasome inhibitor MG132.\",\n      \"method\": \"Ectopic overexpression, Western blot, cell cycle analysis, ubiquitin-proteasome inhibitor rescue experiment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with pathway rescue, mechanistic follow-up; single lab\",\n      \"pmids\": [\"27462866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 knockdown in U87MG glioblastoma cells increases ADAM17 sheddase activity and activates EGFR signaling (elevated pEGFR, pFAK, HB-EGF), enhancing MMP-2 activation and cell migration/invasion. Simultaneous double-knockdown of PDIA6 and ADAM17 reduced pEGFR and invasion, placing PDIA6 as a negative regulator of the ADAM17/EGFR signaling axis in glioblastoma.\",\n      \"method\": \"siRNA knockdown, Western blot, wound-healing assay, Matrigel invasion assay, organotypic culture, zymography\",\n      \"journal\": \"Journal of Neurosurgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic epistasis via double knockdown, multiple functional readouts; single lab\",\n      \"pmids\": [\"27540907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDIA6 interacts with MAP4K1 (HPK1) and inhibits its phosphorylation, leading to suppression of the JNK/c-Jun signaling pathway. PDIA6 knockdown increases cisplatin-induced apoptosis and autophagy in NSCLC cells, while overexpression has the opposite effect, positioning PDIA6 as an inhibitor of the MAP4K1/JNK/c-Jun apoptotic axis.\",\n      \"method\": \"Phospho-kinase array, co-immunoprecipitation, gain- and loss-of-function, in vitro and in vivo xenograft experiments\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of PDIA6-MAP4K1, phospho-kinase array, in vivo validation; single lab\",\n      \"pmids\": [\"30922965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In a forward genetic ENU screen, a hypomorphic Pdia6 mutation in mice causes lymphoid and myeloid hypoplasia. Bone marrow transplantation experiments showed the immune deficiency is cell-extrinsic: PDIA6-deficient bone marrow reconstituted wild-type hosts normally, but wild-type bone marrow failed to reconstitute PDIA6-deficient hosts. PDIA6 was shown to be required for proper folding/secretion of hematopoietic niche factors Wnt3a, BAFF, and IL-7 by extra-hematopoietic stromal cells.\",\n      \"method\": \"ENU forward genetic screen, bone marrow transplantation (competitive and non-competitive), Western blot for Wnt3a/BAFF/IL-7\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous in vivo genetic epistasis via bone marrow transplantation, multiple client proteins identified\",\n      \"pmids\": [\"31985756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDIA6 (P5) forms a dimer via a unique leucine-valine adhesive motif in the N-terminal thioredoxin-like domain, featuring periodic repeats of Leu/Val at the 3rd or 4th position on 15-residue anti-parallel α-helices stabilized by salt bridges and C-capping interactions. A monomeric P5 mutant with disrupted adhesive motif shows structural instability and induces ER stress. Dimerization is required for PDIA6 to inactivate IRE1α via intermolecular disulfide bond reduction and for Ca2+-dependent chaperone function regulation in vitro.\",\n      \"method\": \"X-ray crystallography/structure determination, mutagenesis, in vitro IRE1α disulfide reduction assay, ER stress reporter assay\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination with mutagenesis validation and in vitro functional assays\",\n      \"pmids\": [\"33857433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDIA6 overexpression in pancreatic cancer cells promotes deubiquitination of β-catenin and PD-L1 through interaction with CSN5 (COP9 signalosome subunit 5), upregulating their expression and promoting cancer progression and NK cell evasion. CSN5 shRNA partially reversed these effects.\",\n      \"method\": \"Co-immunoprecipitation of PDIA6-CSN5, gain- and loss-of-function, ubiquitination assays, xenograft models, NK cell cytotoxicity assays\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional rescue by CSN5 knockdown; single lab\",\n      \"pmids\": [\"34325342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDIA6 displays a novel RNA-binding activity identified by RNA interactome capture (RIC) in melanoma cells. Mapping revealed an RNA-binding domain within PDIA6, and this RNA-binding activity is required for its tumorigenic properties in metastatic progression assays.