Affinage

PDIA4

Protein disulfide-isomerase A4 · UniProt P13667

Length
645 aa
Mass
72.9 kDa
Annotated
2026-06-10
56 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDIA4 (ERp72) is an ER-resident protein disulfide isomerase that catalyzes oxidative protein folding and disulfide bond formation/isomerization and serves as a molecular chaperone for secretory proteins (PMID:2295602, PMID:8477750, PMID:8300576). It carries three CGHC-containing thioredoxin-like catalytic domains whose roles are partitioned, with domains 1 and 2 governing catalytic efficiency and domain 3 governing substrate binding affinity, while a C-terminal KEEL motif retains it in the ER (PMID:2295602, PMID:16333982); structural studies define the spatial arrangement of its five thioredoxin-like domains and show that, unlike ERp57, it does not bind calnexin (PMID:19446521, PMID:20600112). As a chaperone it associates with maturing secretory substrates including thyroglobulin, apolipoprotein B-100, and antibodies, persisting through the ER and into the Golgi, and binds short peptides in an ATP-independent manner (PMID:7916014, PMID:9694898, PMID:12397072, PMID:10441153, PMID:32878739). PDIA4 cooperates with other PDI family members, stimulating the chaperone and oxidative folding activity of P5 (PMID:34827105). Beyond the ER lumen it acts at the platelet surface, where its a and a' active sites directly engage and activate the αIIbβ3 integrin to drive platelet aggregation, secretion, and arterial thrombosis (PMID:28576878, PMID:29052936). PDIA4 is induced by ER stress and integrated into UPR signaling, where it binds oligomeric IRE1α to restrain the IRE1α/XBP1s branch (PMID:2254345, PMID:39743023, PMID:41121130), and under ER stress can redistribute to the cytosol via DNAJB12/14 and SGTA to inhibit caspase-3 and wild-type p53, promoting cancer cell survival (PMID:41120732). Across disease contexts it drives ROS production in β-cells through interactions with Ndufs3 and p22phox and promotes tumor growth, ferroptosis resistance, and metabolic dysfunction (PMID:34542937, PMID:36935456, PMID:36906674, PMID:24464223). A de novo PDIA4 mutation (V417I) was identified in a patient with complex congenital heart disease, with PDIA4 loss reducing WNT/β-catenin signaling in endothelial cells (PMID:41853143).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1990 High

    Establishing the molecular identity of the protein: cloning revealed three PDI-type CGHC active sites and a functional ER retention signal, framing it as a multi-catalytic ER folding enzyme rather than a single-site oxidoreductase.

    Evidence cDNA cloning, sequencing, and mutagenesis of the C-terminal KEEL signal with secretion readout in transfected cells

    PMID:2254345 PMID:2295602

    Open questions at the time
    • Direct enzymatic isomerase activity not yet demonstrated
    • Functional contribution of each active site undefined
    • Retention shown to have capacity limits but mechanism beyond KEEL recognition unclear
  2. 1994 High

    Confirming catalytic function: purified protein catalyzed insulin reduction and renaturation of denatured reduced substrates under defined redox conditions, establishing bona fide disulfide formation and isomerization activity.

    Evidence In vitro insulin reduction and protein renaturation assays with purified CaBP2 (rat ortholog), redox titration

    PMID:8300576 PMID:8477750

    Open questions at the time
    • Physiological substrates in cells not identified
    • Synergism patterns with other PDIs not mechanistically explained
  3. 1993 Medium

    A reported cysteine protease activity raised the possibility of a degradative role for the enzyme on other ER residents, an activity not reconciled with its disulfide isomerase function in later work.

    Evidence In vitro proteolysis assay with purified liver ERp72, inhibitor and Ca2+ modulation studies

    PMID:8408057

    Open questions at the time
    • Protease activity not independently confirmed in subsequent literature
    • Relationship to thioredoxin catalytic sites unresolved
    • Physiological relevance unclear
  4. 2002 Medium

    Defining its chaperone clientele: cross-linking and fractionation showed sustained association with secretory substrates (thyroglobulin, apoB-100, TAP-translocated peptides) through the secretory pathway, establishing PDIA4 as a folding chaperone for client proteins.

    Evidence Cross-linking co-IP, sequential IP, subcellular fractionation, and microsomal peptide-binding assays in thyroid, hepatic, and antibody-producing cells

    PMID:10441153 PMID:12397072 PMID:7916014 PMID:9694898

    Open questions at the time
    • Whether binding reflects catalytic engagement vs holdase function not separated
    • Substrate specificity determinants undefined
  5. 2010 High

    Resolving how the multi-domain enzyme works: domain-resolved kinetics and crystal structures partitioned catalytic efficiency and substrate binding among the active sites and defined the spatial arrangement of all thioredoxin-like domains, distinguishing PDIA4 from ERp57 by ruling out calnexin binding.

