{"gene":"PDIA6","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2004,"finding":"ERp5/PDIA6 is present on platelet intracellular membranes and is rapidly recruited to the cell surface upon platelet agonist stimulation; blocking surface ERp5 with inhibitory antibodies decreases platelet aggregation, fibrinogen binding, and P-selectin exposure, and ERp5 physically associates with integrin β3 subunit during platelet stimulation.","method":"Platelet membrane fractionation, inhibitory antibody blocking, co-immunoprecipitation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional antibody blocking in a single lab with multiple orthogonal readouts","pmids":["15466936"],"is_preprint":false},{"year":2014,"finding":"PDIA6 interacts with IRE1α and enhances IRE1α activity (monitored by IRE1α phosphorylation and XBP1 mRNA splicing) in response to ER Ca2+ disruption; miR-322 suppresses PDIA6 mRNA stability, and ER Ca2+ depletion reduces miR-322 abundance, thereby increasing PDIA6 levels and IRE1α activity in a feedback loop modulating the UPR.","method":"Co-immunoprecipitation, shRNA knockdown, XBP1 mRNA splicing assay, IRE1α phosphorylation assay, miRNA manipulation, in vivo mouse and C. elegans experiments","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal functional assays, validated in vivo in two organisms","pmids":["24917591"],"is_preprint":false},{"year":2014,"finding":"PDIA6 knockdown in cisplatin-resistant lung adenocarcinoma cells stimulates cell death via a non-canonical pathway sharing necroptosis features, distinct from the mitochondrial apoptosis pathway restored by PDIA4 inactivation, indicating PDIA6 mediates a specific pro-survival signaling branch in chemoresistant cells.","method":"shRNA knockdown, pharmacological inhibition, cell death assays, ER proteomics","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological inhibition with defined cell-death pathway readouts, single lab","pmids":["24464223"],"is_preprint":false},{"year":2015,"finding":"ERp5/PDIA6 is released at thrombus sites in vivo and its inhibition with anti-ERp5 antibody decreases platelet deposition (70%) and fibrin accumulation (62%) in a laser-injury mouse model; ERp5 binds β3 integrin with a KD of 21 µM (measured by surface plasmon resonance), and active-site cysteine residues are not required for this binding.","method":"Laser-injury mouse thrombosis model, anti-ERp5 antibody inhibition, surface plasmon resonance, in vitro disulfide reductase assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo model, SPR binding measurement with defined KD, mutagenesis of active-site cysteines, multiple orthogonal methods","pmids":["25624318"],"is_preprint":false},{"year":2015,"finding":"PDIA6 interacts with PERK and IRE1 and inhibits their UPR signaling; in insulin-producing cells, PDIA6 silencing reduces insulin production ~5-fold and glucose-stimulated insulin secretion 3–4-fold by enhancing IRE1 RIDD activity toward insulin transcripts (up to 4-fold), while not substantially affecting XBP1 splicing or PERK activity under physiological glucose conditions.","method":"shRNA silencing, insulin secretion assay, IRE1 RIDD fluorescent reporter assay, XBP1 mRNA splicing assay, intact islet assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic silencing, functional reporter, secretion assay), clear mechanistic separation of IRE1 activities, replicated in cell lines and intact islets","pmids":["26487694"],"is_preprint":false},{"year":2016,"finding":"PDIA6 overexpression in HeLa cells promotes cell proliferation by suppressing phosphorylation of β-catenin at Ser45 and Ser33/Ser37/Thr41, thereby inhibiting its ubiquitin-proteasome-mediated degradation, increasing nuclear β-catenin accumulation, and upregulating Wnt/β-catenin target genes cyclin D1 and c-Myc.","method":"Ectopic overexpression, Western blot for β-catenin phosphorylation and nuclear fractionation, proteasome inhibitor (MG132) rescue, proliferation assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical and cellular assays, single lab, mechanistic pathway placement via MG132 rescue","pmids":["27462866"],"is_preprint":false},{"year":2016,"finding":"PDIA6 co-immunoprecipitates with wild-type proinsulin and approximately 10-fold more PDIA6 (but not other PDI family members) is associated with misfolded Akita proinsulin (Cys96Tyr mutation) in pancreatic beta cells, identifying PDIA6 as a selective reductase that may target misfolded proinsulin to ER degradation.","method":"Co-immunoprecipitation with FLAG-tagged proinsulin, quantitative comparison across PDI family members, two independent beta cell lines (MIN6 and βTC-6)","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP validated in two independent cell lines, selectivity established by comparing multiple PDI family members","pmids":["26947243"],"is_preprint":false},{"year":2016,"finding":"PDIA6 knockdown in U87MG glioblastoma cells increases ADAM17 sheddase activity, MMP-2 activation, and EGFR pathway signaling (pEGFR, pFAK, integrin α5β3, MT1-MMP), leading to increased cell migration and invasion; simultaneous double-knockdown of PDIA6 and ADAM17 reduces pEGFR and pFAK, suggesting PDIA6 normally suppresses EGFR-mediated invasion by restraining ADAM17 activity.","method":"siRNA knockdown, wound-healing assay, Matrigel invasion assay, Western blot, zymography, EGFR inhibitor rescue","journal":"Journal of neurosurgery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by double knockdown, multiple readouts, pharmacological rescue, single lab","pmids":["27540907"],"is_preprint":false},{"year":2019,"finding":"PDIA6 interacts with MAP4K1 and inhibits its phosphorylation, thereby suppressing the downstream JNK/c-Jun signaling pathway to inhibit cisplatin-induced apoptosis and autophagy in NSCLC cells.","method":"Co-immunoprecipitation, human phospho-kinase array, gain-of-function and loss-of-function strategies, in vitro and in vivo apoptosis/autophagy assays","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with pathway validation by phospho-kinase array, in vitro and in vivo models, single lab","pmids":["30922965"],"is_preprint":false},{"year":2020,"finding":"PDIA6 deficiency in mice caused by a hypomorphic ENU allele results in lymphoid and myeloid hypoplasia that is rescued by transplanting PDIA6-deficient bone marrow into wild-type irradiated recipients, demonstrating the requirement for PDIA6 is extrinsic to hematopoietic cells; PDIA6 is required for proper folding of Wnt3a, BAFF, IL-7, and other factors produced by the extra-hematopoietic compartment.","method":"ENU forward genetic screen, bone marrow transplantation rescue, Western blot for Wnt3a/BAFF/IL-7 folding","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via bone marrow transplantation rescue, multiple substrate identification, validated in vivo mouse model","pmids":["31985756"],"is_preprint":false},{"year":2021,"finding":"PDIA6 interacts with CSN5 (COP9 signalosome subunit 5) in pancreatic cancer cells; PDIA6 overexpression promotes CSN5-mediated deubiquitination of β-catenin and PD-L1, stabilizing their expression, and these effects are partially reversed by CSN5 shRNA knockdown.","method":"Co-immunoprecipitation, ubiquitination assay, shRNA rescue experiments, gain-of-function and loss-of-function studies","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and shRNA rescue in single lab","pmids":["34325342"],"is_preprint":false},{"year":2021,"finding":"A point mutation (Phe175Ser) in the second thioredoxin domain of Pdia6 