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Showing PDIA3 — ERP57 is a alias.

PDIA3

Protein disulfide-isomerase A3 · UniProt P30101

Length
505 aa
Mass
56.8 kDa
Annotated
2026-06-10
100 papers in source corpus 48 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDIA3 (ERp57/GRP58) is a stress-inducible, ER-resident thiol-disulfide oxidoreductase that catalyzes disulfide formation, reduction, and isomerization in newly synthesized glycoproteins, functioning within the calnexin/calreticulin chaperone cycle (PMID:8109975, PMID:8050492, PMID:14871896, PMID:17170699). It is recruited to substrates through a glucose-trimming-dependent association with calnexin and calreticulin mediated by its b' domain, and traps mixed-disulfide intermediates with heavily glycosylated, multi-disulfide clients whose folding is impaired upon ERp57 loss (PMID:9153243, PMID:17170699, PMID:17215875). Specific clients include MHC class I heavy chain—where ERp57 forms a covalent disulfide-linked heterodimer with tapasin in the peptide-loading complex to enable peptide proofreading, as resolved by crystallography of the editing complex—as well as CD1d, prion protein, and influenza hemagglutinin, the last requiring ERp57 for oxidative folding and oligomerization (PMID:9637923, PMID:12239218, PMID:17459881, PMID:26170458, PMID:30735910, PMID:36104323). Beyond canonical folding, ERp57 modulates STAT3 signaling from the ER lumen in a manner rescued by ER-targeted but not cytoplasmic protein, and its homozygous disruption is embryonic-lethal (PMID:20022947). At the cell surface and in caveolae, PDIA3 acts as the 1,25(OH)2D3-MARRS receptor, partnering with caveolin-1, VDR, and PLAA to drive rapid PLA2–PKC–ERK signaling, calcium uptake, and PGE2 release, with chaperone-domain residues (K214, R282, C406) required for these membrane responses (PMID:17224270, PMID:20843786, PMID:20682787, PMID:23896121, PMID:22484374, PMID:23660595). Extracellularly, ERp57 governs redox-dependent processes including platelet aIIbb3 activation, thrombosis, and fibrin deposition, and it specifically oxidizes and inactivates transglutaminase 2 (PMID:22207737, PMID:22168334, PMID:25156521, PMID:29305423). PDIA3 additionally exhibits Bak-dependent proapoptotic activity at mitochondria and, in the nucleus, binds specific DNA sequences via a redox-dependent conformational change of its C-terminal a' domain to participate in stress-response and transcription-factor complexes (PMID:12083768, PMID:17283067, PMID:25697356). Transcription of Pdia3 is itself driven by CLOCK and ATF4, integrating it into circadian and metabolic-stress programs (PMID:27883226, PMID:39293433).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1994 High

    Establishing that the protein was a genuine ER oxidoreductase, not the phospholipase C it had been misidentified as, defined the molecular activity that anchors all later work.

    Evidence Antibody identification, sequencing, COS-cell expression, and insulin-reduction enzymatic assay

    PMID:8050492 PMID:8109975

    Open questions at the time
    • Endogenous substrates not yet identified
    • Mechanism of substrate selection unknown
  2. 1997 High

    Showing ERp57 binds glycoproteins in a glucose-trimming-dependent manner with calnexin/calreticulin placed it within the lectin-chaperone folding cycle.

    Evidence Co-IP, pulse-chase, and glucosidase inhibitor treatment

    PMID:9153243

    Open questions at the time
    • Specific catalytic contribution to client disulfides not yet measured
    • Domain mediating chaperone binding not defined
  3. 2002 Medium

    Identification of nuclear ERp57 bound to DNA and localization of redox-dependent DNA-binding to the a' domain opened an unexpected nuclear/transcriptional role.

    Evidence In vivo DNA-protein cross-linking, nuclear fractionation, and recombinant deletion-mutant DNA-binding assays

    PMID:11948688 PMID:12083768

    Open questions at the time
    • Functional consequence on transcription not demonstrated
    • How an ER protein reaches the nucleus unresolved
  4. 2004 High

    Biophysical characterization of the four-domain architecture and quantitative redox potentials defined the catalytic capacity for reduction, isomerization, and oxidation.

    Evidence Analytical ultracentrifugation, in vitro thiol-disulfide exchange, and redox potential measurement of purified protein

    PMID:14871896

    Open questions at the time
    • Domain assignment of substrate vs partner binding not yet established
    • In-cell relevance of measured potentials not tested
  5. 2006 High

    Knockout-validated substrate trapping and b'-domain mapping consolidated the calnexin/calreticulin-dependent folding mechanism and explained partner specificity.

    Evidence Mixed-disulfide trapping in ERp57 knockout cells, chaperone-interaction perturbation, and domain analysis

    PMID:17170699 PMID:17215875

    Open questions at the time
    • Not all multi-disulfide substrates depend on calnexin/calreticulin
    • Full client repertoire incomplete
  6. 2007 High

    Resolving the covalent ERp57-tapasin-MHC I trimeric complex and the redox-driven intermolecular a'-disulfide mechanism of DNA binding mechanistically separated the folding and nuclear activities.

    Evidence Disulfide-complex isolation with MHC I cysteine mutagenesis; C406S mutagenesis and thioredoxin-reductase reversal of a'-domain dimers

    PMID:17061245 PMID:17283067 PMID:17459881

    Open questions at the time
    • Stoichiometry of nuclear vs ER pools unquantified
    • Direct transcriptional targets not yet functionally validated
  7. 2008 High

    Demonstrating ER-luminal control of STAT3 and obligate CRT co-translocation during immunogenic cell death extended ERp57 beyond folding into signaling and immunity.

    Evidence Compartment-targeted rescue in gene-trap knockout mice for STAT3; CRT point-mutant rescue, knockdown, and tumor models for surface translocation

    PMID:18464797 PMID:20022947

    Open questions at the time
    • Molecular mechanism by which luminal ERp57 alters STAT3 unclear
    • Route of co-translocation to the cell surface undefined
  8. 2010 High

    Genetic and structure-function dissection established PDIA3 as the essential 1,25(OH)2D3-MARRS receptor mediating rapid caveolar membrane signaling and calcium uptake.