    Evidence Site-directed mutagenesis with kinetic analysis, X-ray crystallography of bb' and a0a fragments, SAXS, ITC, and NMR

    PMID:16333982 PMID:19446521 PMID:20600112

    Open questions at the time
    • No structure of full-length protein in complex with substrate
    • Conformational dynamics during catalysis not captured
  6. 2007 Medium

    Linking folding capacity to disease: ERp72 forms covalent complexes with mutant thyroglobulin and maintains client cysteines reduced, connecting persistent ERp72-substrate aggregates to thyrocyte pathology.

    Evidence Non-reducing SDS-PAGE, co-IP, and inducible overexpression with pulse-chase/ERAD analysis in thyroid cells

    PMID:17200118

    Open questions at the time
    • Causal link to apoptosis not directly demonstrated
    • Single lab
  7. 2008 Medium

    Identifying redox regulation and an extra-ER localization: Nox1 binds the ERp72 N-terminus and oxidizes it to inhibit reductase activity, with co-localization at the plasma membrane, placing PDIA4 in cell-surface ROS signaling.

    Evidence Reciprocal co-IP, GST pulldown, mutagenesis, reductase activity assay, and confocal microscopy

    PMID:18620548

    Open questions at the time
    • Mechanism of plasma-membrane targeting unexplained
    • Physiological consequence of Nox1-mediated inhibition unclear
  8. 2018 High

    Establishing a vascular function: conditional knockout, active-site mutant rescue, and a function-blocking antibody showed extracellular ERp72 directly activates αIIbβ3 integrin via its a and a' sites to drive platelet activation and thrombosis.

    Evidence Tie2-Cre conditional KO, intravital thrombosis models, active-site mutant rescue, β3-null platelet binding, and humanized blocking antibody across platelet functional assays

    PMID:28576878 PMID:29052936

    Open questions at the time
    • How an ER enzyme reaches the platelet surface not resolved
    • Full set of surface substrates beyond αIIbβ3 not defined
  9. 2023 Medium

    Defining a β-cell ROS-generating role: PDIA4 enzymatic activity and its interactions with Ndufs3 and p22phox drive ROS production, with genetic and pharmacological inhibition reversing diabetic phenotypes in mice.

    Evidence KO/OE in diabetic mice, co-IP of Pdia4-Ndufs3 and Pdia4-p22phox, enzymatic inhibition (PS1/GHTT), ROS and ETC complex I assays

    PMID:34542937 PMID:36935456

    Open questions at the time
    • Direct redox substrate within the Ndufs3/p22phox complex not identified
    • Single lab
  10. 2025 Medium

    Connecting PDIA4 to UPR control and cytosolic apoptosis suppression: it binds oligomeric IRE1α to restrain IRE1α/XBP1s signaling, and under ER stress relocates to the cytosol via DNAJB12/14 and SGTA to inhibit caspase-3 and wild-type p53, promoting cancer cell survival.

    Evidence Co-IP with cross-linking (IRE1α, caspase-3, p53), subcellular fractionation, ER-retention mutants, CRISPR KO, and in vivo tumor/DKD models

    PMID:28576878 PMID:39743023 PMID:41120732

    Open questions at the time
    • Direct vs indirect inhibition of caspase-3/p53 not fully separated
    • Mechanism of ER-to-cytosol retrotranslocation incompletely defined
    • Single lab for cytosolic relocalization model
  11. 2026 Low

    Implicating PDIA4 in a developmental disorder: a de novo V417I mutation in congenital heart disease and PDIA4-dependent WNT/β-catenin signaling in endothelial cells link the gene to cardiac development.

    Evidence Whole-exome sequencing of a patient and siRNA knockdown in HUVECs with WNT reporter and β-catenin Western blots

    PMID:41853143

    Open questions at the time
    • Single patient, no segregation or functional rescue of the variant
    • Mechanism connecting PDIA4 to β-catenin undefined
    • No in vivo developmental model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a KEEL-retained ER lumen enzyme reaches multiple extracytoplasmic and cytosolic sites of action (platelet surface, plasma membrane, cytosol) through a unified trafficking mechanism remains unresolved.
  • No unifying model for escape from ER retention
  • Surface and cytosolic substrate repertoires incompletely mapped
  • Whether different localizations share the same catalytic chemistry unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 4 GO:0044183 protein folding chaperone 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-109582 Hemostasis 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CASP3CYBAIRE1AITGB3NDUFS3NOX1P5TP53