\",\n      \"method\": \"RNA interactome capture (RIC), domain mapping, loss-of-function with in vitro metastasis assays\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIC with domain mapping and functional validation; single lab\",\n      \"pmids\": [\"35848924\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDIA6 is an ER-resident oxidoreductase with two thioredoxin-like domains that dimerizes via a unique leucine-valine adhesive motif; it selectively interacts with and attenuates IRE1α (via intermolecular disulfide bond reduction) and PERK to modulate the UPR, associates with BiP to process client proteins including misfolded proinsulin, promotes MICA shedding on tumor cell surfaces via disulfide exchange, contributes to hematopoiesis by folding niche-secreted factors (Wnt3a, BAFF, IL-7), regulates cancer cell proliferation and signaling through the Wnt/β-catenin and MAP4K1/JNK pathways, and possesses an unconventional RNA-binding activity required for its tumorigenic properties.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PDIA6 is an ER-resident oxidoreductase of the protein disulfide isomerase superfamily that functions as a homodimer to regulate ER protein quality control and unfolded protein response (UPR) signaling. It contains two thioredoxin-like domains and dimerizes via a leucine-valine adhesive motif essential for its oxidoreductase and chaperone activities; monomeric mutants fail to reduce IRE1α intermolecular disulfides and induce ER stress [PMID:7590364, PMID:33857433]. PDIA6 forms a non-covalent complex with BiP to process client substrates, preferentially targets misfolded proinsulin for ER-associated degradation, and selectively modulates UPR sensors IRE1α and PERK—inhibiting RIDD activity to maintain insulin mRNA in pancreatic β-cells [PMID:19887585, PMID:26947243, PMID:26487694, PMID:24917591]. Beyond the ER, PDIA6 supports hematopoiesis cell-extrinsically by folding secreted factors including Wnt3a, BAFF, and IL-7, and possesses an unconventional RNA-binding activity required for its pro-metastatic function in melanoma [PMID:31985756, PMID:35848924].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Cloning of human P5/PDIA6 established its membership in the PDI superfamily, revealing two thioredoxin-like domains that predicted oxidoreductase function.\",\n      \"evidence\": \"cDNA cloning and sequence homology analysis\",\n      \"pmids\": [\"7590364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated at this stage\", \"ER retention mechanism not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Detection of PDIA6 in mitochondria in addition to ER raised the question of whether it has compartment-specific functions beyond its canonical ER role.\",\n      \"evidence\": \"Organelle fractionation, immuno-electron microscopy, and proteinase protection in bovine liver\",\n      \"pmids\": [\"18424807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mitochondrial substrates or functions identified\", \"Functional consequence of mitochondrial localization unknown\", \"Not confirmed in human cells\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery of a stable non-covalent PDIA6–BiP complex with preferential activity toward BiP client substrates distinguished PDIA6 from other PDI family members and established a cooperative ER quality control mechanism.\",\n      \"evidence\": \"Co-immunoprecipitation and substrate trapping assays in mammalian cells comparing multiple PDI family members\",\n      \"pmids\": [\"19887585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of specific BiP client substrates processed by PDIA6 not fully catalogued\", \"Stoichiometry of the PDIA6–BiP complex not determined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"In vitro reconstitution revealed that PDIA6 possesses anti-chaperone activity—catalyzing non-native intermolecular disulfides in lysozyme refolding—distinguishing its enzymatic behavior from PDIA3.\",\n      \"evidence\": \"Oxidative refolding assay with recombinant porcine PDIA6 and lysozyme substrate\",\n      \"pmids\": [\"20152940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Anti-chaperone activity demonstrated only with porcine homolog in vitro\", \"Relevance to in vivo substrate folding unclear\", \"Relationship to BiP-dependent activity not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"PDIA6 was identified as a direct regulator of the IRE1α arm of the UPR, interacting with IRE1α to modulate its phosphorylation and XBP1 splicing in response to ER Ca²⁺ depletion, with its own abundance controlled post-transcriptionally by miR-322.\",\n      \"evidence\": \"Co-immunoprecipitation, XBP1 splicing and phosphorylation assays, miRNA manipulation in cell culture and in vivo mouse/C. elegans models\",\n      \"pmids\": [\"24917591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDIA6 acts on IRE1α via direct disulfide exchange or allosteric mechanism was not resolved\", \"Contribution of miR-322 regulation in non-stress conditions unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"PDIA6 was shown to interact with both PERK and IRE1α and to selectively inhibit IRE1α RIDD activity at physiological glucose in β-cells, thereby protecting insulin mRNA—resolving how PDIA6 fine-tunes distinct outputs of the same UPR sensor.