    Evidence Tissue-specific conditional knockouts (intestine, osteoblast lineage), ligand binding analysis, and bidirectional silencing/overexpression with PKC/PKA/calcium readouts

    PMID:20576531 PMID:20682787 PMID:20843786

    Open questions at the time
    • How an oxidoreductase transduces a steroid ligand signal mechanistically unresolved
    • Surface targeting/orientation of PDIA3 incompletely defined
  9. 2012 High

    Mapping the caveolar receptor module (VDR, caveolin-1, PLAA) defined an interdependent two-receptor system for vitamin D rapid responses and photoprotection.

    Evidence Reciprocal co-IP, multi-component silencing, and downstream PLA2/c-Src/thymine-dimer readouts

    PMID:22322599 PMID:22484374 PMID:23896121

    Open questions at the time
    • Direct ligand-binding residues on PDIA3 not mapped
    • Topology coordinating extracellular PLAA with intracellular effectors unclear
  10. 2014 High

    Tissue-specific knockouts plus active-site mutagenesis established the extracellular redox role of ERp57 in platelet activation, thrombosis, and fibrin deposition.

    Evidence Platelet- and endothelial-specific knockouts, laser- and FeCl3-thrombosis models, inhibitory antibodies, and active-site mutants

    PMID:22168334 PMID:22207737 PMID:25156521

    Open questions at the time
    • Identity of all relevant surface redox substrates beyond aIIbb3 incomplete
    • Source of surface/extracellular ERp57 not fully defined
  11. 2015 High

    Reconstitution and substrate work defined discrete cytoprotective/proapoptotic and proteostatic functions, including Bak-dependent apoptosis and PrP maturation control.

    Evidence In vitro reconstitution with purified PDIA3 in Bak/Bax knockout systems; conditional KO and transgenic mice for PrP glycoforms

    PMID:25697356 PMID:26170458 PMID:26361352

    Open questions at the time
    • How an ER protein engages mitochondrial Bak mechanistically unclear
    • Physiological trigger of proapoptotic vs cytoprotective modes undefined
  12. 2018 High

    Quantitative kinetics identified TG2 as a specific extracellular oxidation target, demonstrating ERp57 acts as a dedicated redox regulator of a secreted enzyme.

    Evidence In vitro oxidation with purified proteins, rate-constant measurement, and siRNA in HUVECs

    PMID:29305423

    Open questions at the time
    • Physiological contexts where ERp57 oxidizes TG2 in vivo not established
    • Other extracellular substrates not catalogued
  13. 2019 High

    Defining the CLOCK transcriptional input and influenza HA folding requirement linked PDIA3 expression and client folding to circadian/host-pathogen physiology.

    Evidence ChIP/luciferase and in vivo rescue for CLOCK regulation; co-IP, inhibitor, and lung-epithelial conditional KO for HA folding

    PMID:27883226 PMID:30735910

    Open questions at the time
    • Breadth of CLOCK-driven PDIA3 functions unknown
    • Therapeutic window of PDIA3 inhibition in infection undefined
  14. 2024 High

    Identification of an ATF4–PDIA3–RhoA–YAP axis in adipose macrophages established PDIA3 as a redox effector in metabolic-stress inflammation and a therapeutic target.

    Evidence snRNA-seq, ATF4 promoter ChIP, RhoA/YAP signaling assays, and in vivo siRNA-liposome knockdown in a high-fat-diet model

    PMID:39293433

    Open questions at the time
    • Redox mechanism by which PDIA3 controls RhoA not fully resolved
    • Generality across macrophage populations untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ER oxidoreductase is partitioned and targeted across ER lumen, plasma membrane/caveolae, mitochondria, nucleus, and extracellular space to execute its distinct functions remains the central unresolved question.
  • Trafficking signals beyond KDEL/myristoylation incompletely defined
  • Quantitative balance among compartmental pools unknown
  • Whether catalytic redox activity underlies all noncanonical roles untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 5 GO:0140096 catalytic activity, acting on a protein 5 GO:0003677 DNA binding 4 GO:0016491 oxidoreductase activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005634 nucleus 4 GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-109582 Hemostasis 2 R-HSA-5357801 Programmed Cell Death 2
Partners
CALRCANXCAV1PLAASTAT3TAPBPTGM2VDR
Complex memberships
1,25D3-MARRS caveolar receptor complexMHC class I peptide-loading complexcalnexin/calreticulin chaperone cycle