in mice causes progressive loss of pancreatic β-cell identity (reduced Ins2, Mafa, Slc2a2; increased α-cell markers Mafb and glucagon) without increased apoptosis, leading to hypoinsulinemia and overt diabetes.","method":"ENU mouse model with missense mutation, immunofluorescence, molecular marker analysis, glucose/insulin measurements, histology","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with domain-specific mutation, multiple orthogonal molecular and cellular readouts","pmids":["34487921"],"is_preprint":false},{"year":2022,"finding":"PDIA6 displays a novel RNA-binding activity in melanoma cells; its RNA-binding domain was mapped, and RNA binding is required for PDIA6's tumorigenic/metastatic properties, as demonstrated by RNA interactome capture and functional validation assays.","method":"RNA interactome capture (RIC), RNA-binding domain mapping, functional in vitro assays for metastatic properties","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIC method plus domain mapping and functional validation, single lab","pmids":["35848924"],"is_preprint":false},{"year":2024,"finding":"PDIA6 and ERp44 constitutively interact via disulfide bonds in the ER; they have opposing effects on selective ER retention (sERr) of glycoproteins during ER stress recovery—ERp44 deletion accelerates recovery while PDIA6 deletion slows it; when ERp44 is absent, PDIA6 partitions more into sERr complexes with tyrosine kinase receptor clients.","method":"Pulse-chase analysis, PDIA6 and ERp44 deletion cell lines, co-immunoprecipitation, disulfide interaction analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deletion of both proteins with functional epistasis, Co-IP for interaction, single lab","pmids":["39621446"],"is_preprint":false},{"year":2024,"finding":"PDIA6 depletion in kidney proximal tubule cells (HK2) intensifies ER stress and impairs primary ciliogenesis; ferroptosis inhibition corrects the disrupted ciliogenesis caused by PDIA6 depletion, placing PDIA6-mediated ER stress upstream of ferroptotic death and cilia regulation.","method":"PDIA6 knockdown, cilia imaging, ER stress markers, ferroptosis inhibitor rescue","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with pharmacological rescue establishing epistasis, multiple cellular readouts, single lab","pmids":["39044457"],"is_preprint":false},{"year":2025,"finding":"Ca2+ triggers PDIA6 condensation into quality control granules in the ER via transient electrostatic interactions between its first and third thioredoxin-like domains (not low-complexity domains); PDIA6 condensates recruit proinsulin, accelerating oxidative proinsulin folding and suppressing proinsulin aggregation, essential for insulin secretion.","method":"Phase separation assays, NMR/structural analysis of domain interactions, proinsulin folding kinetics assay, aggregation suppression assay, live-cell imaging of ER condensates","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of condensation in vitro, structural domain mapping, functional folding assays, multiple orthogonal methods in single rigorous study","pmids":["41219432"],"is_preprint":false},{"year":2025,"finding":"ERp5/PDIA6 deficiency in platelets (platelet-specific knockout mice) increases platelet aggregation, granule secretion, and integrin αIIbβ3 activation; recombinant ERp5 (both wild-type and active-site mutant) inhibits fibrinogen binding to platelets via steric hindrance interfering with integrin αIIbβ3 ligation, demonstrating enzymatic activity is not required for this inhibitory function.","method":"Platelet-specific conditional knockout mice, platelet aggregation assays, integrin activation assays, recombinant protein (wild-type and active-site mutant) treatment, FeCl3 thrombosis model","journal":"Platelets","confidence":"High","confidence_rationale":"Tier 2 / Strong — platelet-specific KO mouse model, active-site mutagenesis of recombinant protein, multiple functional assays, in vivo thrombosis model","pmids":["39882729"],"is_preprint":false},{"year":2026,"finding":"PDIA6 directly interacts with TRAF4 at its N-terminal (1-277) domain and catalyzes disulfide bond formation at Cys39/Cys42 and Cys83/Cys106 of TRAF4; these disulfide bonds are required for TRAF4's E3 ubiquitin ligase activity facilitating AKT ubiquitination; PDIA6 also stabilizes TRAF4 by competing with SMURF1 to prevent TRAF4 ubiquitination and proteasomal degradation, sustaining AKT/mTOR signaling in ESCC.","method":"Pull-down mass spectrometry, co-immunoprecipitation, protein-protein docking, ubiquitination assay, cycloheximide chase, TRAF4 Cys mutant rescue experiments (C42A, C83A)","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — pull-down MS identification, active-site Cys mutagenesis rescue, ubiquitination assay, in vitro and in vivo validation, multiple orthogonal methods","pmids":["41761079"],"is_preprint":false},{"year":2026,"finding":"PDIA6 deficiency in spermatocytes (Stra8-Cre/Pdia6fl/fl mice) causes acrosome fragmentation and detachment, disrupted acroplaxome, disorganized flagellar axonemes, and impaired acrosome reaction and calcium mobilization; PDIA6 is required for disulfide bond formation in zona pellucida binding protein (ZPBP) synthesis, and its loss induces ER stress and apoptosis in testes.","method":"Conditional knockout mouse model, electron microscopy, immunofluorescence, calcium measurement, MPB labeling, quantitative proteomics mass spectrometry","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout model, ultrastructural analysis, substrate identification by proteomics, multiple orthogonal readouts","pmids":["41654813"],"is_preprint":false},{"year":2026,"finding":"PDIA6 directly associates with SCD1 (stearoyl-CoA desaturase 1) through an interface centered on Asp44 of SCD1, restricting SCD1 ubiquitin-proteasome-mediated degradation and maintaining SCD1-dependent fatty acid desaturation; PDIA6 drives lipid metabolic reprogramming sustaining monounsaturated fatty acid-enriched neutral lipid pools in gastric cancer.","method":"Co-immunoprecipitation, structural interface analysis, ubiquitination assay, multi-omics profiling, in vivo xenograft","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with defined binding interface, ubiquitination functional assay, multi-omics, single lab","pmids":["42234404"],"is_preprint":false},{"year":2026,"finding":"PCA (protocatechuic acid) binds PDIA6 (identified by activity-based protein profiling), and Co-IP mass spectrometry shows PCA enhances the interaction between PDIA6 and IRE1, suppressing the IRE1-XBP1s signaling pathway; PDIA6 knockdown alone inhibits lipid accumulation in hepatocytes and eliminates PCA's therapeutic effect.","method":"Activity-based protein profiling (ABPP), Co-IP mass spectrometry, PDIA6 knockdown, lipid accumulation assays","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ABPP target identification, Co-IP-MS for interaction, genetic knockdown epistasis, single lab","pmids":["41831804"],"is_preprint":false},{"year":2023,"finding":"GRh2 (ginsenoside Rh2) directly binds ERp5/PDIA6 protein (confirmed by molecular docking, microscale thermophoresis, and cellular thermal shift assay), reduces ERp5 expression, prevents soluble MICA shedding, and upregulates membrane MICA expression, thereby enhancing NK cell cytotoxicity against breast cancer cells via the NKG2D-MICA axis.","method":"Molecular docking, microscale thermophoresis, cellular thermal shift assay, flow cytometry, ELISA, immunofluorescence","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal binding methods, functional NK-cell assay, single lab","pmids":["38043385"],"is_preprint":false},{"year":2024,"finding":"RBM47 binds the 3'-UTR of PDIA6 mRNA (confirmed by RIP-PCR and dual-luciferase reporter assay) and stabilizes PDIA6 mRNA, increasing PDIA6 protein expression in pancreatic cancer cells; PDIA6 overexpression rescues the proliferation and immune evasion defects caused by RBM47 knockdown, placing PDIA6 downstream of RBM47.","method":"RNA immunoprecipitation (RIP)-PCR, dual-luciferase reporter assay, rescue experiments, metabolomics","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-PCR and luciferase for mRNA binding, rescue epistasis, single lab","pmids":["39741300"],"is_preprint":false},{"year":2024,"finding":"Ca2+-driven PDIA6 phase separation into liquid-like condensates (mediated by electrostatic interactions between its first and third thioredoxin-like domains) recruits PDIA3 and proinsulin, increasing local concentrations and achieving ~30-fold enhancement of proinsulin folding while inhibiting proinsulin aggregation.","method":"Phase separation/condensate assays, domain interaction mapping, proinsulin folding kinetics, aggregation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstitution and functional assays reported in preprint, not yet peer-reviewed; peer-reviewed version (PMID 41219432) confirms core findings","pmids":[],"is_preprint":true},{"year":2019,"finding":"Myricetin inhibits ERp5/PDIA6 reductase activity in vitro; fluorescence quenching showed myricetin binds ERp5 with similar affinity to PDI, and molecular docking identified non-covalent binding sites; myricetin inhibited only PDI and ERp5 reductase activities and not other thiol isomerases tested.","method":"In vitro reductase activity assay, fluorescence quenching, molecular docking","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus binding measurements, selectivity profile established, single lab","pmids":["32116678"],"is_preprint":false},{"year":2026,"finding":"Pachymic acid binds specifically to residues D221 and T166 of PDIA6 (identified by chemical proteomics and co-immunoprecipitation), leading to upregulation of G6PD and STAT3; through this PDIA6/G6PD/STAT3 axis, PA delays mesenchymal stem cell senescence and ameliorates senile osteoporosis in vivo.","method":"Chemical proteomics, co-immunoprecipitation, G6PD and STAT3 activity assays, in vivo senile osteoporosis mouse model","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical proteomics with defined binding residues, Co-IP, in vivo validation, single lab","pmids":["41707960"],"is_preprint":false}],"current_model":"PDIA6 is an ER-resident disulfide isomerase/oxidoreductase with two thioredoxin-like domains that catalyzes disulfide bond formation and rearrangement during protein folding; it regulates the UPR by physically interacting with and modulating both IRE1α (enhancing its activity) and PERK (inhibiting its signaling), selectively controls IRE1's RIDD activity to regulate insulin production, undergoes Ca2+-driven condensation into quality control granules—mediated by electrostatic interactions between its first and third thioredoxin domains—to accelerate oxidative proinsulin folding and suppress aggregation, is recruited to the platelet surface upon activation where it inhibits integrin αIIbβ3–fibrinogen ligation by steric hindrance, interacts with TRAF4 to catalyze its functional disulfide bonds and stabilize it against proteasomal degradation sustaining AKT/mTOR signaling, interacts with CSN5 to promote deubiquitination of β-catenin and PD-L1, and additionally functions as an unconventional RNA-binding protein whose RNA-binding activity is required for its pro-metastatic properties."},"narrative":{"mechanistic_narrative":"PDIA6 is an ER-resident thioredoxin-domain disulfide isomerase/reductase that catalyzes disulfide bond formation and rearrangement during oxidative protein folding and uses these biochemical activities to set the gain of the unfolded protein response and to chaperone secreted-protein clients [PMID:24917591, PMID:31985756, PMID:41219432]. It physically engages the principal UPR sensors, binding and enhancing IRE1α activity (IRE1α phosphorylation and XBP1 splicing) in response to ER Ca2+ disruption while also interacting with PERK and IRE1 to restrain their signaling; in insulin-producing cells it selectively limits IRE1 RIDD activity toward insulin transcripts to sustain insulin production and secretion [PMID:24917591, PMID:26487694]. PDIA6 chaperones proinsulin folding both as a selective reductase that recognizes misfolded (Akita) proinsulin and, upon a Ca2+ trigger, by condensing into ER quality-control granules through electrostatic interactions between its first and third thioredoxin-like domains, recruiting proinsulin to accelerate oxidative folding and suppress aggregation [PMID:26947243, PMID:41219432]; consistent with a non-redundant role in β-cell biology, a missense mutation in its second thioredoxin domain causes loss of β-cell identity and overt diabetes in mice [PMID:34487921]. More broadly it provides the folding capacity required for secreted factors produced by the non-hematopoietic stroma (Wnt3a, BAFF, IL-7) and for disulfide bond formation in the sperm protein ZPBP during spermatogenesis [PMID:31985756, PMID:41654813]. At the platelet surface, PDIA6 (ERp5) is recruited upon activation and binds the integrin β3 subunit, inhibiting αIIbβ3–fibrinogen ligation by steric hindrance independent of its catalytic cysteines [PMID:25624318, PMID:39882729]. In cancer it acts as a pro-survival and pro-metastatic factor through multiple effector interactions: it catalyzes functional disulfide bonds on TRAF4 and stabilizes it against degradation to sustain AKT/mTOR signaling, cooperates with CSN5 to deubiquitinate and stabilize β-catenin and PD-L1, stabilizes SCD1 to reprogram lipid metabolism, and additionally functions as an unconventional RNA-binding protein whose RNA-binding activity is required for its metastatic properties [PMID:41761079, PMID:34325342, PMID:42234404, PMID:35848924].","teleology":[{"year":2004,"claim":"Established that PDIA6/ERp5 is not solely an intracellular folding enzyme but is surface-recruited on activated platelets and engages integrin β3, linking a thiol isomerase to hemostatic function.","evidence":"Platelet membrane fractionation, inhibitory antibody blocking, and co-IP with β3 in stimulated platelets","pmids":["15466936"],"confidence":"Medium","gaps":["Whether surface engagement is catalytic or conformational was not resolved","Reciprocal in vivo requirement not tested"]},{"year":2014,"claim":"Defined PDIA6 as a positive regulator of IRE1α within a Ca2+/miR-322 feedback loop, providing a mechanism by which ER stress tunes UPR output through PDIA6 abundance.","evidence":"Reciprocal Co-IP, shRNA knockdown, XBP1 splicing and IRE1α phosphorylation assays, miRNA manipulation, mouse and C. elegans models","pmids":["24917591"],"confidence":"High","gaps":["Direct enzymatic action on IRE1α cysteines not demonstrated","Did not reconcile with later inhibitory effect on IRE1/PERK"]},{"year":2015,"claim":"Refined PDIA6's UPR role to selective control of IRE1 RIDD activity toward insulin transcripts, distinguishing it from XBP1-splicing regulation and connecting it to β-cell insulin output.","evidence":"shRNA silencing, IRE1 RIDD fluorescent reporter, insulin secretion assays in cells and intact islets","pmids":["26487694"],"confidence":"High","gaps":["Structural basis