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 ERp72 (PDIA4) contains three copies of the CGHC-containing active site sequences of protein disulfide isomerase, identifying it as a PDI family member with potential disulfide isomerase activity. The KEEL sequence at its C-terminus functions as an ER retention signal, as demonstrated by in vitro mutagenesis and transient expression assays showing dramatically increased secretion of the KEEL-deleted mutant. cDNA cloning, sequencing, in vitro mutagenesis, transient expression assays The Journal of biological chemistry High 2295602
1990 ERp72 mRNA is induced by ER stress conditions (tunicamycin and calcium ionophore A23187) in CHO cells, identifying ERp72 as a member of the glucose-regulated protein (GRP) family. High-level overexpression leads to secretion of the overproduced ERp72 specifically, suggesting the ER retention mechanism has capacity limits and involves more than just KDEL/KEEL recognition. Northern blotting, stable overexpression in CHO cells, secretion assays The Journal of biological chemistry Medium 2254345
1993 ERp72 purified from rat and mouse liver ER exhibits cysteine protease activity, degrading other ER resident proteins such as PDI and calreticulin. The proteolytic activity is inhibited by cysteine protease inhibitors and acidic phospholipids. Ca2+ differentially modulates activity depending on the substrate. Protein purification (four sequential chromatographies), in vitro proteolysis assay, inhibitor studies, immunoblot The Journal of biological chemistry Medium 8408057
1993 CaBP2 (rat homolog of ERp72/PDIA4) possesses significant protein disulfide isomerase activity, catalyzing the reduction of insulin in the presence of reductants, establishing enzymatic PDI activity for this protein. In vitro insulin reduction assay with purified CaBP2 European journal of biochemistry High 8477750
1994 CaBP2 (rat ERp72/PDIA4) and CaBP1 catalyze the renaturation of denatured reduced proteins (Fab fragment and RNase AIII), demonstrating disulfide bond formation and isomerization activity. Renaturation rate is dependent on GSH/GSSG ratio (maximum at 1:1) and amount of enzyme. PDI shows moderate synergism with CaBP2 but no synergism when combined with CaBP1; PPI shows synergism with PDI, CaBP2, and CaBP1 but not combinations of PDIs. In vitro protein renaturation assays (biological activity recovery), redox condition titration The Journal of biological chemistry High 8300576
1994 ERp72 associates with thyroglobulin (Tg) during its maturation in thyroid cells (FRTL-5 and PCC13), as demonstrated by chemical cross-linking and co-immunoprecipitation. ERp72, BiP, and grp94 form high molecular weight complexes with Tg. ERp72 also co-immunoprecipitates with BiP and grp94 after cross-linking, suggesting ERp72 functions as a molecular chaperone for Tg maturation, potentially as part of a macromolecular complex. Chemical cross-linking, co-immunoprecipitation, sucrose density gradient centrifugation The Journal of biological chemistry Medium 7916014
1998 ERp72 co-immunoprecipitates with apolipoprotein B-100 (apoB-100) from HepG2 cells following cross-linking, and also associates with truncated apoB forms in C127 cells lacking MTP, indicating ERp72 binding to apoB is independent of lipidation. Ternary complexes containing apoB-100, MTP, and ERp72 were identified by sequential immunoprecipitation. ERp72-apoB interactions persist for at least 2 hours, suggesting roles in folding advanced intermediates and/or targeting misfolded apoB for degradation. Cross-linking, co-immunoprecipitation, sequential immunoprecipitation, pulse-chase The Journal of biological chemistry Medium 9694898
1999 ERp72 binds TAP-translocated peptides in the ER lumen, establishing ERp72 as a peptide-binding chaperone. ERp72 interacts with peptide substrates ranging from 8 to 40 amino acids in an ATP-independent manner, with broad but not identical substrate selectivity compared to other ER chaperones. TAP-mediated peptide translocation into microsomes, peptide-binding assays Biochemistry Medium 10441153
2002 ERp72 associates with nascent lipidated apoB in both ER and Golgi compartments, as shown by immunoprecipitation of sucrose-gradient-fractionated subcellular compartments. ERp72 was found associated with sialylated apoB in Golgi, indicating ERp72 chaperone interactions with apoB persist through the secretory pathway into trans-Golgi network. Subcellular fractionation (sucrose gradient), KBr density gradient centrifugation, immunoprecipitation, Western blotting The Journal of biological chemistry Medium 12397072
