Affinage

PDIA3

Protein disulfide-isomerase A3 · UniProt P30101

Length
505 aa
Mass
56.8 kDa
Annotated
2026-04-29
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDIA3 (ERp57/GRP58) is a thiol-disulfide oxidoreductase of the protein disulfide isomerase family that operates across multiple cellular compartments to catalyze oxidative folding, regulate redox-dependent signaling, and modulate immune recognition. In the ER, PDIA3 associates with calnexin and calreticulin via its b' domain to catalyze disulfide bond formation in glycoprotein substrates including influenza hemagglutinin and the prion protein, and forms a disulfide-linked heterodimer with tapasin that stabilizes the MHC class I peptide-loading complex and enables peptide proofreading, as resolved by a 2.7 Å crystal structure (PMID:9153243, PMID:14732712, PMID:17459881, PMID:36104323, PMID:26170458). At the plasma membrane, PDIA3 localizes to caveolae where it functions as a 1α,25(OH)₂D₃ receptor that activates PLA2/PKC signaling interdependently with VDR, mediates platelet aggregation and fibrin deposition through its isomerase activity, oxidatively inactivates extracellular transglutaminase 2, and co-translocates with calreticulin during immunogenic cell death to promote anti-tumor immunity (PMID:20843786, PMID:23896121, PMID:22207737, PMID:25156521, PMID:29305423, PMID:18464797). PDIA3 also participates in nuclear functions including redox-dependent DNA binding via its oxidized a' domain homodimer, regulation of STAT3 phosphorylation and STAT3-dependent transcription, and γ-H2AX-mediated DNA damage signaling (PMID:17283067, PMID:19995546, PMID:19372559).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Establishing that ERp57 is a glycoprotein-specific chaperone resolved the question of how the calnexin/calreticulin cycle recruits an oxidoreductase: ERp57 interacts selectively with N-glycosylated membrane proteins in a glucose-trimming-dependent manner.

    Evidence Co-immunoprecipitation with glycosylation inhibitor controls in mammalian cells

    PMID:9153243

    Open questions at the time
    • Substrate specificity determinants beyond glycosylation not defined
    • No structural data on ERp57–lectin chaperone interface at this stage
  2. 1998 High

    Placing ERp57 inside the MHC class I peptide-loading complex answered how antigen presentation recruits an oxidoreductase and linked ER quality control to adaptive immunity.

    Evidence Reciprocal co-immunoprecipitation and biochemical fractionation of MHC class I complexes

    PMID:9637923

    Open questions at the time
    • Nature of the ERp57–tapasin linkage unknown
    • Whether ERp57 catalytic activity is required for peptide loading not tested
  3. 2002 Medium

    Mapping DNA-binding activity to the oxidized a' domain revealed an unexpected nuclear function for an ER oxidoreductase, raising the question of how redox state toggles ERp57 between chaperone and transcriptional roles.

    Evidence Recombinant domain deletion mutagenesis with in vitro DNA-binding assays

    PMID:12083768

    Open questions at the time
    • In vivo relevance of DNA binding not established
    • Mechanism of nuclear import undefined
  4. 2003 High

    Defining the four-domain (abb'a') architecture and mapping the calreticulin/calnexin interaction to the b' domain provided the structural framework for understanding how ERp57 is recruited to glycoprotein substrates.

    Evidence Limited proteolysis, recombinant domain expression, chemical cross-linking, CD spectroscopy, and mass spectrometry

    PMID:14732712

    Open questions at the time
    • No high-resolution structure of ERp57–calreticulin complex
    • Catalytic efficiency relative to PDI only partially characterized
  5. 2004 Medium

    Demonstrating ERp57 within STAT3–DNA complexes on the α2-macroglobulin enhancer established that ERp57 participates directly in transcription factor–DNA assemblies, not merely in protein folding.

    Evidence EMSA, DNA affinity chromatography, and chromatin immunoprecipitation in two cell types

    PMID:15451439

    Open questions at the time
    • Mechanism by which ERp57 modulates STAT3 DNA binding unknown
    • Whether ERp57 catalytic activity is required not tested
  6. 2006 High

    ERp57 knockout cells revealed that ERp57 is specifically required for post-translational (not co-translational) oxidative folding of influenza HA, delineating the temporal window of ERp57 action in the calnexin cycle.

    Evidence ERp57 knockout cell lines with pulse-chase folding assays for influenza HA and other substrates

    PMID:16407314

    Open questions at the time
    • ERp72 partial compensation complicates full loss-of-function interpretation
    • Scope of ERp57-dependent substrates not comprehensively cataloged
  7. 2007 High

    Identifying the disulfide-linked ERp57–tapasin heterodimer and a trimeric ERp57–tapasin–MHC I heavy chain complex defined the redox chemistry at the heart of peptide loading, showing ERp57 directly engages the peptide-binding groove.