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 ERp61/GRP58 (PDIA3) is a stress-inducible luminal ER protein with thiol:protein disulfide oxidoreductase activity, confirmed by insulin-reduction assay. It possesses a C-terminal QEDL ER-retention signal. PI-PLC activity is separable from ERp61, and expression of ERp61 in COS cells did not increase PI-PLC activity, definitively disproving its misidentification as phospholipase C. Antibody identification, amino acid sequencing, expression in COS cells, enzymatic assay (insulin reduction), immunocytochemistry Archives of biochemistry and biophysics High 8050492 8109975
1997 ERp57 interacts specifically with N-glycosylated integral membrane proteins in a glucose-trimming-dependent manner, and binds in combination with either calnexin or calreticulin, demonstrating that ERp57 acts in concert with these lectin chaperones to modulate glycoprotein folding. Co-immunoprecipitation, pulse-chase labeling, glucosidase inhibitor treatment The Journal of biological chemistry High 9153243
1998 ERp57 is a component of the MHC class I peptide-loading complex, associating with calnexin/calreticulin-bound MHC class I molecules, implicating it in the folding of MHC class I at a critical step in peptide loading. Co-immunoprecipitation, biochemical fractionation Current biology : CB Medium 9637923
2002 ERp57 is present in the nucleus of mammalian cells and interacts with DNA in vivo. It associates with nuclear matrix-associated regions (S/MAR-like sequences) and can be cross-linked to DNA in intact viable HeLa and 3T3 cells. DNA-protein cross-linking (two independent cross-linking agents), immunofluorescence, nuclear fractionation Journal of cellular biochemistry Medium 11948688
2002 Calnexin, calreticulin, and ERp57 cooperate in disulfide bond formation in CD1d heavy chain in a glucose-trimming-dependent manner; blocking glycan-dependent chaperone interactions with glucosidase inhibitors substantially impairs complete disulfide bond formation in CD1d. Co-immunoprecipitation, glucosidase inhibitor treatment (castanospermine, N-butyldeoxynojirimycin), pulse-chase analysis The Journal of biological chemistry High 12239218
2002 The DNA-binding activity of ERp57 is localized to the C-terminal a' domain; only the oxidized form of ERp57 binds DNA, and this activity is redox-state dependent. Recombinant deletion mutants expressed in E. coli, DNA-binding assays, redox manipulation Biochemical and biophysical research communications Medium 12083768
2003 PDIA3 (ERp60) is a component of a nuclear multiprotein complex (with HMGB1, HMGB2, HSC70, GAPDH) that preferentially binds DNA with thioguanine incorporated, identified by protein mass spectrometry, implicating PDIA3 in the cellular sensor for DNA damage caused by anticancer nucleoside analogues. Protein mass spectrometry, DNA-affinity pulldown, nuclear complex isolation Cancer research Medium 12517784
2004 ERp57 comprises four structural domains (a, b, b', a'), has an elongated shape (~3.4 nm diameter × 16.8 nm length), redox potentials of −0.167 V (a domain) and −0.156 V (a' domain), and efficiently catalyzes disulfide reduction, isomerization, and dithiol oxidation in vitro. Analytical ultracentrifugation, in vitro thiol-disulfide exchange assays, redox potential measurements The Journal of biological chemistry High 14871896
2004 ERp57 is found in STAT3-DNA complexes at the α2-macroglobulin gene enhancer (M14 melanoma) and SIE sequence (HepG2 after IL-6 stimulation); anti-ERp57 antibody blocks STAT3 binding to its consensus DNA sequence, indicating ERp57 is a necessary component of the DNA-bound STAT3 complex. EMSA, DNA-affinity experiments, chromatin immunoprecipitation, antibody blocking Biochemical and biophysical research communications Medium 15451439
2006 ERp57 traps mixed disulfide intermediates with endogenous substrates that are mostly heavily glycosylated, disulfide-bonded proteins sharing common structural domains. Folding of two endogenous substrates is impaired in ERp57 knockout cells, and prevention of calnexin/calreticulin interaction perturbs folding of some but not all multi-disulfide substrates. Mixed disulfide trapping, ERp57 knockout cells, calnexin/calreticulin interaction perturbation The EMBO journal High 17170699
2006 ERp57 and Ref-1/APE interact in vivo in multiple human cell lines (HepG2, M14, Raji), and this interaction increases under oxidative stress. ERp57, when reduced by the thioredoxin-reductase/thioredoxin system, stimulates AP-1 binding to DNA, and ERp57-overexpressing HeLa cells are protected against hydrogen peroxide-induced cell death. Immunoprecipitation, EMSA (AP-1 binding assay), cell viability assay, stable transfection Free radical biology & medicine Medium 16962936
2006 The b' domain of ERp57 mediates targeting to calnexin/calreticulin and determines substrate and partner preferences, distinguishing ERp57 from PDI whose analogous domain has different structural features. Structural/domain analysis, biochemical domain-swap experiments Biochemistry and cell biology Medium 17215875
2007 ERp57 binds specific DNA sequences in HeLa cells in vivo, identified by ChIP and cloning of immunoprecipitated fragments. Nine of ten binding sites are in non-coding regions of genes, seven in introns, including genes encoding DNA repair proteins, suggesting a role in transcriptional regulation of stress-response genes. Chromatin immunoprecipitation, cloning and sequencing of immunoprecipitated DNA Journal of cellular physiology Medium 17061245