\",\n      \"evidence\": \"shRNA knockdown, RIDD fluorescent reporter in intact islets, insulin secretion ELISA, PERK inhibitor epistasis\",\n      \"pmids\": [\"26487694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for selective RIDD inhibition versus XBP1 splicing not determined\", \"Whether PDIA6 directly catalyzes disulfide rearrangement on PERK not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"PDIA6 was found to preferentially associate with misfolded (Akita) proinsulin over wild-type proinsulin (~10-fold enrichment), implicating it as a specificity factor that routes misfolded substrates toward ER-associated degradation.\",\n      \"evidence\": \"Co-immunoprecipitation of FLAG-tagged wild-type and Akita proinsulin, mass spectrometry in two β-cell lines\",\n      \"pmids\": [\"26947243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDIA6 reductase activity is required for ERAD targeting not tested\", \"Downstream ERAD machinery partners not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Studies in glioblastoma and HeLa cells linked PDIA6 to cancer cell signaling: PDIA6 inhibits ADAM17-mediated EGFR activation in glioblastoma, and its overexpression stabilizes β-catenin by suppressing phosphorylation-dependent degradation, connecting PDIA6 to proliferative and invasive pathways.\",\n      \"evidence\": \"siRNA and overexpression approaches with epistasis (double knockdown of ADAM17, MG132 rescue), Western blotting for phospho-β-catenin\",\n      \"pmids\": [\"27540907\", \"27462866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between PDIA6 and ADAM17 or β-catenin not demonstrated by reciprocal Co-IP\", \"Whether these effects depend on PDIA6 oxidoreductase activity unknown\", \"Single-lab observations for each cancer type\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"An ENU hypomorphic allele in mice revealed that PDIA6 is required for hematopoiesis through a cell-extrinsic mechanism—proper folding of secreted Wnt3a, BAFF, and IL-7 by the non-hematopoietic stroma—expanding PDIA6's role beyond cell-autonomous ER quality control.\",\n      \"evidence\": \"Forward genetic screen, bone marrow transplant rescue, Western blot for secreted cytokines\",\n      \"pmids\": [\"31985756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which PDIA6 catalytic domain mediates folding of each cytokine not determined\", \"Whether complete PDIA6 loss is embryonic lethal not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural and mutagenesis studies resolved that PDIA6 functions as a dimer via a leucine-valine adhesive motif, and that dimerization is required for IRE1α disulfide reduction and Ca²⁺-dependent chaperone regulation—establishing the quaternary structure as essential for function.\",\n      \"evidence\": \"Crystal structure determination, adhesive motif mutagenesis, in vitro IRE1α disulfide reduction and chaperone assays\",\n      \"pmids\": [\"33857433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length dimer structure with substrates not available\", \"Whether dimerization affects PERK interaction not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of unconventional RNA-binding activity in PDIA6, mapped to a specific domain and shown to be required for pro-metastatic function in melanoma, revealed a non-canonical function for this oxidoreductase.\",\n      \"evidence\": \"RNA interactome capture in melanoma cells, domain mapping, migration/invasion assays with RNA-binding mutants\",\n      \"pmids\": [\"35848924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of bound RNA targets not catalogued\", \"Mechanism by which RNA binding promotes metastasis unknown\", \"Whether RNA binding is conserved beyond melanoma not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for PDIA6's selective inhibition of RIDD versus XBP1 splicing on IRE1α, the identity of RNA targets underlying its pro-metastatic RNA-binding function, and whether its mitochondrial localization serves a physiological role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of PDIA6 in complex with IRE1α or PERK\", \"RNA targets of PDIA6 not identified\", \"Mitochondrial function of PDIA6 uncharacterized\", \"Complete loss-of-function phenotype in mammals not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 3, 4, 10]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 4, 5, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 5, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"PDIA6–BiP complex\"\n    ],\n    \"partners\": [\n      \"HSPA5\",\n      \"ERN1\",\n      \"EIF2AK3\",\n      \"MAP4K1\",\n      \"COPS5\",\n      \"ADAM17\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PDIA6 is an ER-resident protein disulfide isomerase that functions as an oxidoreductase, chaperone, and signaling modulator