    Evidence Site-directed cysteine mutagenesis, co-immunoprecipitation, and intracellular redox manipulation

    PMID:17459881 PMID:17822402

    Open questions at the time
    • Atomic structure not yet available
    • How ERp57 cooperates with PDI in MHC I redox regulation unclear
  8. 2007 High

    Showing that oxidation drives ERp57 a' domain homodimerization via active-site cysteines (with C406 essential) and that thioredoxin reductase reverses it defined a redox switch controlling DNA-binding competence.

    Evidence Site-directed mutagenesis, mass spectrometry, and thioredoxin reductase reduction assay on recombinant protein

    PMID:17283067

    Open questions at the time
    • Physiological oxidant that activates the switch in vivo unknown
    • Genome-wide DNA binding targets not mapped
  9. 2008 High

    Demonstrating that ERp57 co-translocates with calreticulin to the cell surface during immunogenic cell death—and that their direct interaction is strictly required—established ERp57 as a gatekeeper of immunogenic signaling in cancer therapy.

    Evidence CRT point mutants abolishing ERp57 interaction, shRNA knockdown, mass spectrometry, and in vivo mouse tumor models with anthracycline treatment

    PMID:18464797

    Open questions at the time
    • Mechanism of ER-to-surface translocation pathway undefined
    • Whether ERp57 catalytic activity is required for surface exposure not tested
  10. 2009 Medium

    Placing PDIA3 upstream of γ-H2AX but not p53 phosphorylation positioned it in a distinct branch of the DNA damage response, expanding its nuclear roles beyond transcription.

    Evidence siRNA knockdown with Western blot and immunofluorescence for γ-H2AX after cytarabine treatment

    PMID:19372559

    Open questions at the time
    • Direct substrate or kinase target of PDIA3 in H2AX phosphorylation unknown
    • Single lab, single DNA-damaging agent tested
    • Whether the effect is through redox modulation of ATM/ATR not addressed
  11. 2010 High

    Localizing PDIA3 to caveolae and demonstrating it mediates rapid 1α,25(OH)₂D₃-induced PLA2/PKC signaling—abolished by silencing and augmented by overexpression—established PDIA3 as a membrane receptor for vitamin D₃ in bone.

    Evidence Confocal co-localization with caveolin-1, siRNA/overexpression, PKC and PGE₂ assays in osteoblasts; Pdia3 knockout mouse showing embryonic lethality and skeletal defects

    PMID:20576531 PMID:20843786

    Open questions at the time
    • Direct ligand-binding site on PDIA3 for 1,25(OH)₂D₃ not structurally defined
    • Mechanism of PDIA3 escape from ER to plasma membrane not resolved
  12. 2011 High

    Showing that ERp57 isomerase activity on the platelet surface is required for αIIbβ3 activation, P-selectin expression, and in vivo hemostasis revealed an extracellular catalytic function of ERp57 in thrombosis.

    Evidence Inhibitory anti-ERp57 antibody, catalytically inactive mutant, tail bleeding assay, and FeCl₃ thrombosis model in mice

    PMID:22207737

    Open questions at the time
    • Direct disulfide substrate on αIIbβ3 not identified
    • Mechanism of ERp57 secretion from platelets not defined
  13. 2013 High

    Demonstrating that PDIA3 and VDR form an interdependent caveolar signaling complex—with PDIA3 coupling to PLAA and VDR to c-Src—resolved how two receptors cooperate in rapid membrane vitamin D₃ responses and showed that chaperone domains and myristoylation are required for signaling.

    Evidence Reciprocal co-immunoprecipitation of PDIA3/VDR/caveolin-1, siRNA silencing of each component, site-directed mutagenesis of calreticulin-interaction and catalytic residues

    PMID:23660595 PMID:23896121

    Open questions at the time
    • Structural basis of PDIA3–VDR interaction not defined
    • How myristoylation targets PDIA3 to caveolae not mechanistically resolved
  14. 2014 High

    Conditional platelet- and endothelial-specific ERp57 knockouts pinpointed the cell types and the specific active site (second CGHC motif) required for fibrin deposition, establishing ERp57 isomerase activity as a direct regulator of coagulation.

    Evidence Pf4-Cre and Tie2-Cre conditional knockouts, laser-induced thrombosis with intravital microscopy, recombinant active-site mutant rescue

    PMID:25156521

    Open questions at the time
    • Coagulation factor substrate of the second active site not identified
    • Relative contribution of platelet vs. endothelial ERp57 not fully resolved
  15. 2018 High

    Kinetic demonstration that ERp57 oxidizes the Cys370–Cys371 allosteric disulfide of transglutaminase 2 at rates 400–2000-fold faster than small molecules identified ERp57 as the physiological extracellular inactivator of TG2.