2007 ERp57 forms a trimeric disulfide complex with MHC class I heavy chain and tapasin within the peptide-loading complex associated with TAP. Direct mutation of a conserved structural cysteine in MHC class I implicates an interaction between ERp57 and the MHC class I peptide-binding groove. Disulfide-linked complex isolation, site-directed mutagenesis, co-immunoprecipitation The Journal of biological chemistry High 17459881
2007 The DNA-binding activity of the ERp57 a' domain depends on a redox-dependent conformational change: the first cysteine of the CGHC active site (C406) is required, and DNA-binding competent species form intermolecular disulfide bridges between two a' domains rather than intramolecular oxidation. NADH-dependent thioredoxin reductase can reverse these intermolecular disulfides and abolish DNA-binding. Site-directed mutagenesis (C406S), recombinant domain biochemistry, redox manipulation, thioredoxin reductase activity assay The Journal of biological chemistry High 17283067
2007 ERp57 (as 1,25D3-MARRS receptor) is present in matrix vesicles of growth plate chondrocytes alongside PLA2 and caveolin-1. 1α,25(OH)2D3 binding to ERp57 on matrix vesicles activates PLA2, producing lysophospholipids that cause MV membrane disorganization and release of active MMPs; direct activation of MMP-3 in MVs requires ERp57. Biochemical fractionation, enzymatic assays (PLA2, PKC, MMP), immunoprecipitation, antibody blocking The Journal of steroid biochemistry and molecular biology Medium 17224270
2008 CRT and ERp57 co-translocate to the plasma membrane surface during anthracycline-induced immunogenic cell death. A direct CRT-ERp57 interaction is strictly required: CRT point mutants that fail to interact with ERp57 cannot restore ERp57 surface translocation in CRT-/- cells. ERp57-low tumor cells fail to expose CRT and fail to elicit anti-tumor immune responses. Mass spectrometry, immunofluorescence, co-immunoprecipitation, retroviral shRNA knockdown, CRT point mutant rescue experiments, in vivo tumor models Cell death and differentiation High 18464797
2008 ERp57 is present in mitochondria and associates with mitochondrial μ-calpain. ERp57-associated mitochondrial μ-calpain cleaves apoptosis-inducing factor (AIF) to a truncated form; PDI inhibitors (DTNB, PAO) cause degradation of the mitochondrial μ-calpain large subunit and inhibit AIF release from the inner mitochondrial membrane. MALDI-TOFMS peptide mass fingerprinting, immunoprecipitation, casein zymography, antibody inhibition, isolated mitochondria assays Biochimica et biophysica acta Medium 18559257
2009 ERp57 modulates STAT3 signaling from the lumen of the ER: STAT3-dependent signaling is increased in ERp57-deficient mice, and this is rescued by ER-targeted ERp57 but not cytoplasmic-targeted ERp57. ERp57 effects on STAT3 signaling are enhanced by luminal complex formation with calreticulin. ERp57 knockout (Pdia3 gene trap) causes embryonic lethality at E13.5. Gene trap knockout mouse, beta-galactosidase reporter, ER-targeted vs. cytoplasmic-targeted ERp57 rescue constructs, STAT3 signaling assays The Journal of biological chemistry High 20022947
2009 PDIA3 knockdown in cancer cells renders them insensitive to chemotherapy-induced DNA damage signaling: PDIA3 knockdown abolishes H2AX phosphorylation (γ-H2AX) after cytarabine exposure, placing PDIA3 in the H2AX branch of the DNA damage response distinct from the p53 branch. siRNA knockdown, Western blot, immunofluorescence microscopy, cell proliferation assay Molecular cancer therapeutics Medium 19372559
2009 ERp57 knockdown in human endothelial cells protects against hyperoxia- or tunicamycin-induced apoptosis by inhibiting caspase-3 activation and increasing BiP/GRP78 induction; conversely, ERp57 overexpression exacerbates apoptosis and reduces BiP/GRP78 induction. siRNA knockdown, overexpression, flow cytometry (apoptosis), Western blot (caspase-3, BiP/GRP78) American journal of physiology. Lung cellular and molecular physiology Medium 19411306
2010 Pdia3 mediates 1,25(OH)2D3-stimulated rapid membrane responses in osteoblasts: Pdia3 is localized in caveolae co-localizing with caveolin-1. Pdia3 silencing abolishes 1,25(OH)2D3-induced PKC activation and PGE2 release; Pdia3 overexpression augments these responses. Downstream mediators PLAA and arachidonic acid act independently of Pdia3. Pdia3 siRNA silencing, overexpression, co-localization with lipid rafts/caveolin-1, PKC activity assay, PGE2 measurement, ERK1/2 phosphorylation assay The Journal of biological chemistry High 20843786
2010 Intestinal epithelial cell-specific knockout of the 1,25D3-MARRS receptor (PDIA3/ERp57) abolishes 1,25D3-stimulated rapid calcium uptake and PKA activation in enterocytes, demonstrating that PDIA3 is the essential mediator of steroid hormone-stimulated calcium uptake in mammalian intestinal cells. Villin-cre conditional knockout, saturation binding analysis with [3H]1,25D3, calcium uptake assay, PKA activity assay, Western blot, confocal microscopy The Journal of biological chemistry High 20682787
2010 Homozygous Pdia3 disruption causes embryonic lethality. Pdia3+/- heterozygous mice show bone abnormalities (increased metaphyseal bone volume, reduced cortical bone area/thickness). Silencing of Pdia3 in osteoblast-like MC3T3-E1 cells abolishes 1α,25(OH)2D3-induced rapid PKC activation; overexpression augments it. Gene targeting (homologous recombination), μCT analysis, Pdia3 siRNA and overexpression in osteoblasts, PKC activity assay The Journal of steroid biochemistry and molecular biology High 20576531