across multiple cellular contexts. It dimerizes via a leucine-valine adhesive motif in its N-terminal thioredoxin-like domain, and this dimer is required for structural stability, Ca²⁺-dependent chaperone activity, and inactivation of IRE1α through intermolecular disulfide bond reduction [PMID:33857433]. PDIA6 forms a complex with BiP to process client proteins, preferentially associates with misfolded proinsulin, and is essential for folding and secretion of hematopoietic niche factors (Wnt3a, BAFF, IL-7) by stromal cells, such that its loss causes cell-extrinsic immune deficiency in mice [PMID:19887585, PMID:26947243, PMID:31985756]. Beyond the ER, PDIA6 acts at the cell surface to promote MICA shedding through disulfide exchange-mediated immune evasion [PMID:17495932], negatively regulates the ADAM17/EGFR axis [PMID:27540907], stabilizes β-catenin by preventing its phosphorylation-dependent degradation [PMID:27462866], and possesses an unconventional RNA-binding activity required for its tumorigenic properties [PMID:35848924].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Cloning of PDIA6 established it as a PDI family member with two thioredoxin-like domains, placing it within the oxidoreductase superfamily but leaving its specific substrates and cellular roles unknown.\",\n      \"evidence\": \"cDNA cloning and sequence analysis of human P5\",\n      \"pmids\": [\"7590364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated\", \"No substrates identified\", \"No cellular function assigned\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that cell-surface PDIA6 reduces the α3-domain disulfide bond of MICA to enable its proteolytic shedding revealed the first specific substrate and an extracellular function in tumor immune evasion, expanding its role beyond the ER lumen.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, and pharmacological inhibition of thioreductase activity on tumor cell lines\",\n      \"pmids\": [\"17495932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the sheddase protease activated by MICA reduction not determined\", \"Whether PDIA6 acts on other NKG2D ligands unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Detection of PDIA6 in mitochondria by multiple orthogonal methods indicated dual ER–mitochondrial localization, raising the question of organelle-specific functions.\",\n      \"evidence\": \"Affinity chromatography, Western blot, mass spectrometry, cell fractionation, proteinase protection, and immuno-electron microscopy\",\n      \"pmids\": [\"18424807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mitochondrial substrate or function identified\", \"Mechanism of mitochondrial targeting unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of a non-covalent PDIA6–BiP complex with distinct client specificity compared to ERp57 and ERp46 established PDIA6 as a functionally specialized ER chaperone partner rather than a redundant PDI family member.\",\n      \"evidence\": \"Co-IP and substrate specificity trapping assays comparing PDI family members\",\n      \"pmids\": [\"19887585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of endogenous BiP clients processed by PDIA6 not comprehensively defined\", \"Structural basis of PDIA6–BiP interaction not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that PDIA6 physically interacts with IRE1α and enhances its signaling selectively during ER Ca²⁺ depletion—regulated by miR-322—revealed PDIA6 as a UPR modulator and introduced a feedback circuit connecting calcium homeostasis to UPR branch selection.\",\n      \"evidence\": \"Co-IP of PDIA6–IRE1α, miRNA manipulation, XBP1 splicing assay, in vivo mouse and C. elegans ER stress models\",\n      \"pmids\": [\"24917591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDIA6 acts on IRE1α via disulfide exchange or allosteric mechanism not resolved at this stage\", \"Effect on ATF6 and PERK disputed between studies\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Functional dissection in β-cells showed PDIA6 attenuates IRE1α RIDD activity toward insulin mRNA without affecting XBP1 splicing, and also interacts with PERK, demonstrating selective modulation of distinct IRE1α outputs and a broader UPR regulatory role than initially appreciated.\",\n      \"evidence\": \"shRNA silencing, fluorescent RIDD reporter in intact islets, PERK inhibitor experiments\",\n      \"pmids\": [\"26487694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PDIA6 differentially controls RIDD vs. XBP1 splicing mechanistically is unresolved\", \"Stoichiometry and dynamics of PDIA6–IRE1α vs. PDIA6–PERK complexes not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Multiple studies converged to show PDIA6 stabilizes β-catenin by suppressing its phosphorylation and proteasomal degradation, promoting Wnt target gene expression, while also preferentially associating with misfolded proinsulin and negatively regulating the ADAM17/EGFR axis—broadening its known substrates and signaling roles in both cancer and ER quality control.