    Evidence In vitro rate constant measurements, siRNA knockdown increasing extracellular TG2 activity, immunofluorescence co-localization in endothelial cells

    PMID:29305423

    Open questions at the time
    • In vivo confirmation in TG2-dependent disease models not performed
    • Whether other PDI family members contribute to TG2 regulation not excluded
  16. 2019 High

    Lung epithelial-specific PDIA3 deletion reduced influenza viral burden, confirming PDIA3 as a host factor required for HA maturation in vivo and validating it as an antiviral target.

    Evidence Conditional epithelial-specific Pdia3 knockout mice infected with H1N1/H3N2, PDI inhibitor LOC14, co-immunoprecipitation of PDIA3–HA

    PMID:30735910

    Open questions at the time
    • Whether PDIA3 inhibition affects other respiratory viruses not tested
    • Therapeutic window of PDI inhibitors in vivo not established
  17. 2019 High

    Linking PDIA3 to vitamin D₃-induced STAT3 nuclear translocation and MCOLN3-dependent lysosomal acidification for Helicobacter pylori clearance unified the membrane receptor and STAT3-regulatory functions of PDIA3 in a single signaling axis.

    Evidence CRISPR knockout and siRNA in gastric epithelial cells, co-immunoprecipitation of PDIA3–STAT3, ChIP-PCR for MCOLN3, Ca²⁺ imaging, bacterial CFU assays

    PMID:30612517

    Open questions at the time
    • Whether this pathway operates in other cell types beyond gastric epithelium unknown
    • Direct ligand-binding evidence for 1,25(OH)₂D₃–PDIA3 at atomic level still lacking
  18. 2022 High

    The 2.7 Å crystal structure of the tapasin–ERp57 heterodimer with peptide-receptive MHC class I provided the atomic mechanism for peptide proofreading, showing how ERp57's disulfide linkage to tapasin stabilizes the editing complex.

    Evidence X-ray crystallography at 2.7 Å resolution with functional mutagenesis validation

    PMID:36104323

    Open questions at the time
    • Dynamic conformational changes during peptide exchange not captured by static structure
    • Structure of the full six-component PLC (with TAP1/TAP2) not yet resolved
  19. 2024 Medium

    Identifying PDIA3 as an ATF4-transcribed effector that imposes redox control on RhoA–YAP signaling in inflammatory adipose macrophages extended PDIA3's extracellular thiol-exchange functions to metabolic inflammation.

    Evidence Single-nucleus RNA-seq, PDIA3 siRNA-loaded liposomes in vivo reducing adipose inflammation and HFD-induced obesity, RhoA activity and YAP signaling assays