for selective RIDD versus splicing modulation unknown","Apparent opposite sign of UPR effect versus 2014 study unexplained"]},{"year":2015,"claim":"Demonstrated in vivo that ERp5 is required for thrombus formation and binds β3 with measurable affinity independent of its catalytic cysteines, separating its binding from its enzymatic activity.","evidence":"Laser-injury mouse thrombosis model, anti-ERp5 antibody, surface plasmon resonance (KD 21 µM), active-site cysteine mutagenesis","pmids":["25624318"],"confidence":"High","gaps":["Source of surface ERp5 (platelet vs endothelial) not fully defined","Mechanism of integrin inhibition not yet established here"]},{"year":2016,"claim":"Established PDIA6 as a selective reductase that discriminates misfolded proinsulin, beginning to define its client specificity in β-cell quality control.","evidence":"Co-IP with FLAG-proinsulin and quantitative comparison across PDI family members in two beta-cell lines","pmids":["26947243"],"confidence":"Medium","gaps":["Fate of bound misfolded proinsulin (degradation vs refolding) not directly traced","Catalytic mechanism on proinsulin disulfides not resolved"]},{"year":2016,"claim":"Identified pro-tumor signaling functions in which PDIA6 stabilizes β-catenin and restrains ADAM17/EGFR-driven invasion, extending its role beyond folding into oncogenic signaling control.","evidence":"Overexpression with β-catenin phosphorylation/fractionation and MG132 rescue; siRNA with ADAM17 double-knockdown epistasis and invasion assays","pmids":["27462866","27540907"],"confidence":"Medium","gaps":["Whether β-catenin stabilization requires PDIA6 catalytic activity unclear","Direct substrates linking PDIA6 to ADAM17 not identified"]},{"year":2019,"claim":"Linked PDIA6 to chemoresistance by showing it suppresses MAP4K1/JNK signaling to block cisplatin-induced apoptosis and autophagy in lung cancer.","evidence":"Co-IP, phospho-kinase array, gain/loss-of-function, in vitro and in vivo apoptosis/autophagy assays","pmids":["30922965"],"confidence":"Medium","gaps":["Whether MAP4K1 is a direct disulfide substrate not tested","Relationship to ER stress pathways not defined"]},{"year":2020,"claim":"Defined a cell-extrinsic role: PDIA6 in the non-hematopoietic stroma is required to fold secreted factors (Wnt3a, BAFF, IL-7) needed for hematopoiesis, demonstrating client-folding function in vivo.","evidence":"ENU hypomorph mouse, bone marrow transplantation rescue, folding Western blots of secreted clients","pmids":["31985756"],"confidence":"High","gaps":["Direct disulfide catalysis on each client not biochemically mapped","Which stromal cell type provides the activity not pinpointed"]},{"year":2021,"claim":"Connected PDIA6 thioredoxin-domain function to β-cell maintenance and added a CSN5-dependent deubiquitination mechanism stabilizing β-catenin and PD-L1 in cancer.","evidence":"Domain-specific Phe175Ser ENU mouse with β-cell marker analysis; Co-IP, ubiquitination, and CSN5 shRNA rescue in pancreatic cancer cells","pmids":["34487921","34325342"],"confidence":"High","gaps":["How a catalytic-domain mutation alters identity programs mechanistically unclear","Whether PDIA6 directly modifies CSN5 or substrates not shown"]},{"year":2022,"claim":"Revealed an unconventional RNA-binding activity for PDIA6 required for its tumorigenic and metastatic properties, expanding its molecular repertoire beyond redox catalysis.","evidence":"RNA interactome capture, RNA-binding domain mapping, functional metastasis assays in melanoma","pmids":["35848924"],"confidence":"Medium","gaps":["RNA targets and their downstream effects not identified","Relationship of RNA-binding to ER localization unresolved"]},{"year":2024,"claim":"Placed PDIA6 within ER homeostasis networks: it constitutively partners ERp44 with opposing roles in selective ER retention, and its loss intensifies ER stress to drive ferroptosis and impair ciliogenesis.","evidence":"Pulse-chase with PDIA6/ERp44 deletion cells and disulfide-interaction Co-IP; PDIA6 knockdown with ER-stress markers and ferroptosis-inhibitor rescue in HK2 cells","pmids":["39621446","39044457"],"confidence":"Medium","gaps":["Molecular determinants of sERr client partitioning not fully defined","Direct link between ER stress and cilia machinery unresolved"]},{"year":2025,"claim":"Provided a structural-mechanistic basis for proinsulin folding: Ca2+ drives PDIA6 condensation via first/third thioredoxin-domain electrostatics, concentrating proinsulin to accelerate folding and suppress aggregation, and confirmed steric (non-catalytic) integrin inhibition in platelets.","evidence":"In vitro phase-separation reconstitution, NMR/structural domain mapping, proinsulin folding kinetics; platelet-specific KO mice with wild-type and active-site-mutant recombinant ERp5","pmids":["41219432","39882729"],"confidence":"High","gaps":["In vivo physiological trigger and dynamics of condensation not fully characterized","Stoichiometry of condensate clients beyond proinsulin/PDIA3 not defined"]},{"year":2026,"claim":"Demonstrated catalytic and stabilizing control of oncogenic effectors: PDIA6 forms functional disulfides on TRAF4 and protects it from SMURF1-mediated degradation to sustain AKT/mTOR, stabilizes SCD1 to reprogram lipid metabolism, and is required for ZPBP disulfide formation in spermatogenesis.","evidence":"Pull-down MS, Cys-mutant rescue, ubiquitination and CHX-chase assays for TRAF4; Co-IP/interface analysis and ubiquitination for SCD1; conditional KO mouse with proteomics for ZPBP","pmids":["41761079","42234404","41654813"],"confidence":"High","gaps":["Whether SCD1 stabilization requires catalytic cysteines not established","How a single isomerase coordinates such diverse client outcomes unclear"]},{"year":null,"claim":"It remains unresolved how PDIA6's distinct activities—disulfide catalysis, Ca2+-driven condensation, UPR-sensor modulation, integrin steric inhibition, and RNA binding—are integrated and selectively deployed across cell types and stimuli.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking catalytic versus non-catalytic functions","RNA-binding targets and their interplay with folding activity unknown","Reconciliation of IRE1α-enhancing versus IRE1/PERK-inhibitory reports incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,9,15,17,18]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,16,24]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[9,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,17,19]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,13,15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,16]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,4,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,15,18]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[0,3,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,12,19]}],"complexes":["ER quality control granule (Ca2+-induced PDIA6 condensate)"],"partners":["IRE1Α","PERK","ITGB3","TRAF4","CSN5","SCD1","ERP44","MAP4K1"],"other_free_text":[]}},"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 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platelet stimulation.\",\n      \"method\": \"Platelet membrane fractionation, inhibitory antibody blocking, co-immunoprecipitation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional antibody blocking in a single lab with multiple orthogonal readouts\",\n      \"pmids\": [\"15466936\"],\n      \"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+ disruption; miR-322 suppresses PDIA6 mRNA stability, and ER Ca2+ depletion reduces miR-322 abundance, thereby increasing PDIA6 levels and IRE1α activity in a feedback loop modulating the UPR.