2005 All three thioredoxin homology domains of ERp72 contribute to PDI activity but with distinct roles: domains 1 and 2 primarily determine catalytic efficiency (kcat), while domain 3 primarily determines substrate binding affinity (Km). Domain 2 participates in both binding and catalysis depending on combinatorial context. Site-directed mutagenesis (cysteine-to-serine substitutions), in vitro insulin reduction assay, kinetic analysis Cell stress & chaperones High 16333982
2007 ERp72 forms covalent complexes with mutant thyroglobulin Tg-G2320R in thyroid cells. Inducible overexpression of ERp72 increases the ability of cells to maintain Tg cysteines in a reduced state. A small ERAD-resistant fraction of mutant Tg remains in covalent association with ERp72 even 2 days post-synthesis, suggesting persistent ERp72-Tg covalent aggregates may contribute to thyrocyte apoptosis. Non-reducing SDS-PAGE, co-immunoprecipitation, inducible overexpression, pulse-chase, ERAD analysis The Journal of biological chemistry Medium 17200118
2008 NADPH oxidase 1 (Nox1) physically associates with ERp72 involving the N-terminus of ERp72 encompassing a Ca2+-binding site and the first thioredoxin-like motif, as shown by co-immunoprecipitation, GST pulldown, and mutational analysis. Nox1-generated ROS oxidize ERp72 and inhibit its reductase activity. EGF stimulates Nox1 activity, which in turn mediates EGF-induced suppression of ERp72 reductase activity. ERp72 and Nox1 co-localize at the plasma membrane. Co-immunoprecipitation, GST pulldown, site-directed mutagenesis, reductase activity assay, confocal microscopy The Biochemical journal Medium 18620548
2009 X-ray crystal structure of the central non-catalytic domains (bb') of ERp72 reveals strong similarity to ERp57 in domain architecture, but ERp72 does not interact with calnexin as shown by isothermal titration calorimetry and NMR spectroscopy. SAXS analysis of full-length ERp72 defines the relative positions of all five thioredoxin-like domains and identifies potential substrate/chaperone binding sites. X-ray crystallography, SAXS, isothermal titration calorimetry (ITC), NMR spectroscopy Structure High 19446521
2010 X-ray crystal structure of the N-terminal a0a catalytic fragment of ERp72 reveals: the a0 domain contains an additional N-terminal beta-strand and a different beta5-alpha4 loop conformation relative to other thioredoxin-like domains; a conserved arginine in the a domain inserts into the hydrophobic core and makes a salt bridge with a conserved glutamate near the catalytic site. A full-length structural model positions all three catalytic sites facing each other with adjacent hydrophobic patches likely involved in substrate binding. X-ray crystallography, structural modeling Journal of molecular biology High 20600112
2014 PDIA4 inactivation (pharmacological and genetic knockdown) directly stimulates cisplatin-induced cell death in CDDP-resistant lung cancer cells specifically by restoring a classical mitochondrial apoptosis pathway, distinguishing PDIA4's mechanism from that of PDIA6 which operates through a non-canonical necroptosis-like pathway. Pharmacological inhibition, siRNA knockdown, cell death assays, mitochondrial membrane permeabilization assays, proteomics Cell death and differentiation Medium 24464223
2017 ERp72 supports arterial thrombosis through its a and a' CGHC active sites. ERp72-null platelets show defective aggregation, JON/A binding (αIIbβ3 activation), P-selectin expression, and ATP secretion. Recombinant ERp72 with functional a and a' sites fully rescues these defects while ERp72 with inactivated a and a' sites inhibits platelet function in wild-type mice. ERp72 binds poorly to β3-null platelets and generates thiols in αIIbβ3, indicating direct interaction with αIIbβ3 integrin as a substrate. Conditional knockout mice (Tie2-Cre/ERp72fl/fl), intravital microscopy (laser and FeCl3 injury models), platelet aggregation assays, recombinant protein rescue with active-site mutants, JON/A binding, P-selectin expression, ATP secretion, β3-null mouse experiments Blood High 28576878