2011 ERp57 on the platelet surface mediates platelet aggregation, hemostasis, and thrombosis: inhibitory anti-ERp57 antibodies block αIIbβ3 activation and P-selectin expression, inhibit platelet aggregation, prolong tail bleeding times, and inhibit FeCl3-induced thrombosis in mice. Catalytically inactive ERp57 inhibits platelet aggregation when added exogenously. Inhibitory antibodies, mouse tail bleeding assay, FeCl3 thrombosis model, αIIbβ3 activation assay, P-selectin expression, functional assay with inactive ERp57 Blood High 22168334 22207737
2012 Pdia3 and VDR co-localize in caveolae on osteoblast plasma membranes and both interact with caveolin-1 by immunoprecipitation. Pdia3 interacts with PLAA while VDR interacts with c-Src. Silencing either Pdia3 or VDR, or caveolin-1, inhibits both PLA2 and c-Src rapid responses to 1α,25(OH)2D3, demonstrating interdependent functioning of the two receptors. Co-immunoprecipitation, siRNA silencing, co-localization, PLA2 and c-Src activity assays Cellular signalling High 23896121
2012 VDR and ERp57 interact in nonnuclear extracts (co-IP) and are both required for 1,25(OH)2D3-mediated photoprotection against thymine dimers: antibody neutralization of ERp57 (Ab099) and ERp57 siRNA completely block photoprotection in normal fibroblasts, while VDR null cells also lack photoprotection. Co-immunoprecipitation, siRNA knockdown, neutralizing antibody (Ab099), thymine dimer quantification, VDR mutant fibroblasts Molecular endocrinology Medium 22322599
2012 PLAA is required for Pdia3-mediated 1α,25(OH)2D3-dependent PKC activation: PLAA co-localizes with Pdia3 and caveolin-1 in caveolae; Pdia3-immunoprecipitated samples contain PLAA only after 1,25D3 treatment; PLAA silencing abolishes 1,25D3-dependent PLA2 and PKC activation and PGE2 release. PLAA is located on the extracellular face of the plasma membrane. Co-immunoprecipitation (ligand-dependent), PLAA silencing, PLA2/PKC activity assays, PGE2 measurement, cross-linking studies The Journal of steroid biochemistry and molecular biology High 22484374
2012 Diosgenin activates the 1,25D3-MARRS (PDIA3) pathway in cortical neurons; PDIA3 knockdown completely inhibits diosgenin-induced axonal growth, and neutralizing antibody against PDIA3 diminishes diosgenin's axonal regeneration effect in Aβ(1-42)-induced axonal atrophy. siRNA knockdown, neutralizing antibody, axonal growth measurement, Alzheimer's disease mouse model Scientific reports Medium 22837815
2013 Chaperone functional domains of Pdia3 (calreticulin-interaction residues K214, R282 and catalytic site C406) are required for proper rapid membrane responses to 1α,25(OH)2D3. Removal of the KDEL ER-retention signal increases plasma membrane Pdia3 localization and augments baseline PKC, but myristoylation (not palmitoylation) is required for PKC activation. Site-directed mutagenesis, overexpression constructs with/without KDEL, PKC activity assay, PGE2 measurement, plasma membrane fractionation Molecular endocrinology High 23660595
2013 ERp57 contributes to EGF receptor signaling: siRNA knockdown of ERp57 in MDA-MB-468 cells impairs EGFR internalization and phosphorylation without affecting EGFR protein expression or EGF binding. siRNA knockdown, EGFR internalization assay, EGFR phosphorylation (Western blot), EGF binding assay Journal of cellular biochemistry Medium 23696074
2013 ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line in vivo (confirmed by ChIP). ERp57 silencing by RNAi produces significant downregulation of target gene expression. APE/Ref-1 also directly associates with ERp57-targeted DNA regions. Chromatin immunoprecipitation, siRNA silencing, in vitro biotin-streptavidin binding assay Gene Medium 23587917
2014 ERp57 is required for fibrin deposition in vivo. Platelet-specific ERp57 knockout (Pf4-Cre/ERp57fl/fl) reduces fibrin deposition; endothelial cell-specific knockout (Tie2-Cre/ERp57fl/fl) further reduces it. ERp57 inhibits thrombin generation in vitro. The second active site isomerase activity of ERp57 is required for fibrin deposition and platelet accumulation. Conditional knockout mice (platelet-specific and endothelial-specific), laser-induced thrombosis model, active-site mutants of ERp57, thrombin generation assay Journal of thrombosis and haemostasis High 25156521
2015 ERp57 physically interacts with PrP (prion protein) and controls its maturation and steady-state levels; conditional nervous system-specific ERp57 knockout reduces mono- and nonglycosylated PrP forms in brain, while ERp57 transgenic mice show increased PrP levels. PrP interacts with ERp57 and PDIA1 but not ERp72. Co-immunoprecipitation, conditional nervous system knockout, ERp57 transgenic mice, Western blot for PrP glycoforms The Journal of biological chemistry High 26170458
2015 PDIA3 possesses Bak-dependent (but not Bax-dependent) proapoptotic activity: purified PDIA3 protein induces Bak oligomerization and mitochondrial outer membrane permeabilization in vitro; PDIA3 overexpression exacerbates apoptosis whereas knockdown alleviates it. The proapoptotic activity requires Bak. In vitro reconstitution with purified PDIA3, Bak/Bax knockout cells, mitochondrial outer membrane permeabilization assay, overexpression and siRNA knockdown The Journal of biological chemistry High 25697356