    PMID:39293433

    Open questions at the time
    • Direct RhoA disulfide substrate of PDIA3 not biochemically confirmed
    • Single study; independent replication pending
    • Whether the effect is cell-autonomous to macrophages not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of 1α,25(OH)₂D₃ binding to PDIA3 at the plasma membrane, the mechanism by which PDIA3 escapes ER retention to reach the cell surface, and the identity of the coagulation factor disulfide substrates acted upon by ERp57's second active site during thrombosis.
  • No ligand-bound PDIA3 structure for vitamin D₃
  • ER-to-surface trafficking pathway undefined
  • Coagulation disulfide substrates not identified
  • Genome-wide catalog of ERp57-dependent glycoprotein substrates incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016491 oxidoreductase activity 7 GO:0098772 molecular function regulator activity 6 GO:0060089 molecular transducer activity 4 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 6 GO:0005783 endoplasmic reticulum 6 GO:0005886 plasma membrane 5 GO:0005576 extracellular region 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-109582 Hemostasis 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1 R-HSA-9612973 Autophagy 1
Partners
CALRCANXCAV1PLAASTAT3TAPBPTGM2VDR
Complex memberships
Calnexin/calreticulin cycleMHC class I peptide-loading complexPDIA3-VDR-caveolin-1 membrane complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 ERp57 is a component of the MHC class I peptide-loading complex, associating with calreticulin and calnexin to assist MHC class I folding at a critical step in peptide loading. Co-immunoprecipitation, biochemical fractionation Current Biology High 9637923
1997 ERp57 interacts specifically with N-glycosylated integral membrane proteins in a glucose-trimming-dependent manner, acting in concert with calnexin and calreticulin to modulate glycoprotein folding. Co-immunoprecipitation, glycosylation inhibitor experiments Journal of Biological Chemistry High 9153243
2003 ERp57's domain structure consists of four domains (abb'a'); its b' domain mediates interaction with calreticulin/calnexin P domains, and multiple domains are required for calreticulin association. ERp57 catalyzes oxidative folding of glycoproteins including RNase A, though less effectively than PDI. Limited proteolysis, N-terminal sequencing, recombinant domain expression, chemical cross-linking, CD spectroscopy, electrospray mass spectrometry Journal of Biological Chemistry High 14732712
2006 ERp57 deletion impairs post-translational oxidative folding of influenza hemagglutinin (an obligate calnexin substrate) without affecting co-translational disulfide formation; ERp72 partially compensates for orphan ERp57 substrates. ERp57 knockout cell lines, pulse-chase folding assays, ER stress markers Journal of Biological Chemistry High 16407314
2007 ERp57 forms a stable disulfide-linked heterodimer with tapasin within the MHC class I peptide-loading complex; a novel trimeric complex of MHC class I heavy chain–ERp57–tapasin is formed via ERp57's interaction with the MHC class I peptide-binding groove, and ERp57 and PDI act in concert to regulate MHC class I redox status during antigen presentation. Co-immunoprecipitation, site-directed mutagenesis of cysteine residues, intracellular redox manipulation Journal of Biological Chemistry High 17459881
2006 ERp57 interacts with Ref-1/APE in vivo (co-immunoprecipitation confirmed in three cell types); ERp57 reduced by the thioredoxin-reductase/thioredoxin system stimulates AP-1 binding to its consensus DNA sequence, and ERp57 overexpression protects cells against hydrogen peroxide-induced killing, indicating cooperative activity with Ref-1 in reductive activation of transcription factors. Co-immunoprecipitation, EMSA, stable transfection/overexpression, cell viability assays Free Radical Biology & Medicine Medium 16962936
2004 ERp57 is found in STAT3-DNA complexes bound to the α2-macroglobulin gene enhancer; an anti-ERp57 antibody inhibits STAT3 binding to its consensus sequence on DNA, indicating ERp57 is a necessary component of the DNA-bound STAT3 complex. EMSA, DNA affinity experiments, chromatin immunoprecipitation Biochemical and Biophysical Research Communications Medium 15451439
2009 ERp57 depletion in M14 melanoma cells decreases STAT3 phosphorylation on tyrosine 705 and completely suppresses IL-6-induced CRP expression; ERp57 is required both at the site of STAT3 phosphorylation and at the nuclear level for STAT3-dependent gene regulation. siRNA knockdown, ChIP, Western blot, RT-PCR, in vitro DNA-binding assays Archives of Biochemistry and Biophysics Medium 19995546
2002 The DNA-binding activity of ERp57 resides in its C-terminal a' domain, and this binding is strongly dependent on the oxidized redox state of the protein. Recombinant domain expression, deletion mutagenesis, in vitro DNA-binding assays Biochemical and Biophysical Research Communications Medium 12083768
2007 ERp57 C-terminal a' domain DNA-binding activity depends on redox-dependent conformational change: oxidation drives formation of an intermolecular homodimer via disulfide bridges between active-site cysteines (not intramolecular), and mutation of C406 (first cysteine of –CGHC– motif) abolishes DNA binding. NADH-dependent thioredoxin reductase can reduce and thus inactivate the dimer. Site-directed mutagenesis, recombinant protein biochemistry, mass spectrometry, thioredoxin reductase assay Journal of Biological Chemistry High 17283067
2007 ERp57 binds specific DNA sequences in vivo in HeLa cells; chromatin-immunoprecipitated targets include non-coding regions of identified genes, two of which encode DNA repair proteins, suggesting ERp57 participates in transcriptional regulation of stress-response genes. Chromatin immunoprecipitation, cloning and sequencing of immunoprecipitated DNA Journal of Cellular Physiology Medium 17061245