2018 ERp72 levels increase at the platelet surface during platelet activation. A humanized monoclonal antibody blocking ERp72 enzyme activity inhibits platelet aggregation, granule secretion, calcium mobilization, and integrin activation, establishing that extracellular ERp72 thiol isomerase activity is required for platelet activation and thrombosis in vivo. Humanized antibody generation (HuCAL), platelet functional assays (aggregation, granule secretion, calcium flux, integrin activation), in vivo thrombosis model Journal of thrombosis and haemostasis High 29052936
2021 Pdia4 promotes ROS production in pancreatic β-cells via its action on the pathway involving Ndufs3 and p22phox. Ablation of Pdia4 reduces ROS, islet destruction, blood glucose, and HbA1c while increasing insulin secretion; overexpression has the opposite effects. A Pdia4 inhibitor (GHTT) suppresses diabetic development in mice. Genetic knockout and overexpression in diabetic mice, ROS assays, blood glucose/HbA1c measurements, insulin secretion assays, mechanistic pathway analysis (Ndufs3, p22phox) EMBO molecular medicine Medium 34542937
2021 P5 (a PDI family member) forms non-covalent interactions with ERp72, and ERp72 stimulates the chaperone activity of P5. PDI up-regulates the oxidative folding enzymatic activity of P5. These results show that complex formation between PDI family members synergistically accelerates protein folding and prevents aggregation. Far-western blot, chaperone activity assay, oxidative folding assay Biology Medium 34827105
2022 PDIA4 promotes GBM cell proliferation and aerobic glycolysis by activating the PI3K/AKT/mTOR signaling pathway. PDIA4 knockdown reduces phosphorylation of PI3K, AKT, and mTOR; addition of the PI3K/AKT/mTOR activator 740Y-P reverses the effects of PDIA4 knockdown, placing PDIA4 upstream of this pathway. siRNA knockdown, Western blotting (phospho-PI3K/AKT/mTOR), pathway activator rescue, in vitro and in vivo tumor growth assays Biochemical and biophysical research communications Medium 35131603
2022 PDIA4 knockdown decreases palmitate-induced insulin resistance and inflammation in C2C12 skeletal muscle cells. Metformin modulates PDIA4 expression and alleviates insulin resistance both in vitro and in vivo (high-fat diet mouse model), suggesting PDIA4 participates in ER stress-mediated insulin resistance in skeletal muscle. siRNA knockdown in C2C12 cells, high-fat diet mouse model, insulin resistance assays, inflammatory cytokine measurement Frontiers in endocrinology Medium 36619574
2022 PDIA4 promotes obesity-associated inflammation and metabolic dysfunction in adipocytes by downregulating adiponectin. Pharmacological and genetic inhibition of PDIA4 reverses lipid accumulation, inflammation, and impaired glucose uptake in hypertrophic adipocytes; this is mechanistically linked to adiponectin upregulation upon PDIA4 inhibition. siRNA knockdown, pharmacological inhibition, high-fat diet mouse model, adiponectin measurement, lipid accumulation and glucose uptake assays BioFactors Medium 35674710
2023 PDIA4 inhibitor PS1 reduces ROS production in β-cells by inhibiting the enzymatic activity of Pdia4 and reducing the interaction between Pdia4 and Ndufs3 or p22phox, demonstrating that the Pdia4/Ndufs3 and Pdia4/p22phox protein interactions are required for Pdia4-mediated ROS regulation. PS1 reverses diabetes in db/db mice. In vitro Pdia4 enzymatic inhibition assay (IC50 determination), co-immunoprecipitation (Pdia4-Ndufs3 and Pdia4-p22phox), ROS assays, electron transport chain complex 1 activity assay, in vivo db/db mouse model Cellular and molecular life sciences Medium 36935456
2023 PDIA4 promotes ferroptosis resistance in renal cell carcinoma by sustaining ATF4 and its downstream target SLC7A11. Downregulation of PDIA4 suppresses ATF4 and SLC7A11, increasing ferroptosis sensitivity. Salinomycin suppresses PDIA4 by increasing its autophagic degradation, thereby sensitizing RCC cells to ferroptosis. siRNA knockdown, ectopic overexpression, Western blotting (ATF4, SLC7A11), ferroptosis assays, autophagy inhibition/induction experiments, xenograft mouse model Cell death & disease Medium 36906674
2023 PDIA4 is required for LCMV infection; LCMV glycoprotein is the main viral component responsible for upregulating PDIA4. Inhibition of ATF6-mediated ER stress prevents PDIA4 upregulation during LCMV infection. PDIA4 affects LCMV viral RNA synthesis and release. Quantitative proteomics, ATF6 inhibition, PDIA4 knockdown, viral RNA synthesis and release assays Viruses Medium 38140584