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, XBP1 mRNA splicing assay, IRE1α phosphorylation assay, miRNA manipulation, in vivo mouse and C. elegans experiments\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal functional assays, validated in vivo in two organisms\",\n      \"pmids\": [\"24917591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDIA6 knockdown in cisplatin-resistant lung adenocarcinoma cells stimulates cell death via a non-canonical pathway sharing necroptosis features, distinct from the mitochondrial apoptosis pathway restored by PDIA4 inactivation, indicating PDIA6 mediates a specific pro-survival signaling branch in chemoresistant cells.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibition, cell death assays, ER proteomics\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological inhibition with defined cell-death pathway readouts, single lab\",\n      \"pmids\": [\"24464223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERp5/PDIA6 is released at thrombus sites in vivo and its inhibition with anti-ERp5 antibody decreases platelet deposition (70%) and fibrin accumulation (62%) in a laser-injury mouse model; ERp5 binds β3 integrin with a KD of 21 µM (measured by surface plasmon resonance), and active-site cysteine residues are not required for this binding.\",\n      \"method\": \"Laser-injury mouse thrombosis model, anti-ERp5 antibody inhibition, surface plasmon resonance, in vitro disulfide reductase assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo model, SPR binding measurement with defined KD, mutagenesis of active-site cysteines, multiple orthogonal methods\",\n      \"pmids\": [\"25624318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDIA6 interacts with PERK and IRE1 and inhibits their UPR signaling; in insulin-producing cells, PDIA6 silencing reduces insulin production ~5-fold and glucose-stimulated insulin secretion 3–4-fold by enhancing IRE1 RIDD activity toward insulin transcripts (up to 4-fold), while not substantially affecting XBP1 splicing or PERK activity under physiological glucose conditions.\",\n      \"method\": \"shRNA silencing, insulin secretion assay, IRE1 RIDD fluorescent reporter assay, XBP1 mRNA splicing assay, intact islet assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic silencing, functional reporter, secretion assay), clear mechanistic separation of IRE1 activities, replicated in cell lines and intact islets\",\n      \"pmids\": [\"26487694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 overexpression in HeLa cells promotes cell proliferation by suppressing phosphorylation of β-catenin at Ser45 and Ser33/Ser37/Thr41, thereby inhibiting its ubiquitin-proteasome-mediated degradation, increasing nuclear β-catenin accumulation, and upregulating Wnt/β-catenin target genes cyclin D1 and c-Myc.\",\n      \"method\": \"Ectopic overexpression, Western blot for β-catenin phosphorylation and nuclear fractionation, proteasome inhibitor (MG132) rescue, proliferation assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical and cellular assays, single lab, mechanistic pathway placement via MG132 rescue\",\n      \"pmids\": [\"27462866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 co-immunoprecipitates with wild-type proinsulin and approximately 10-fold more PDIA6 (but not other PDI family members) is associated with misfolded Akita proinsulin (Cys96Tyr mutation) in pancreatic beta cells, identifying PDIA6 as a selective reductase that may target misfolded proinsulin to ER degradation.\",\n      \"method\": \"Co-immunoprecipitation with FLAG-tagged proinsulin, quantitative comparison across PDI family members, two independent beta cell lines (MIN6 and βTC-6)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP validated in two independent cell lines, selectivity established by comparing multiple PDI family members\",\n      \"pmids\": [\"26947243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDIA6 knockdown in U87MG glioblastoma cells increases ADAM17 sheddase activity, MMP-2 activation, and EGFR pathway signaling (pEGFR, pFAK, integrin α5β3, MT1-MMP), leading to increased cell migration and invasion; simultaneous double-knockdown of PDIA6 and ADAM17 reduces pEGFR and pFAK, suggesting PDIA6 normally suppresses EGFR-mediated invasion by restraining ADAM17 activity.\",\n      \"method\": \"siRNA knockdown, wound-healing assay, Matrigel invasion assay, Western blot, zymography, EGFR inhibitor rescue\",\n      \"journal\": \"Journal of neurosurgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by double knockdown, multiple readouts, pharmacological rescue, single lab\",\n      \"pmids\": [\"27540907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDIA6 interacts with MAP4K1 and inhibits its phosphorylation, thereby suppressing the downstream JNK/c-Jun signaling pathway to inhibit cisplatin-induced apoptosis and autophagy in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, human phospho-kinase array, gain-of-function and loss-of-function strategies, in vitro and in vivo apoptosis/autophagy assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with pathway validation by phospho-kinase array, in vitro and in vivo models, single lab\",\n      \"pmids\": [\"30922965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PDIA6 deficiency in mice caused by a hypomorphic ENU allele results in lymphoid and myeloid hypoplasia that is rescued by transplanting PDIA6-deficient bone marrow into wild-type irradiated recipients, demonstrating the requirement for PDIA6 is extrinsic to hematopoietic cells; PDIA6 is required for proper folding of Wnt3a, BAFF, IL-7, and other factors produced by the extra-hematopoietic compartment.\",\n      \"method\": \"ENU forward genetic screen, bone marrow transplantation rescue, Western blot for Wnt3a/BAFF/IL-7 folding\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via bone marrow transplantation rescue, multiple substrate identification, validated in vivo mouse model\",\n      \"pmids\": [\"31985756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDIA6 interacts with CSN5 (COP9 signalosome subunit 5) in pancreatic cancer cells; PDIA6 overexpression promotes CSN5-mediated deubiquitination of β-catenin and PD-L1, stabilizing their expression, and these effects are partially reversed by CSN5 shRNA knockdown.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, shRNA rescue experiments, gain-of-function and loss-of-function studies\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and shRNA rescue in single lab\",\n      \"pmids\": [\"34325342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A point mutation (Phe175Ser) in the second thioredoxin domain of Pdia6 in mice causes progressive loss of pancreatic β-cell identity (reduced Ins2, Mafa, Slc2a2; increased α-cell markers Mafb and glucagon) without increased apoptosis, leading to hypoinsulinemia and overt diabetes.\",\n      \"method\": \"ENU mouse model with missense mutation, immunofluorescence, molecular marker analysis, glucose/insulin measurements, histology\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with domain-specific mutation, multiple orthogonal molecular and cellular readouts\",\n      \"pmids\": [\"34487921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDIA6 displays a novel RNA-binding activity in melanoma cells; its RNA-binding domain was mapped, and RNA binding is required for PDIA6's tumorigenic/metastatic properties, as demonstrated by RNA interactome capture and functional validation assays.