2008 ERp57 co-translocates with calreticulin to the plasma membrane surface in anthracycline-induced immunogenic apoptosis; direct protein-protein interaction between CRT and ERp57 is strictly required for their co-translocation, as CRT point mutants failing to interact with ERp57 cannot restore ERp57 surface exposure. ERp57 knockdown abrogates CRT surface exposure and renders tumors resistant to anthracycline chemotherapy in vivo. Mass spectrometry, immunofluorescence, co-immunoprecipitation, CRT point mutants, shRNA knockdown, in vivo mouse tumor models Cell Death and Differentiation High 18464797
2009 PDIA3 is essential for H2AX phosphorylation (γ-H2AX) in response to cytarabine-induced DNA damage; PDIA3 knockdown abolishes γ-H2AX accumulation while leaving p53 phosphorylation intact, placing PDIA3 in a distinct branch of the DNA damage response. siRNA knockdown, Western blot, immunofluorescence microscopy Molecular Cancer Therapeutics Medium 19372559
2010 PDIA3 is located in caveolae (co-localizing with lipid rafts and caveolin-1) at the plasma membrane of osteoblasts and mediates 1,25(OH)2D3-induced rapid PLA2-dependent PGE2 release and PKC activation; silencing PDIA3 abolishes these responses while overexpression augments them. Confocal co-localization with caveolin-1, siRNA silencing, overexpression, PKC and PGE2 activity assays, gene expression analysis Journal of Biological Chemistry High 20843786
2010 Homozygous Pdia3 disruption causes early embryonic lethality; heterozygous Pdia3+/- mice show skeletal abnormalities; in osteoblast-like cells, Pdia3 silencing abolishes 1,25(OH)2D3-induced rapid PKC activation while overexpression augments it, confirming Pdia3 mediates membrane-initiated 1,25(OH)2D3 signaling in bone. Gene knockout mouse, µCT analysis, siRNA, overexpression, PKC activity assays Journal of Steroid Biochemistry and Molecular Biology High 20576531
2013 PDIA3 co-localizes and interacts with VDR and caveolin-1 at the plasma membrane of osteoblasts; both PDIA3 and VDR interact with caveolin-1 by immunoprecipitation; PDIA3 interacts with PLAA whereas VDR interacts with c-Src; silencing either receptor or caveolin-1 inhibits both PLA2 and c-Src activation, demonstrating interdependent function of the two receptors in rapid membrane responses to 1,25(OH)2D3. Co-immunoprecipitation, confocal co-localization, siRNA silencing, kinase activity assays Cellular Signalling High 23896121
2013 Chaperone functional domains of PDIA3 (K214/R282 calreticulin-interaction sites and C406 isomerase catalytic site) and myristoylation are required for 1,25(OH)2D3-induced PKC activation at the plasma membrane; PDIA3 lacking the KDEL ER-retention signal shows increased plasma membrane localization but the stimulatory effect on PKC requires intact chaperone domains. Site-directed mutagenesis, overexpression of mutant constructs, PKC activity assays, subcellular fractionation Molecular Endocrinology High 23660595
2011 ERp57 is expressed on the platelet surface and is required for platelet aggregation, hemostasis, and thrombosis; inhibitory anti-ERp57 antibody blocks ERp57 activity, inhibits αIIbβ3 activation and P-selectin expression, prolongs bleeding time, and inhibits FeCl3-induced thrombosis in mice. Catalytically inactive ERp57 inhibits platelet aggregation. Inhibitory antibody, recombinant ERp57 addition, tail bleeding assay, in vivo thrombosis model, flow cytometry Blood High 22207737
2014 ERp57 is required for fibrin deposition in vivo; platelet-specific (Pf4-Cre) and endothelial-specific (Tie2-Cre) conditional ERp57 knockout each reduce fibrin deposition; ERp57 isomerase activity of the second active site is required for both fibrin deposition and platelet accumulation; recombinant ERp57 corrects the fibrin deposition defect, indicating a direct effect on coagulation. Conditional knockout mice, laser-induced thrombosis intravital microscopy, inhibitory antibody, recombinant active-site mutant ERp57, in vitro thrombin generation assay Journal of Thrombosis and Haemostasis High 25156521
2015 ERp57 physically interacts with the prion protein (PrP) and controls its maturation and steady-state levels; ERp57 gain- and loss-of-function in cell culture alters PrP levels; conditional nervous system ERp57 knockout reduces mono- and non-glycosylated PrP forms in brain; ERp57 transgenic mice show increased endogenous PrP levels. Co-immunoprecipitation, gain/loss-of-function cell culture, conditional knockout mouse, Western blot Journal of Biological Chemistry High 26170458
2018 ERp57 oxidatively inactivates transglutaminase 2 (TG2) via the allosteric Cys370–Cys371 disulfide bond with a rate constant 400–2000-fold higher than small-molecule oxidants; ERp57 co-localizes with extracellular TG2 in endothelial cells; siRNA-mediated ERp57 knockdown increases TG2 transamidation activity extracellularly, establishing ERp57 as the physiological oxidative inactivator of TG2. In vitro enzymatic assay with rate constant measurement, siRNA knockdown, immunofluorescence co-localization, transamidation activity assay Journal of Biological Chemistry High 29305423
2019 PDIA3 directly interacts with influenza A virus hemagglutinin (HA) and is required for its efficient disulfide bond formation and oligomerization (maturation); lung epithelial-specific PDIA3 deletion reduces viral burden and lung inflammation in mice; PDI inhibitor LOC14 decreases intramolecular HA disulfide bonds and viral replication in H1N1 and H3N2 infection. Co-immunoprecipitation, conditional (epithelial-specific) PDIA3 knockout mouse, viral load quantification, PDI inhibitor treatment, Western blot for disulfide status Redox Biology High 30735910