2024 PDIA4 overexpression suppresses IRE1α/sXBP1 signaling under high glucose conditions by binding to the oligomeric form of IRE1α. High glucose triggers release of GRP78 from IRE1α and increased interaction between IRE1α and PDIA4 (demonstrated by immunoprecipitation and cross-linking assays). PDIA4 overexpression in DKD mouse models mitigates tubular injury and NLRP3 inflammasome activation. Immunoprecipitation, chemical cross-linking, PDIA4 overexpression and silencing, IRE1α knockdown, in vivo STZ and db/db mouse models Biochimica et biophysica acta. Molecular basis of disease Medium 39743023
2024 ERp72 (PDIA4) plays a negative regulatory role in autoantibody-induced arthritis. ERp72 knockout mice exhibit exacerbated arthritis with greater joint swelling, bone/cartilage erosion, synovial inflammation, increased IL-1β, IL-6, TNF-α, and decreased IL-10 in inflamed joints, demonstrating that ERp72 suppresses inflammatory cytokine production in the context of autoantibody-induced joint inflammation. Cre-LoxP conditional knockout mice, K/BxN serum transfer arthritis model, joint histology, cytokine measurement (qPCR, ELISA) Scandinavian journal of rheumatology Medium 38975658
2025 Under ER stress, PDIA4 redistributes from the ER to the cytosol facilitated by the c-tail-anchored proteins DNAJB12 and DNAJB14 and the cytosolic HSC70-cochaperone SGTA. In the cytosol, PDIA4 forms inhibitory interactions with caspase-3 and wt-p53, attenuating their activities and increasing cancer cell proliferation/survival. Silencing PDIA4, DNAJB12/14, or SGTA rescues caspase-3 and wt-p53 activity. PDIA4 must originate from the ER to exert this cytosolic inhibitory function. siRNA knockdown of PDIA4/DNAJB12/DNAJB14/SGTA, subcellular fractionation, co-immunoprecipitation (PDIA4-caspase-3, PDIA4-p53), ER-retention mutant experiments, caspase-3 and p53 activity assays Oncogene Medium 41120732
2025 PDIA4 knockout in multiple myeloma cells activates the IRE1α/XBP1s branch of the unfolded protein response, impairs proliferation, induces G1-phase arrest, and sensitizes cells to bortezomib. In vivo, PDIA4 knockout suppresses tumor growth in RPMI-8226 xenografts. CRISPR/Cas9 knockout, UPR pathway analysis (IRE1α/XBP1s), cell cycle analysis, bortezomib sensitivity assays, xenograft mouse model Journal of translational medicine Medium 41121130
2025 PDIA4 delivered by HO-1-modified BMMSC-derived small extracellular vesicles activates the PDIA4/HSP90/MYC axis in macrophages, inhibiting MYC ubiquitination and degradation, thereby promoting reparative (M2-like) macrophage polarization and alleviating ischemia-reperfusion injury in steatotic liver grafts. sEV delivery of PDIA4, co-immunoprecipitation (PDIA4-HSP90, HSP90-MYC), MYC ubiquitination assay, macrophage polarization assays, in vivo liver transplant model Biochimica et biophysica acta. Molecular basis of disease Low 40494182
2026 PDIA4 deficiency in human umbilical vein endothelial cells inhibits the protein levels of total and nuclear β-catenin and downstream WNT/β-catenin signaling pathway activity, suggesting PDIA4 modulates cardiac development through this pathway. A de novo PDIA4 mutation (V417I) was found in a patient with complex congenital heart disease. siRNA knockdown in HUVECs, Western blotting (β-catenin), WNT pathway reporter assay, whole-exome sequencing Frontiers in genetics Low 41853143
2026 The Hippo pathway effector TEAD4 directly transcriptionally upregulates PDIA4 expression in TNBC cells. THP treatment activates Hippo kinase cascade, leading to YAP phosphorylation and degradation, which reduces YAP/TEAD4 interaction and TEAD4 DNA-binding, thereby suppressing PDIA4 transcription and disrupting ER proteostasis. ChIP assay (TEAD4 binding to PDIA4 promoter), YAP/TEAD4 co-IP, PDIA4 rescue experiments, in vitro and in vivo cancer models Advanced science Medium 41926654
2020 PDIa4 (PDIA4) is required for efficient monoclonal antibody production in CHO cells. PDIa4 knockdown reduces secreted antibody and causes accumulation of immature antibodies intracellularly. Recombinant PDIa4 can refold denatured antibodies and Fab fragments in vitro, demonstrating direct disulfide bond formation activity on antibody substrates. siRNA knockdown in CHO cells, antibody secretion quantification, in vitro refolding assay with recombinant PDIa4 Journal of bioscience and bioengineering Medium 32878739