\",\n      \"method\": \"RNA interactome capture (RIC), RNA-binding domain mapping, functional in vitro assays for metastatic properties\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIC method plus domain mapping and functional validation, single lab\",\n      \"pmids\": [\"35848924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDIA6 and ERp44 constitutively interact via disulfide bonds in the ER; they have opposing effects on selective ER retention (sERr) of glycoproteins during ER stress recovery—ERp44 deletion accelerates recovery while PDIA6 deletion slows it; when ERp44 is absent, PDIA6 partitions more into sERr complexes with tyrosine kinase receptor clients.\",\n      \"method\": \"Pulse-chase analysis, PDIA6 and ERp44 deletion cell lines, co-immunoprecipitation, disulfide interaction analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion of both proteins with functional epistasis, Co-IP for interaction, single lab\",\n      \"pmids\": [\"39621446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDIA6 depletion in kidney proximal tubule cells (HK2) intensifies ER stress and impairs primary ciliogenesis; ferroptosis inhibition corrects the disrupted ciliogenesis caused by PDIA6 depletion, placing PDIA6-mediated ER stress upstream of ferroptotic death and cilia regulation.\",\n      \"method\": \"PDIA6 knockdown, cilia imaging, ER stress markers, ferroptosis inhibitor rescue\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with pharmacological rescue establishing epistasis, multiple cellular readouts, single lab\",\n      \"pmids\": [\"39044457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ca2+ triggers PDIA6 condensation into quality control granules in the ER via transient electrostatic interactions between its first and third thioredoxin-like domains (not low-complexity domains); PDIA6 condensates recruit proinsulin, accelerating oxidative proinsulin folding and suppressing proinsulin aggregation, essential for insulin secretion.\",\n      \"method\": \"Phase separation assays, NMR/structural analysis of domain interactions, proinsulin folding kinetics assay, aggregation suppression assay, live-cell imaging of ER condensates\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of condensation in vitro, structural domain mapping, functional folding assays, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41219432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ERp5/PDIA6 deficiency in platelets (platelet-specific knockout mice) increases platelet aggregation, granule secretion, and integrin αIIbβ3 activation; recombinant ERp5 (both wild-type and active-site mutant) inhibits fibrinogen binding to platelets via steric hindrance interfering with integrin αIIbβ3 ligation, demonstrating enzymatic activity is not required for this inhibitory function.\",\n      \"method\": \"Platelet-specific conditional knockout mice, platelet aggregation assays, integrin activation assays, recombinant protein (wild-type and active-site mutant) treatment, FeCl3 thrombosis model\",\n      \"journal\": \"Platelets\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — platelet-specific KO mouse model, active-site mutagenesis of recombinant protein, multiple functional assays, in vivo thrombosis model\",\n      \"pmids\": [\"39882729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PDIA6 directly interacts with TRAF4 at its N-terminal (1-277) domain and catalyzes disulfide bond formation at Cys39/Cys42 and Cys83/Cys106 of TRAF4; these disulfide bonds are required for TRAF4's E3 ubiquitin ligase activity facilitating AKT ubiquitination; PDIA6 also stabilizes TRAF4 by competing with SMURF1 to prevent TRAF4 ubiquitination and proteasomal degradation, sustaining AKT/mTOR signaling in ESCC.\",\n      \"method\": \"Pull-down mass spectrometry, co-immunoprecipitation, protein-protein docking, ubiquitination assay, cycloheximide chase, TRAF4 Cys mutant rescue experiments (C42A, C83A)\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — pull-down MS identification, active-site Cys mutagenesis rescue, ubiquitination assay, in vitro and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"41761079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PDIA6 deficiency in spermatocytes (Stra8-Cre/Pdia6fl/fl mice) causes acrosome fragmentation and detachment, disrupted acroplaxome, disorganized flagellar axonemes, and impaired acrosome reaction and calcium mobilization; PDIA6 is required for disulfide bond formation in zona pellucida binding protein (ZPBP) synthesis, and its loss induces ER stress and apoptosis in testes.\",\n      \"method\": \"Conditional knockout mouse model, electron microscopy, immunofluorescence, calcium measurement, MPB labeling, quantitative proteomics mass spectrometry\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout model, ultrastructural analysis, substrate identification by proteomics, multiple orthogonal readouts\",\n      \"pmids\": [\"41654813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PDIA6 directly associates with SCD1 (stearoyl-CoA desaturase 1) through an interface centered on Asp44 of SCD1, restricting SCD1 ubiquitin-proteasome-mediated degradation and maintaining SCD1-dependent fatty acid desaturation; PDIA6 drives lipid metabolic reprogramming sustaining monounsaturated fatty acid-enriched neutral lipid pools in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation, structural interface analysis, ubiquitination assay, multi-omics profiling, in vivo xenograft\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with defined binding interface, ubiquitination functional assay, multi-omics, single lab\",\n      \"pmids\": [\"42234404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PCA (protocatechuic acid) binds PDIA6 (identified by activity-based protein profiling), and Co-IP mass spectrometry shows PCA enhances the interaction between PDIA6 and IRE1, suppressing the IRE1-XBP1s signaling pathway; PDIA6 knockdown alone inhibits lipid accumulation in hepatocytes and eliminates PCA's therapeutic effect.\",\n      \"method\": \"Activity-based protein profiling (ABPP), Co-IP mass spectrometry, PDIA6 knockdown, lipid accumulation assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ABPP target identification, Co-IP-MS for interaction, genetic knockdown epistasis, single lab\",\n      \"pmids\": [\"41831804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GRh2 (ginsenoside Rh2) directly binds ERp5/PDIA6 protein (confirmed by molecular docking, microscale thermophoresis, and cellular thermal shift assay), reduces ERp5 expression, prevents soluble MICA shedding, and upregulates membrane MICA expression, thereby enhancing NK cell cytotoxicity against breast cancer cells via the NKG2D-MICA axis.\",\n      \"method\": \"Molecular docking, microscale thermophoresis, cellular thermal shift assay, flow cytometry, ELISA, immunofluorescence\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal binding methods, functional NK-cell assay, single lab\",\n      \"pmids\": [\"38043385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM47 binds the 3'-UTR of PDIA6 mRNA (confirmed by RIP-PCR and dual-luciferase reporter assay) and stabilizes PDIA6 mRNA, increasing PDIA6 protein expression in pancreatic cancer cells; PDIA6 overexpression rescues the proliferation and immune evasion defects caused by RBM47 knockdown, placing PDIA6 downstream of RBM47.