2019 Vitamin D3 activates PDIA3 as a receptor at the cell surface of gastric epithelial cells, promoting nuclear translocation of a PDIA3-STAT3 protein complex and subsequent upregulation of MCOLN3 channels, leading to enhanced lysosomal Ca2+ release, restoration of lysosomal acidification, and autolysosomal clearance of Helicobacter pylori. PDIA3 CRISPR knockout and siRNA knockdown, neutralizing antibody, co-immunoprecipitation of PDIA3-STAT3, ChIP-PCR, Ca2+ imaging, CFU assays in vitro and in vivo Autophagy High 30612517
2022 Crystal structure (2.7 Å) of the tapasin–ERp57 heterodimer in complex with peptide-receptive MHC class I reveals atomic details of client recognition and the mechanistic basis for tapasin's selector function in peptide proofreading; ERp57 is disulfide-linked to tapasin via its redox active site and stabilizes the complex. X-ray crystallography at 2.7 Å, functional mutagenesis validation Nature Communications High 36104323
2007 ERp57-deficient MHC class I peptide-loading complexes (using tapasin C95A mutant unable to disulfide-link ERp57) are prone to ER aggregation, demonstrating that ERp57 is required for the stability of the core loading complex. Fluorescently-tagged tapasin mutant expression, FRET analysis, confocal microscopy, cell fractionation Traffic Medium 17822402
2016 The circadian gene Clock activates Pdia3 transcription by binding the E-box promoter element; forced expression of Pdia3 rescues osteogenic disorders and inhibits apoptosis in Clock mutant mice; siRNA ablation of PDIA3 blocks compensatory effects of Clock overexpression in osteoblasts. Luciferase reporter assay, ChIP, in vivo forced expression/knockout in ClockΔ19 mutant mice, siRNA knockdown Journal of Bone and Mineral Research Medium 27883226
2021 ERp57 is a host factor required for hepatitis B virus (HBV) membrane fusion and infection; computational modeling identified an allosteric cross-strand disulfide bond in the HBV S glycoprotein, and ERp57-mediated thiol/disulfide exchange triggers its isomerization, exposing the fusion peptide in preS1. Computational modeling, experimental infection assays, ERp57 functional perturbation eLife Medium 34190687
2024 In adipose tissue macrophages, ATF4 transcribes PDIA3, which imposes redox control on RhoA activity and strengthens pro-inflammatory and migratory properties of a maladaptive macrophage subpopulation (iMAMs) through RhoA-YAP signaling; siRNA-loaded liposomes targeting Pdia3 repress adipose inflammation and HFD-induced obesity. Single-nucleus RNA sequencing, ATF4 ChIP (inferred from transcription), PDIA3 siRNA liposome delivery in vivo, RhoA activity assays, YAP signaling readouts Cell Metabolism Medium 39293433
2015 PDIA3 knockdown and ENO1 knockdown in primary murine alveolar epithelial type II cells reduce ATI cell marker T1α expression, indicating PDIA3 is required downstream of Wnt/β-catenin signaling for ATII-to-ATI trans-differentiation. siRNA knockdown, proteomics (mass spectrometry), immunoblotting, pharmacological Wnt inhibition Disease Models & Mechanisms Medium 26035385
2015 ERp57 overexpression in transgenic mice enhances locomotor recovery, myelin removal, macrophage infiltration, and axonal regeneration after sciatic nerve injury, demonstrating a functional role for ERp57 in peripheral nerve regeneration. ERp57 transgenic mouse, sciatic nerve crush model, behavioral testing, histological analysis PLOS ONE Medium 26361352
2014 Wnt5a signals through a CaMKII/PLA2/PGE2/PKC cascade in osteoblasts that requires PDIA3, PLAA, and VDR; PDIA3 membrane complex components (Pdia3, PLAA, caveolin-1, CaM) physically interact with Wnt5a receptors/co-receptors (ROR2, FZD2, FZD5) as shown by co-immunoprecipitation, and these interactions change with ligand treatment. Co-immunoprecipitation, siRNA silencing, pharmacological inhibitors, PKC activity assays Biochimica et Biophysica Acta Medium 24946135
2018 Punicalagin (from pomegranate) binds purified PDIA3 with high affinity and acts as a non-competitive inhibitor of PDIA3 reductase activity in vitro; this inhibitory effect is reduced in PDIA3-silenced neuroblastoma cells, confirming PDIA3 as the relevant target. Fluorescence quenching, isothermal titration calorimetry, in vitro reductase assay, PDIA3 siRNA knockdown, cell viability assay Biochimie Medium 29425676
2019 ERp57 upregulation in clear cell renal carcinoma cells binds STAT3 protein and enhances STAT3-mediated transcriptional activity of ILF3; ILF3 in turn binds ERp57 mRNA to enhance its stability, creating a positive feedback loop (ERp57/STAT3/ILF3) that promotes ccRCC proliferation. Co-immunoprecipitation, proximity ligation assay, ChIP, RIP, oligo pull-down, promoter luciferase assay, in vivo xenograft Journal of Experimental & Clinical Cancer Research Medium 31747963
2020 PDIA3 knockdown in trophoblasts inhibits MDM2 expression and consequently elevates p53 and p21, promoting apoptosis and inhibiting proliferation; overexpression of PDIA3 reverses these effects, placing PDIA3 upstream of the MDM2/p53/p21 pathway in trophoblast biology. siRNA knockdown, PDIA3 overexpression, RNA sequencing, Western blot, flow cytometry, EdU proliferation assay Reproduction Medium 32585639
2021 PDIA3 inhibition in club cells of the lung attenuates osteopontin (SPP1) production and bleomycin-induced lung fibrosis; SPP1 is identified as a major PDIA3 interactor in fibrosis by proteomics; club cell-specific Pdia3 ablation decreases parenchymal club cells and fibrosis in mice. Club cell-specific PDIA3 knockout, PDI inhibitor LOC14, proteomics/interactome analysis, bleomycin mouse fibrosis model, SPP1 blocking Thorax Medium 34400514