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 ERp72, an abundant luminal endoplasmic reticulum protein, contains three copies of the active site sequences of protein disulfide isomerase. The Journal of biological chemistry 230 2295602
1990 The stress response in Chinese hamster ovary cells. Regulation of ERp72 and protein disulfide isomerase expression and secretion. The Journal of biological chemistry 163 2254345
2014 The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma. Cell death and differentiation 101 24464223
1994 Several endoplasmic reticulum stress proteins, including ERp72, interact with thyroglobulin during its maturation. The Journal of biological chemistry 85 7916014
1998 Multiple molecular chaperones interact with apolipoprotein B during its maturation. The network of endoplasmic reticulum-resident chaperones (ERp72, GRP94, calreticulin, and BiP) interacts with apolipoprotein b regardless of its lipidation state. The Journal of biological chemistry 80 9694898
1994 Effects of CaBP2, the rat analog of ERp72, and of CaBP1 on the refolding of denatured reduced proteins. Comparison with protein disulfide isomerase. The Journal of biological chemistry 77 8300576
1991 Competitive inhibition of a set of endoplasmic reticulum protein genes (GRP78, GRP94, and ERp72) retards cell growth and lowers viability after ionophore treatment. Molecular and cellular biology 75 2046663
2002 Nascent lipidated apolipoprotein B is transported to the Golgi as an incompletely folded intermediate as probed by its association with network of endoplasmic reticulum molecular chaperones, GRP94, ERp72, BiP, calreticulin, and cyclophilin B. The Journal of biological chemistry 71 12397072
1993 Protein degradation by ERp72 from rat and mouse liver endoplasmic reticulum. The Journal of biological chemistry 69 8408057
2019 PDIA4: The basic characteristics, functions and its potential connection with cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 68 31794946
2023 PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma. Cell death & disease 65 36906674
2017 The disulfide isomerase ERp72 supports arterial thrombosis in mice. Blood 61 28576878
1993 CaBP2 is a rat homolog of ERp72 with proteindisulfide isomerase activity. European journal of biochemistry 57 8477750
1999 Identification of novel peptide binding proteins in the endoplasmic reticulum: ERp72, calnexin, and grp170. Biochemistry 56 10441153
2007 Oxidoreductase interactions include a role for ERp72 engagement with mutant thyroglobulin from the rdw/rdw rat dwarf. The Journal of biological chemistry 42 17200118
2009 Structure of the noncatalytic domains and global fold of the protein disulfide isomerase ERp72. Structure (London, England : 1993) 41 19446521
1993 Serum antibodies from halothane hepatitis patients react with the rat endoplasmic reticulum protein ERp72. Chemical research in toxicology 40 8292737
2018 A humanized monoclonal antibody that inhibits platelet-surface ERp72 reveals a role for ERp72 in thrombosis. Journal of thrombosis and haemostasis : JTH 34 29052936
1998 Erp72 expression activated by transient cerebral ischemia or disturbance of neuronal endoplasmic reticulum calcium stores. Metabolic brain disease 31 9570640
1992 Molecular characterization and expression of an alfalfa protein with sequence similarity to mammalian ERp72, a glucose-regulated endoplasmic reticulum protein containing active site sequences of protein disulphide isomerase. The Plant journal : for cell and molecular biology 27 1303795
2008 A possible biochemical link between NADPH oxidase (Nox) 1 redox-signalling and ERp72. The Biochemical journal 25 18620548
1998 Role of calcium in the activation of erp72 and heme oxygenase-1 expression on depletion of endoplasmic reticulum calcium stores in rat neuronal cell culture. Neuroscience letters 21 9655603
2022 PDIA4 promotes glioblastoma progression via the PI3K/AKT/m-TOR pathway. Biochemical and biophysical research communications 20 35131603
2020 MicroRNA-378a-3p contributes to ovarian cancer progression through downregulating PDIA4. Immunity, inflammation and disease 20 33159506
2010 Structure of the catalytic a(0)a fragment of the protein disulfide isomerase ERp72. Journal of molecular biology 20 20600112
2023 Small extracellular vesicles-transported lncRNA TDRKH-AS1 derived from AOPPs-treated trophoblasts initiates endothelial cells pyroptosis through PDIA4/DDIT4 axis in preeclampsia. Journal of translational medicine 17 37488572
2022 PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle. Frontiers in endocrinology 17 36619574
2021 Pdia4 regulates β-cell pathogenesis in diabetes: molecular mechanism and targeted therapy. EMBO molecular medicine 17 34542937