2015 ERp57 overexpression in the nervous system enhances locomotor recovery after sciatic nerve injury, associated with enhanced myelin removal, macrophage infiltration, and axonal regeneration, defining a functional role for ERp57 in peripheral nerve regeneration. ERp57 transgenic mice (prion promoter-driven overexpression), sciatic nerve crush model, behavioral assessment, histological analysis PloS one Medium 26361352
2016 The circadian gene Clock transcriptionally activates Pdia3 by binding an E-box promoter element; luciferase and ChIP assays confirm Clock-dependent regulation. Forced PDIA3 expression rescues osteogenic defects in Clock mutant mice, and RNAi ablation of PDIA3 completely blocks the compensatory effect of Clock overexpression in osteoblasts. Luciferase reporter assay, chromatin immunoprecipitation, RNA interference, in vivo rescue experiments in ClockΔ19 mutant mice Journal of bone and mineral research High 27883226
2018 ERp57 specifically oxidizes and inactivates extracellular transglutaminase 2 (TG2) with a rate constant 400–2000-fold higher than small-molecule oxidants and markedly higher specificity than other secreted redox proteins. ERp57 co-localizes with extracellular TG2 in HUVECs, and siRNA-mediated ERp57 knockdown increases TG2 transamidation activity extracellularly. In vitro oxidation assays with purified proteins, rate constant measurements, co-localization by immunofluorescence, siRNA knockdown in HUVECs, transamidation activity assay The Journal of biological chemistry High 29305423
2018 ERp57 overexpression is protective against mutant SOD1-induced inclusion formation, ER stress, UPS dysfunction, and apoptosis in neuronal cells; conversely, ERp57 silencing enhances mutant SOD1 inclusion formation and toxicity. ERp57 partially co-localizes with TDP-43-positive inclusions in sporadic ALS spinal cord. ERp57 overexpression, siRNA silencing, primary cortical neurons, inclusion body quantification, apoptosis assay, immunofluorescence in human ALS tissue Human molecular genetics Medium 29409023
2019 PDIA3 directly interacts with influenza A virus hemagglutinin (HA) and is required for efficient oxidative folding and oligomerization of HA. PDIA3 inhibition (LOC14) decreases intramolecular disulfide bonds and HA oligomerization in H1N1 and H3N2-infected cells. Lung epithelial-specific PDIA3 deletion in mice reduces viral burden and lung inflammatory markers after IAV infection. Co-immunoprecipitation (ERp57-HA interaction), PDI inhibitor LOC14, disulfide bond analysis, lung-epithelial conditional knockout mice, viral burden measurement, airway mechanics Redox biology High 30735910
2019 ERp57 binds STAT3 protein and enhances STAT3-mediated transcriptional activity of ILF3 in ccRCC cells; ILF3 in turn binds ERp57 mRNA and positively regulates ERp57 expression by enhancing mRNA stability, forming a feedback loop. These interactions were confirmed by Co-IP, ChIP, RIP, and oligo pull-down. Co-immunoprecipitation, chromatin immunoprecipitation, ribonucleoprotein immunoprecipitation, oligo pull-down, promoter luciferase assay Journal of experimental & clinical cancer research Medium 31747963
2019 Drug-induced surface ERp57 in lymphoblasts is dependent on integrin activity: stimulation of α-integrin activity reduces surface ERp57 and CRT. ERp57 is indispensable for extra-ER accumulation of CRT (ERp57-/- cells have minimal cytosolic CRT). The CRT-ERp57 complex is inhibited by α-integrins, and β1-/- cells (reduced α-integrins) show enhanced surface CRT and ERp57. Genetic knockout (ERp57-/-, CRT-/-, β1-/-), differential subcellular immunostaining, integrin agonist/antagonist treatment, flow cytometry Frontiers in oncology Medium 31192123
2021 PDIA3 inhibition in club cells (SCGB1A1+) via Pdia3 conditional ablation or LOC14 inhibitor decreases parenchymal SCGB1A1 cells and lung fibrosis in bleomycin model. SPP1 (osteopontin) was identified as a major PDIA3 interactor in fibrosis; blocking SPP1 attenuates lung fibrosis. Club cell-specific Pdia3 knockout, PDI inhibitor LOC14, co-immunoprecipitation (PDIA3-SPP1), SPP1 blocking, bleomycin fibrosis model, histology Thorax Medium 34400514
2022 Crystal structure at 2.7 Å of the tapasin-ERp57 heterodimer in complex with peptide-receptive MHC class I reveals the molecular details of client recognition: tapasin-ERp57 engages MHC I clients through defined contacts, with elements indispensable for peptide proofreading. ERp57 forms a stable disulfide-linked heterodimer with tapasin in this editing complex. X-ray crystallography (2.7 Å resolution), structural analysis Nature communications High 36104323
2022 In the context of HFHF diet-induced liver damage, lipotoxicity and glucotoxicity promote MHC-II presentation of PDIA3 peptides. Passive transfer of PDIA3-specific T cells or PDIA3-specific antibodies exacerbates hepatocyte death in HFHF-fed but not control-diet mice, demonstrating that PDIA3-directed immune autoreactivity contributes to hepatic damage. MHC-II immunopeptidome analysis, adoptive transfer of PDIA3-specific T cells and antibodies, hepatic transaminase measurement, antigen-specific proliferation assay Science immunology High 35984892
2024 In adipose tissue macrophages (iMAMs), ATF4 acts as a metabolic stress sensor that transcribes PDIA3; PDIA3 then imposes redox control on RhoA activity, strengthening pro-inflammatory and migratory properties of iMAMs through RhoA-YAP signaling. Pdia3 siRNA-loaded liposomes in vivo repress adipose inflammation and HFD-induced obesity. Single-nucleus RNA sequencing, ChIP assay (ATF4 binding to Pdia3 promoter), RhoA activity assay, YAP signaling analysis, siRNA-loaded liposomes in vivo, high-fat diet model Cell metabolism High 39293433