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. The Journal of experimental medicine 423 7650491
2008 The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell death and differentiation 293 18464797
1997 A single amino acid in the p58 killer cell inhibitory receptor controls the ability of natural killer cells to discriminate between the two groups of HLA-C allotypes. Journal of immunology (Baltimore, Md. : 1950) 175 9126959
1997 The direct binding of a p58 killer cell inhibitory receptor to human histocompatibility leukocyte antigen (HLA)-Cw4 exhibits peptide selectivity. The Journal of experimental medicine 165 9126935
1998 The thiol oxidoreductase ERp57 is a component of the MHC class I peptide-loading complex. Current biology : CB 153 9637923
1998 Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors. Proceedings of the National Academy of Sciences of the United States of America 147 9826699
2003 Calnexin, calreticulin, and ERp57: teammates in glycoprotein folding. Cell biochemistry and biophysics 142 14716078
2013 p58(IPK)-mediated attenuation of the proapoptotic PERK-CHOP pathway allows malignant progression upon low glucose. Molecular cell 126 23395000
2005 Cellular functions of endoplasmic reticulum chaperones calreticulin, calnexin, and ERp57. International review of cytology 123 16125546
2008 Regulated association of misfolded endoplasmic reticulum lumenal proteins with P58/DNAJc3. The EMBO journal 121 18923430
2012 Diosgenin is an exogenous activator of 1,25D₃-MARRS/Pdia3/ERp57 and improves Alzheimer's disease pathologies in 5XFAD mice. Scientific reports 119 22837815
2019 Vitamin D3 activates the autolysosomal degradation function against Helicobacter pylori through the PDIA3 receptor in gastric epithelial cells. Autophagy 117 30612517
2007 An iron-sulfur cluster in the C-terminal domain of the p58 subunit of human DNA primase. The Journal of biological chemistry 106 17893144
1997 The thiol-dependent reductase ERp57 interacts specifically with N-glycosylated integral membrane proteins. The Journal of biological chemistry 104 9153243
2011 ERp57/GRP58: a protein with multiple functions. Cellular & molecular biology letters 101 21837552
2007 The ERp57/GRp58/1,25D3-MARRS receptor: multiple functional roles in diverse cell systems. Current medicinal chemistry 96 17456022
2006 Consequences of ERp57 deletion on oxidative folding of obligate and facultative clients of the calnexin cycle. The Journal of biological chemistry 93 16407314
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 92 17215875
2011 The disulfide isomerase ERp57 mediates platelet aggregation, hemostasis, and thrombosis. Blood 86 22207737
2010 Protein-disulfide isomerase-associated 3 (Pdia3) mediates the membrane response to 1,25-dihydroxyvitamin D3 in osteoblasts. The Journal of biological chemistry 84 20843786
1999 The unstable F-box protein p58-Ctf13 forms the structural core of the CBF3 kinetochore complex. The Journal of cell biology 84 10352012
2002 The p58 subunit of human DNA primase is important for primer initiation, elongation, and counting. Biochemistry 79 11939784
2013 Plasma membrane Pdia3 and VDR interact to elicit rapid responses to 1α,25(OH)(2)D(3). Cellular signalling 77 23896121
2004 Failure to proliferate and mitotic arrest of CDK11(p110/p58)-null mutant mice at the blastocyst stage of embryonic cell development. Molecular and cellular biology 75 15060143
2002 Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3. The Journal of biological chemistry 72 12082095
2017 Multifunctional molecule ERp57: From cancer to neurodegenerative diseases. Pharmacology & therapeutics 71 28723413
2012 The role of the vitamin D receptor and ERp57 in photoprotection by 1α,25-dihydroxyvitamin D3. Molecular endocrinology (Baltimore, Md.) 71 22322599
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
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
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
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 54 26035385
2022 ERp57/PDIA3: new insight. Cellular & molecular biology letters 53 35109791
2019 Lung epithelial protein disulfide isomerase A3 (PDIA3) plays an important role in influenza infection, inflammation, and airway mechanics. Redox biology 52 30735910
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 50 19411306