2018 Insertion of 275-bp SINE into first intron of PDIA4 gene is associated with litter size in Xiang pigs. Animal reproduction science 17 29728275
2017 Interleukin-11 up-regulates endoplasmic reticulum stress induced target, PDIA4 in human first trimester placenta and in vivo in mice. Placenta 16 28487027
2005 Functional characterization of 3 thioredoxin homology domains of ERp72. Cell stress & chaperones 16 16333982
1993 Identification of genomic sequences that mediate the induction of the endoplasmic reticulum stress protein, ERp72, by protein traffic. DNA and cell biology 16 8216852
2022 PDIA4, a novel ER stress chaperone, modulates adiponectin expression and inflammation in adipose tissue. BioFactors (Oxford, England) 15 35674710
2020 Effect of the disulfide isomerase PDIa4 on the antibody production of Chinese hamster ovary cells. Journal of bioscience and bioengineering 12 32878739
1997 NF-Y, a CCAAT box-binding protein, is one of the trans-acting factors necessary for the response of the murine ERp72 gene to protein traffic. DNA and cell biology 12 9324314
2024 PDIA4 targets IRE1α/sXBP1 to alleviate NLRP3 inflammasome activation and renal tubular injury in diabetic kidney disease. Biochimica et biophysica acta. Molecular basis of disease 10 39743023
2023 LncRNA FAM225B Regulates PDIA4-Mediated Ovarian Cancer Cell Invasion and Migration via Modulating Transcription Factor DDX17. The breast journal 10 37720188
2022 High expression of PDIA4 promotes malignant cell behavior and predicts reduced survival in cervical cancer. Oncology reports 10 36082822
1992 An antibody that binds a neutrophil membrane protein, ERp72, primes human neutrophils for enhanced oxidative metabolism in response to formyl-methionyl-leucyl-phenylalanine. Implications for ERp72 in the signal transduction pathway for neutrophil priming. Journal of immunology (Baltimore, Md. : 1950) 9 1318337
2023 Pharmacological and mechanistic study of PS1, a Pdia4 inhibitor, in β-cell pathogenesis and diabetes in db/db mice. Cellular and molecular life sciences : CMLS 8 36935456
2022 Albumin (ALB) and protein disulfide isomerase family A member 4 (PDIA4) are novel markers to predict sperm freezability of Erhualian boar. Cryobiology 8 36181861
2023 PDIA4 Is a Host Factor Important for Lymphocytic Choriomeningitis Virus Infection. Viruses 5 38140584
2021 Functional Interplay between P5 and PDI/ERp72 to Drive Protein Folding. Biology 5 34827105
2021 Vascular endothelial ERp72 is involved in the inflammatory response in a rat model of skeletal muscle injury. Molecular medicine reports 4 33398381
2025 Small extracellular vesicles from HO-1 modified BMMSCs alleviate steatotic liver grafts ischemia-reperfusion injury by delivering PDIA4 to promote reparative macrophage polarization. Biochimica et biophysica acta. Molecular basis of disease 3 40494182
2025 Single-cell transcriptomics identifies PDIA4 as a marker of progression and therapeutic vulnerability in multiple myeloma. Journal of translational medicine 2 41121130
2024 Potential Anti-tumor Properties of PDIA4 in Lung Adenocarcinoma. Anticancer research 2 39348977
2025 Non-genetic inactivation of caspase-3 and P53 increases cancer cell fitness by PDIA4 redistribution. Oncogene 1 41120732
2024 Amplifying colorectal cancer progression: impact of a PDIA4/SP1 positive feedback loop by circPDIA4 sponging miR-9-5p. Cancer biology & medicine 1 38907517
2024 A novel role for endoplasmic reticulum protein ERp72 in the pathogenesis of autoantibody-induced arthritis. Scandinavian journal of rheumatology 1 38975658
2026 Homoharringtonine inhibits growth and migration in non-small cell lung cancer via PDIA4-mediated modulation of autophagy and EMT. Archives of pharmacal research 0 41826608
2026 Defects in PDIA4 increase individuals' susceptibility to congenital heart disease. Frontiers in genetics 0 41853143
2026 Tetrastigma Hemsleyanum Polysaccharide Suppresses Triple-Negative Breast Cancer by Disrupting the Hippo-YAP/TEAD4-PDIA4 Axis and Endoplasmic Reticulum Stress Adaptation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41926654
2026 Cholesterol synthases suppress metastasis and stemness through PDIA4/ACLY or SYVN1/SCD1 axis in advanced colorectal cancer. Communications biology 0 41981153
2025 Downregulation of PDIA4 inhibits proliferation and migration in human oral squamous cell carcinoma. Hereditas 0 41185082
1995 Isolation of ERp72 from guinea pig term placentae using heparin Sepharose affinity chromatography. Biochemistry and molecular biology international 0 8535285

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