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell death and differentiation 296 18464797
2006 ERp57 is essential for efficient folding of glycoproteins sharing common structural domains. The EMBO journal 171 17170699
2004 ERp57 is a multifunctional thiol-disulfide oxidoreductase. The Journal of biological chemistry 161 14871896
1998 The thiol oxidoreductase ERp57 is a component of the MHC class I peptide-loading complex. Current biology : CB 153 9637923
2003 Calnexin, calreticulin, and ERp57: teammates in glycoprotein folding. Cell biochemistry and biophysics 143 14716078
2005 Cellular functions of endoplasmic reticulum chaperones calreticulin, calnexin, and ERp57. International review of cytology 124 16125546
2012 Diosgenin is an exogenous activator of 1,25D₃-MARRS/Pdia3/ERp57 and improves Alzheimer's disease pathologies in 5XFAD mice. Scientific reports 120 22837815
1997 The thiol-dependent reductase ERp57 interacts specifically with N-glycosylated integral membrane proteins. The Journal of biological chemistry 104 9153243
2003 A nuclear protein complex containing high mobility group proteins B1 and B2, heat shock cognate protein 70, ERp60, and glyceraldehyde-3-phosphate dehydrogenase is involved in the cytotoxic response to DNA modified by incorporation of anticancer nucleoside analogues. Cancer research 102 12517784
2011 ERp57/GRP58: a protein with multiple functions. Cellular & molecular biology letters 101 21837552
2002 Calnexin, calreticulin, and ERp57 cooperate in disulfide bond formation in human CD1d heavy chain. The Journal of biological chemistry 100 12239218
2007 The ERp57/GRp58/1,25D3-MARRS receptor: multiple functional roles in diverse cell systems. Current medicinal chemistry 96 17456022
2009 ERp57 modulates STAT3 signaling from the lumen of the endoplasmic reticulum. The Journal of biological chemistry 93 20022947
2006 ERp57 and PDI: multifunctional protein disulfide isomerases with similar domain architectures but differing substrate-partner associations. Biochemistry and cell biology = Biochimie et biologie cellulaire 93 17215875
2010 ERp57, a multifunctional endoplasmic reticulum resident oxidoreductase. The international journal of biochemistry & cell biology 89 20079872
2011 The disulfide isomerase ERp57 mediates platelet aggregation, hemostasis, and thrombosis. Blood 88 22207737
2012 The platelet-surface thiol isomerase enzyme ERp57 modulates platelet function. Journal of thrombosis and haemostasis : JTH 86 22168334
2010 Protein-disulfide isomerase-associated 3 (Pdia3) mediates the membrane response to 1,25-dihydroxyvitamin D3 in osteoblasts. The Journal of biological chemistry 85 20843786
2013 Plasma membrane Pdia3 and VDR interact to elicit rapid responses to 1α,25(OH)(2)D(3). Cellular signalling 77 23896121
2010 Intestinal cell calcium uptake and the targeted knockout of the 1,25D3-MARRS (membrane-associated, rapid response steroid-binding) receptor/PDIA3/Erp57. The Journal of biological chemistry 73 20682787
2017 Multifunctional molecule ERp57: From cancer to neurodegenerative diseases. Pharmacology & therapeutics 72 28723413
2012 The role of the vitamin D receptor and ERp57 in photoprotection by 1α,25-dihydroxyvitamin D3. Molecular endocrinology (Baltimore, Md.) 71 22322599
2002 Nuclear localization and DNA interaction of protein disulfide isomerase ERp57 in mammalian cells. Journal of cellular biochemistry 69 11948688
2009 Chromatin-associated proteins HMGB1/2 and PDIA3 trigger cellular response to chemotherapy-induced DNA damage. Molecular cancer therapeutics 68 19372559
2006 Cooperative activity of Ref-1/APE and ERp57 in reductive activation of transcription factors. Free radical biology & medicine 66 16962936
1998 An ERp60-like protein from the filarial parasite Dirofilaria immitis has both transglutaminase and protein disulfide isomerase activity. Proceedings of the National Academy of Sciences of the United States of America 66 9435226
1994 Erp61 is GRP58, a stress-inducible luminal endoplasmic reticulum protein, but is devoid of phosphatidylinositide-specific phospholipase C activity. Archives of biochemistry and biophysics 66 8109975
2009 Differential expression of apoptotic genes PDIA3 and MAP3K5 distinguishes between low- and high-risk prostate cancer. Molecular cancer 64 20035634
2017 P4HB and PDIA3 are associated with tumor progression and therapeutic outcome of diffuse gliomas. Oncology reports 61 29207176
2004 ERp57 is present in STAT3-DNA complexes. Biochemical and biophysical research communications 60 15451439
2019 Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics. Redox biology 55 30735910
2015 Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells. Disease models & mechanisms 55 26035385
2022 ERp57/PDIA3: new insight. Cellular & molecular biology letters 54 35109791
2009 Knockdown of ERp57 increases BiP/GRP78 induction and protects against hyperoxia and tunicamycin-induced apoptosis. American journal of physiology. Lung cellular and molecular physiology 51 19411306
1986 Structure and assembly of the endoplasmic reticulum: biosynthesis and intracellular sorting of ERp61, ERp59, and ERp49, three protein components of murine endoplasmic reticulum. Archives of biochemistry and biophysics 50 3954360
2021 PDIA3: Structure, functions and its potential role in viral infections. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 49 34474345
2008 ERp57-associated mitochondrial μ-calpain truncates apoptosis-inducing factor. Biochimica et biophysica acta 49 18559257
2015 Proapoptotic activities of protein disulfide isomerase (PDI) and PDIA3 protein, a role of the Bcl-2 protein Bak. The Journal of biological chemistry 46 25697356
2008 PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients. Journal of autoimmunity 46 18541406
2007 The stress protein ERp57/GRP58 binds specific DNA sequences in HeLa cells. Journal of cellular physiology 46 17061245
2015 The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein. The Journal of biological chemistry 45 26170458
2015 Functional Role of the Disulfide Isomerase ERp57 in Axonal Regeneration. PloS one 45 26361352
2022 PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes. Science immunology 43 35984892
2006 Interaction of ERp57 and tapasin in the generation of MHC class I-peptide complexes. Current opinion in immunology 43 17150345
2016 The Circadian Gene Clock Regulates Bone Formation Via PDIA3. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 42 27883226
2002 The Caenorhabditis elegans ERp60 homolog protein disulfide isomerase-3 has disulfide isomerase and transglutaminase-like cross-linking activity and is involved in the maintenance of body morphology. The Journal of biological chemistry 41 12424233
2020 PDIA3 correlates with clinical malignant features and immune signature in human gliomas. Aging 39 32687065
1996 ERp60 does not substitute for protein disulphide isomerase as the beta-subunit of prolyl 4-hydroxylase. The Biochemical journal 39 8687406
2016 MiR-330-5p regulates tyrosinase and PDIA3 expression and suppresses cell proliferation and invasion in cutaneous malignant melanoma. The Journal of surgical research 38 27363653
2007 Major histocompatibility complex class I-ERp57-tapasin interactions within the peptide-loading complex. The Journal of biological chemistry 38 17459881