\",\n      \"method\": \"RNA immunoprecipitation (RIP)-PCR, dual-luciferase reporter assay, rescue experiments, metabolomics\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-PCR and luciferase for mRNA binding, rescue epistasis, single lab\",\n      \"pmids\": [\"39741300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ca2+-driven PDIA6 phase separation into liquid-like condensates (mediated by electrostatic interactions between its first and third thioredoxin-like domains) recruits PDIA3 and proinsulin, increasing local concentrations and achieving ~30-fold enhancement of proinsulin folding while inhibiting proinsulin aggregation.\",\n      \"method\": \"Phase separation/condensate assays, domain interaction mapping, proinsulin folding kinetics, aggregation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstitution and functional assays reported in preprint, not yet peer-reviewed; peer-reviewed version (PMID 41219432) confirms core findings\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Myricetin inhibits ERp5/PDIA6 reductase activity in vitro; fluorescence quenching showed myricetin binds ERp5 with similar affinity to PDI, and molecular docking identified non-covalent binding sites; myricetin inhibited only PDI and ERp5 reductase activities and not other thiol isomerases tested.\",\n      \"method\": \"In vitro reductase activity assay, fluorescence quenching, molecular docking\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus binding measurements, selectivity profile established, single lab\",\n      \"pmids\": [\"32116678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Pachymic acid binds specifically to residues D221 and T166 of PDIA6 (identified by chemical proteomics and co-immunoprecipitation), leading to upregulation of G6PD and STAT3; through this PDIA6/G6PD/STAT3 axis, PA delays mesenchymal stem cell senescence and ameliorates senile osteoporosis in vivo.\",\n      \"method\": \"Chemical proteomics, co-immunoprecipitation, G6PD and STAT3 activity assays, in vivo senile osteoporosis mouse model\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical proteomics with defined binding residues, Co-IP, in vivo validation, single lab\",\n      \"pmids\": [\"41707960\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDIA6 is an ER-resident disulfide isomerase/oxidoreductase with two thioredoxin-like domains that catalyzes disulfide bond formation and rearrangement during protein folding; it regulates the UPR by physically interacting with and modulating both IRE1α (enhancing its activity) and PERK (inhibiting its signaling), selectively controls IRE1's RIDD activity to regulate insulin production, undergoes Ca2+-driven condensation into quality control granules—mediated by electrostatic interactions between its first and third thioredoxin domains—to accelerate oxidative proinsulin folding and suppress aggregation, is recruited to the platelet surface upon activation where it inhibits integrin αIIbβ3–fibrinogen ligation by steric hindrance, interacts with TRAF4 to catalyze its functional disulfide bonds and stabilize it against proteasomal degradation sustaining AKT/mTOR signaling, interacts with CSN5 to promote deubiquitination of β-catenin and PD-L1, and additionally functions as an unconventional RNA-binding protein whose RNA-binding activity is required for its pro-metastatic properties.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDIA6 is an ER-resident thioredoxin-domain disulfide isomerase/reductase that catalyzes disulfide bond formation and rearrangement during oxidative protein folding and uses these biochemical activities to set the gain of the unfolded protein response and to chaperone secreted-protein clients [#1, #9, #15]. It physically engages the principal UPR sensors, binding and enhancing IRE1\\u03b1 activity (IRE1\\u03b1 phosphorylation and XBP1 splicing) in response to ER Ca2+ disruption while also interacting with PERK and IRE1 to restrain their signaling; in insulin-producing cells it selectively limits IRE1 RIDD activity toward insulin transcripts to sustain insulin production and secretion [#1, #4]. PDIA6 chaperones proinsulin folding both as a selective reductase that recognizes misfolded (Akita) proinsulin and, upon a Ca2+ trigger, by condensing into ER quality-control granules through electrostatic interactions between its first and third thioredoxin-like domains, recruiting proinsulin to accelerate oxidative folding and suppress aggregation [#6, #15]; consistent with a non-redundant role in \\u03b2-cell biology, a missense mutation in its second thioredoxin domain causes loss of \\u03b2-cell identity and overt diabetes in mice [#11]. More broadly it provides the folding capacity required for secreted factors produced by the non-hematopoietic stroma (Wnt3a, BAFF, IL-7) and for disulfide bond formation in the sperm protein ZPBP during spermatogenesis [#9, #18]. At the platelet surface, PDIA6 (ERp5) is recruited upon activation and binds the integrin \\u03b23 subunit, inhibiting \\u03b1IIb\\u03b23\\u2013fibrinogen ligation by steric hindrance independent of its catalytic cysteines [#3, #16]. In cancer it acts as a pro-survival and pro-metastatic factor through multiple effector interactions: it catalyzes functional disulfide bonds on TRAF4 and stabilizes it against degradation to sustain AKT/mTOR signaling, cooperates with CSN5 to deubiquitinate and stabilize \\u03b2-catenin and PD-L1, stabilizes SCD1 to reprogram lipid metabolism, and additionally functions as an unconventional RNA-binding protein whose RNA-binding activity is required for its metastatic properties [#17, #10, #19, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that PDIA6/ERp5 is not solely an intracellular folding enzyme but is surface-recruited on activated platelets and engages integrin \\u03b23, linking a thiol isomerase to hemostatic function.\",\n      \"evidence\": \"Platelet membrane fractionation, inhibitory antibody blocking, and co-IP with \\u03b23 in stimulated platelets\",\n      \"pmids\": [\"15466936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether surface engagement is catalytic or conformational was not resolved\", \"Reciprocal in vivo requirement not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PDIA6 as a positive regulator of IRE1\\u03b1 within a Ca2+/miR-322 feedback loop, providing a mechanism by which ER stress tunes UPR output through PDIA6 abundance.\",\n      \"evidence\": \"Reciprocal Co-IP, shRNA knockdown, XBP1 splicing and IRE1\\u03b1 phosphorylation assays, miRNA manipulation, mouse and C. elegans models\",\n      \"pmids\": [\"24917591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic action on IRE1\\u03b1 cysteines not demonstrated\", \"Did not reconcile with later inhibitory effect on IRE1/PERK\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined PDIA6's UPR role to selective control of IRE1 RIDD activity toward insulin transcripts, distinguishing it from XBP1-splicing regulation and connecting it to \\u03b2-cell insulin output.\",\n      \"evidence\": \"shRNA silencing, IRE1 RIDD fluorescent reporter, insulin secretion assays in cells and intact islets\",\n      \"pmids\": [\"26487694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for selective RIDD versus splicing modulation unknown\", \"Apparent opposite sign of UPR effect versus 2014 study unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo that ERp5 is required for thrombus formation and binds \\u03b23 with measurable affinity independent of its catalytic cysteines, separating its binding from its enzymatic activity.