\",\n      \"evidence\": \"Overexpression and siRNA knockdown in cancer and β-cell lines, Western blot for β-catenin phosphorylation, MG132 rescue, Co-IP of proinsulin variants, epistasis via PDIA6/ADAM17 double knockdown, in vivo xenografts\",\n      \"pmids\": [\"27462866\", \"27760590\", \"26947243\", \"27540907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether β-catenin stabilization is a direct disulfide-dependent mechanism or indirect is unknown\", \"ADAM17 regulation mechanism (direct disulfide exchange or indirect) not resolved\", \"Cancer pathway findings each from single labs\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PDIA6 was shown to interact with MAP4K1 and inhibit its phosphorylation, suppressing JNK/c-Jun signaling and cisplatin-induced apoptosis in NSCLC, establishing a new cytosolic signaling axis through which PDIA6 promotes chemoresistance.\",\n      \"evidence\": \"Phospho-kinase array, Co-IP of PDIA6–MAP4K1, gain- and loss-of-function, in vivo xenografts\",\n      \"pmids\": [\"30922965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the PDIA6–MAP4K1 interaction is direct and disulfide-dependent not determined\", \"Subcellular site of interaction (ER, cytosol, or surface) not established\", \"Single lab finding\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A forward genetic screen in mice revealed that PDIA6 is essential for hematopoiesis in a cell-extrinsic manner: it is required in stromal cells for proper folding and secretion of Wnt3a, BAFF, and IL-7, linking its ER chaperone function to immune system development.\",\n      \"evidence\": \"ENU mutagenesis screen, competitive and non-competitive bone marrow transplantation, Western blot for niche factors\",\n      \"pmids\": [\"31985756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of niche-secreted PDIA6 client proteins not defined\", \"Whether other hematopoietic cytokines are also PDIA6-dependent not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Crystal structure determination resolved PDIA6 dimerization via a leucine-valine adhesive motif, and mutagenesis proved that the dimer is required for IRE1α inactivation through intermolecular disulfide reduction and for ER proteostasis, providing the first structural explanation for its signaling and chaperone functions.\",\n      \"evidence\": \"X-ray crystallography, site-directed mutagenesis of adhesive motif, in vitro IRE1α disulfide reduction assay, ER stress reporter\",\n      \"pmids\": [\"33857433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of PDIA6 in complex with IRE1α or BiP not available\", \"Whether dimerization is regulated in vivo by redox or calcium signals unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of PDIA6 as an RNA-binding protein with a mapped RNA-binding domain that is required for metastatic progression uncovered an unexpected non-canonical activity, suggesting functional roles beyond its oxidoreductase and chaperone activities.\",\n      \"evidence\": \"RNA interactome capture in melanoma cells, domain mapping, loss-of-function in metastasis assays\",\n      \"pmids\": [\"35848924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA targets of PDIA6 not identified\", \"Whether RNA binding is linked to or independent of its disulfide isomerase activity unknown\", \"Single lab, single cancer type\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the identity of PDIA6's RNA targets, the structural basis of its interaction with IRE1α and PERK in the dimeric state, whether its effects on β-catenin and MAP4K1 involve direct disulfide exchange, and the functional significance of its mitochondrial localization.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No PDIA6–IRE1α or PDIA6–PERK co-crystal structure\", \"RNA targets uncharacterized\", \"Mitochondrial function undefined\", \"Direct vs. indirect mechanism for β-catenin stabilization unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 1, 4, 13]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 4, 13]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [2, 7, 12]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 7, 13]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 4, 7, 12, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 6, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 10, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9, 14, 15]}\n    ],\n    \"complexes\": [\n      \"PDIA6 homodimer\"\n    ],\n    \"partners\": [\n      \"HSPA5\",\n      \"ERN1\",\n      \"EIF2AK3\",\n      \"MICA\",\n      \"MAP4K1\",\n      \"COPS5\",\n      \"INS\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}