2007 1alpha,25(OH)2D3 is an autocrine regulator of extracellular matrix turnover and growth factor release via ERp60 activated matrix vesicle metalloproteinases. The Journal of steroid biochemistry and molecular biology 37 17224270
1999 Binding of the protein disulfide isomerase isoform ERp60 to the nuclear matrix-associated regions of DNA. Journal of cellular biochemistry 37 10022612
2021 Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis. Thorax 36 34400514
2012 Mechanism of Pdia3-dependent 1α,25-dihydroxy vitamin D3 signaling in musculoskeletal cells. Steroids 36 22569272
2006 Phosphoinositide-specific phospholipase C (PI-PLC) beta1 and nuclear lipid-dependent signaling. Biochimica et biophysica acta 36 16624616
2020 A Gallium(III) Complex that Engages Protein Disulfide Isomerase A3 (PDIA3) as an Anticancer Target. Angewandte Chemie (International ed. in English) 35 33448534
2019 PDIA3-regulted inflammation and oxidative stress contribute to the traumatic brain injury (TBI) in mice. Biochemical and biophysical research communications 35 31466719
2005 Nuclear phosphoinositide specific phospholipase C (PI-PLC)-beta 1: a central intermediary in nuclear lipid-dependent signal transduction. Histology and histopathology 35 16136505
2019 Upregulation of ERp57 promotes clear cell renal cell carcinoma progression by initiating a STAT3/ILF3 feedback loop. Journal of experimental & clinical cancer research : CR 34 31747963
2010 Disruption of Pdia3 gene results in bone abnormality and affects 1alpha,25-dihydroxy-vitamin D3-induced rapid activation of PKC. The Journal of steroid biochemistry and molecular biology 34 20576531
2018 Endoplasmic reticulum-resident protein 57 (ERp57) oxidatively inactivates human transglutaminase 2. The Journal of biological chemistry 33 29305423
2016 LEDGF/p75 Overexpression Attenuates Oxidative Stress-Induced Necrosis and Upregulates the Oxidoreductase ERP57/PDIA3/GRP58 in Prostate Cancer. PloS one 33 26771192
2014 The disulfide isomerase ERp57 is required for fibrin deposition in vivo. Journal of thrombosis and haemostasis : JTH 33 25156521
2022 Structure of an MHC I-tapasin-ERp57 editing complex defines chaperone promiscuity. Nature communications 32 36104323
2020 PDIA3 Expression in Glioblastoma Modulates Macrophage/Microglia Pro-Tumor Activation. International journal of molecular sciences 32 33153019
2018 ERp57 is protective against mutant SOD1-induced cellular pathology in amyotrophic lateral sclerosis. Human molecular genetics 32 29409023
2011 Dengue virus infection induces upregulation of hn RNP-H and PDIA3 for its multiplication in the host cell. Virus research 31 22207023
2012 Phospholipase A2 activating protein is required for 1α,25-dihydroxyvitamin D3 dependent rapid activation of protein kinase C via Pdia3. The Journal of steroid biochemistry and molecular biology 30 22484374
2003 Effect of doxycycline-regulated ERp57 expression on specific thrombopoietin productivity of recombinant CHO cells. Biotechnology progress 30 12573023
2010 ER-60 (PDIA3) is highly expressed in a newly established serous ovarian cancer cell line, YDOV-139. International journal of oncology 29 20596667
2016 Largescale Transcriptomics Analysis Suggests Over-Expression of BGH3, MMP9 and PDIA3 in Oral Squamous Cell Carcinoma. PloS one 28 26745629
2015 PDIA3 Knockdown Exacerbates Free Fatty Acid-Induced Hepatocyte Steatosis and Apoptosis. PloS one 28 26214517
2018 Punicalagin, an active pomegranate component, is a new inhibitor of PDIA3 reductase activity. Biochimie 27 29425676
2013 The protein ERp57 contributes to EGF receptor signaling and internalization in MDA-MB-468 breast cancer cells. Journal of cellular biochemistry 27 23696074
2009 Stress-induced expression of protein disulfide isomerase associated 3 (PDIA3) in Atlantic salmon (Salmo salar L.). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 27 19747560
2002 The DNA-binding activity of protein disulfide isomerase ERp57 is associated with the a(') domain. Biochemical and biophysical research communications 27 12083768
2018 Downregulation of PDIA3 inhibits proliferation and invasion of human acute myeloid leukemia cells. OncoTargets and therapy 26 29844689
2015 miR-330-5p inhibits proliferation and migration of keratinocytes by targeting Pdia3 expression. The FEBS journal 26 26402295
1997 Structures of the human gene for the protein disulfide isomerase-related polypeptide ERp60 and a processed gene and assignment of these genes to 15q15 and 1q21. Genomics 26 9205111
2021 Insights into the role of ERp57 in cancer. Journal of Cancer 25 33758622
2020 PDIA3 regulates trophoblast apoptosis and proliferation in preeclampsia via the MDM2/p53 pathway. Reproduction (Cambridge, England) 25 32585639
2019 Integrins and ERp57 Coordinate to Regulate Cell Surface Calreticulin in Immunogenic Cell Death. Frontiers in oncology 25 31192123
2007 Aggregate formation by ERp57-deficient MHC class I peptide-loading complexes. Traffic (Copenhagen, Denmark) 25 17822402
2013 AGR2, ERp57/GRP58, and some other human protein disulfide isomerases. Biochemistry. Biokhimiia 24 24490732
2014 Impaired bone formation in Pdia3 deficient mice. PloS one 23 25405762
2015 A review of 1α,25(OH)2D3 dependent Pdia3 receptor complex components in Wnt5a non-canonical pathway signaling. The Journal of steroid biochemistry and molecular biology 22 25845934
2013 ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line. Gene 22 23587917
2024 PDIA3 defines a novel subset of adipose macrophages to exacerbate the development of obesity and metabolic disorders. Cell metabolism 21 39293433
2019 Influence of Ellagitannins Extracted by Pomegranate Fruit on Disulfide Isomerase PDIA3 Activity. Nutrients 21 30658391
2016 Protein Disulphide Isomerases: emerging roles of PDI and ERp57 in the nervous system and as therapeutic targets for ALS. Expert opinion on therapeutic targets 21 27786579
2021 Cancer Biology of the Endoplasmic Reticulum Lectin Chaperones Calreticulin, Calnexin and PDIA3/ERp57. Progress in molecular and subcellular biology 20 34050867
2017 Endoplasmic reticulum stress-mediated membrane expression of CRT/ERp57 induces immunogenic apoptosis in drug-resistant endometrial cancer cells. Oncotarget 20 28938593
2013 Chaperone properties of pdia3 participate in rapid membrane actions of 1α,25-dihydroxyvitamin d3. Molecular endocrinology (Baltimore, Md.) 19 23660595
2010 Protein kinase C isotypes in signal transduction for the 1,25D3-MARRS receptor (ERp57/PDIA3) in steroid hormone-stimulated phosphate uptake. Steroids 19 20079367
2007 DNA-binding activity of the ERp57 C-terminal domain is related to a redox-dependent conformational change. The Journal of biological chemistry 19 17283067
2025 Plant PI-PLC signaling in stress and development. Plant physiology 18 39928581
2022 Remifentanil Promotes PDIA3 Expression by Activating p38MAPK to Inhibit Intestinal Ischemia/Reperfusion-Induced Oxidative and Endoplasmic Reticulum Stress. Frontiers in cell and developmental biology 18 35155431
2013 Green tea catechins can bind and modify ERp57/PDIA3 activity. Biochimica et biophysica acta 18 23671928
2007 The phosphoinositide-phospholipase C (PI-PLC) pathway in the mouse oocyte. Critical reviews in eukaryotic gene expression 18 17725492
1994 Tissue distribution of ERp61 and association of its increased expression with IgG production in hybridoma cells. Experimental cell research 18 8050492

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