\",\n      \"evidence\": \"Laser-injury mouse thrombosis model, anti-ERp5 antibody, surface plasmon resonance (KD 21 \\u00b5M), active-site cysteine mutagenesis\",\n      \"pmids\": [\"25624318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of surface ERp5 (platelet vs endothelial) not fully defined\", \"Mechanism of integrin inhibition not yet established here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established PDIA6 as a selective reductase that discriminates misfolded proinsulin, beginning to define its client specificity in \\u03b2-cell quality control.\",\n      \"evidence\": \"Co-IP with FLAG-proinsulin and quantitative comparison across PDI family members in two beta-cell lines\",\n      \"pmids\": [\"26947243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fate of bound misfolded proinsulin (degradation vs refolding) not directly traced\", \"Catalytic mechanism on proinsulin disulfides not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified pro-tumor signaling functions in which PDIA6 stabilizes \\u03b2-catenin and restrains ADAM17/EGFR-driven invasion, extending its role beyond folding into oncogenic signaling control.\",\n      \"evidence\": \"Overexpression with \\u03b2-catenin phosphorylation/fractionation and MG132 rescue; siRNA with ADAM17 double-knockdown epistasis and invasion assays\",\n      \"pmids\": [\"27462866\", \"27540907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether \\u03b2-catenin stabilization requires PDIA6 catalytic activity unclear\", \"Direct substrates linking PDIA6 to ADAM17 not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked PDIA6 to chemoresistance by showing it suppresses MAP4K1/JNK signaling to block cisplatin-induced apoptosis and autophagy in lung cancer.\",\n      \"evidence\": \"Co-IP, phospho-kinase array, gain/loss-of-function, in vitro and in vivo apoptosis/autophagy assays\",\n      \"pmids\": [\"30922965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAP4K1 is a direct disulfide substrate not tested\", \"Relationship to ER stress pathways not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a cell-extrinsic role: PDIA6 in the non-hematopoietic stroma is required to fold secreted factors (Wnt3a, BAFF, IL-7) needed for hematopoiesis, demonstrating client-folding function in vivo.\",\n      \"evidence\": \"ENU hypomorph mouse, bone marrow transplantation rescue, folding Western blots of secreted clients\",\n      \"pmids\": [\"31985756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct disulfide catalysis on each client not biochemically mapped\", \"Which stromal cell type provides the activity not pinpointed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected PDIA6 thioredoxin-domain function to \\u03b2-cell maintenance and added a CSN5-dependent deubiquitination mechanism stabilizing \\u03b2-catenin and PD-L1 in cancer.\",\n      \"evidence\": \"Domain-specific Phe175Ser ENU mouse with \\u03b2-cell marker analysis; Co-IP, ubiquitination, and CSN5 shRNA rescue in pancreatic cancer cells\",\n      \"pmids\": [\"34487921\", \"34325342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a catalytic-domain mutation alters identity programs mechanistically unclear\", \"Whether PDIA6 directly modifies CSN5 or substrates not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed an unconventional RNA-binding activity for PDIA6 required for its tumorigenic and metastatic properties, expanding its molecular repertoire beyond redox catalysis.\",\n      \"evidence\": \"RNA interactome capture, RNA-binding domain mapping, functional metastasis assays in melanoma\",\n      \"pmids\": [\"35848924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA targets and their downstream effects not identified\", \"Relationship of RNA-binding to ER localization unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed PDIA6 within ER homeostasis networks: it constitutively partners ERp44 with opposing roles in selective ER retention, and its loss intensifies ER stress to drive ferroptosis and impair ciliogenesis.\",\n      \"evidence\": \"Pulse-chase with PDIA6/ERp44 deletion cells and disulfide-interaction Co-IP; PDIA6 knockdown with ER-stress markers and ferroptosis-inhibitor rescue in HK2 cells\",\n      \"pmids\": [\"39621446\", \"39044457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular determinants of sERr client partitioning not fully defined\", \"Direct link between ER stress and cilia machinery unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a structural-mechanistic basis for proinsulin folding: Ca2+ drives PDIA6 condensation via first/third thioredoxin-domain electrostatics, concentrating proinsulin to accelerate folding and suppress aggregation, and confirmed steric (non-catalytic) integrin inhibition in platelets.\",\n      \"evidence\": \"In vitro phase-separation reconstitution, NMR/structural domain mapping, proinsulin folding kinetics; platelet-specific KO mice with wild-type and active-site-mutant recombinant ERp5\",\n      \"pmids\": [\"41219432\", \"39882729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological trigger and dynamics of condensation not fully characterized\", \"Stoichiometry of condensate clients beyond proinsulin/PDIA3 not defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated catalytic and stabilizing control of oncogenic effectors: PDIA6 forms functional disulfides on TRAF4 and protects it from SMURF1-mediated degradation to sustain AKT/mTOR, stabilizes SCD1 to reprogram lipid metabolism, and is required for ZPBP disulfide formation in spermatogenesis.\",\n      \"evidence\": \"Pull-down MS, Cys-mutant rescue, ubiquitination and CHX-chase assays for TRAF4; Co-IP/interface analysis and ubiquitination for SCD1; conditional KO mouse with proteomics for ZPBP\",\n      \"pmids\": [\"41761079\", \"42234404\", \"41654813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SCD1 stabilization requires catalytic cysteines not established\", \"How a single isomerase coordinates such diverse client outcomes unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PDIA6's distinct activities\\u2014disulfide catalysis, Ca2+-driven condensation, UPR-sensor modulation, integrin steric inhibition, and RNA binding\\u2014are integrated and selectively deployed across cell types and stimuli.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking catalytic versus non-catalytic functions\", \"RNA-binding targets and their interplay with folding activity unknown\", \"Reconciliation of IRE1\\u03b1-enhancing versus IRE1/PERK-inhibitory reports incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 9, 15, 17, 18]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 16, 24]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 17, 19]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 13, 15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 4, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 15, 18]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 3, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 12, 19]}\n    ],\n    \"complexes\": [\n      \"ER quality control granule (Ca2+-induced PDIA6 condensate)\"\n    ],\n    \"partners\": [\n      \"IRE1\\u03b1\",\n      \"PERK\",\n      \"ITGB3\",\n      \"TRAF4\",\n      \"CSN5\",\n      \"SCD1\",\n      \"ERp44\",\n      \"MAP4K1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}