2001 TCR gamma delta cytotoxic T lymphocytes expressing the killer cell-inhibitory receptor p58.2 (CD158b) selectively lyse acute myeloid leukemia cells. Bone marrow transplantation 49 11438826
2021 PDIA3: Structure, functions and its potential role in viral infections. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 48 34474345
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
2009 Role of ERp57 in the signaling and transcriptional activity of STAT3 in a melanoma cell line. Archives of biochemistry and biophysics 43 19995546
2006 Interaction of ERp57 and tapasin in the generation of MHC class I-peptide complexes. Current opinion in immunology 43 17150345
1999 Interactions of DNA with human DNA primase monitored with photoactivatable cross-linking agents: implications for the role of the p58 subunit. Biochemistry 43 10504261
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
2004 Identification and characterization of structural domains of human ERp57: association with calreticulin requires several domains. The Journal of biological chemistry 42 14732712
1997 Molecular basis of HLA-C recognition by p58 natural killer cell inhibitory receptors. Journal of immunology (Baltimore, Md. : 1950) 42 9378975
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
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
2019 PDIA3-regulted inflammation and oxidative stress contribute to the traumatic brain injury (TBI) in mice. Biochemical and biophysical research communications 35 31466719
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
1991 Immunogenicity and sequence analysis of recombinant p58: a neutralization-sensitive, antigenically conserved Babesia bigemina merozoite surface protein. Molecular and biochemical parasitology 34 1944417
2020 A Gallium(III) Complex that Engages Protein Disulfide Isomerase A3 (PDIA3) as an Anticancer Target. Angewandte Chemie (International ed. in English) 33 33448534
2016 LEDGF/p75 Overexpression Attenuates Oxidative Stress-Induced Necrosis and Upregulates the Oxidoreductase ERP57/PDIA3/GRP58 in Prostate Cancer. PloS one 33 26771192
2016 p58(IPK) suppresses NLRP3 inflammasome activation and IL-1β production via inhibition of PKR in macrophages. Scientific reports 33 27113095
2014 The disulfide isomerase ERp57 is required for fibrin deposition in vivo. Journal of thrombosis and haemostasis : JTH 33 25156521
2018 Endoplasmic reticulum-resident protein 57 (ERp57) oxidatively inactivates human transglutaminase 2. The Journal of biological chemistry 32 29305423
2011 Dengue virus infection induces upregulation of hn RNP-H and PDIA3 for its multiplication in the host cell. Virus research 31 22207023
2011 CDK11(p58) is required for centriole duplication and Plk4 recruitment to mitotic centrosomes. PloS one 30 21297952
2003 Effect of doxycycline-regulated ERp57 expression on specific thrombopoietin productivity of recombinant CHO cells. Biotechnology progress 30 12573023
2022 Structure of an MHC I-tapasin-ERp57 editing complex defines chaperone promiscuity. Nature communications 29 36104323
2011 P58-A and P58-B: novel proteins that mediate skeletogenesis in the sea urchin embryo. Developmental biology 29 21362416
2010 ER-60 (PDIA3) is highly expressed in a newly established serous ovarian cancer cell line, YDOV-139. International journal of oncology 29 20596667
2015 PDIA3 Knockdown Exacerbates Free Fatty Acid-Induced Hepatocyte Steatosis and Apoptosis. PloS one 28 26214517
2014 Signaling components of the 1α,25(OH)2D3-dependent Pdia3 receptor complex are required for Wnt5a calcium-dependent signaling. Biochimica et biophysica acta 28 24946135
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
2003 Functional supertype of HLA-A2 in the presentation of Flu matrix p58-66 to induce CD8+ T-cell response in a Northern Chinese population. Tissue antigens 27 12974795
2002 The DNA-binding activity of protein disulfide isomerase ERp57 is associated with the a(') domain. Biochemical and biophysical research communications 27 12083768
1999 Subcellular distribution of the Xenopus p58/lamin B receptor in oocytes and eggs. Journal of cell science 27 10393814
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
2009 Inhibition of G(1) to S phase progression by a novel zinc finger protein P58(TFL) at P-bodies. Molecular cancer research : MCR 26 19531561
2000 The p58-positive pre-golgi intermediates consist of distinct subpopulations of particles that show differential binding of COPI and COPII coats and contain vacuolar H(+)-ATPase. Journal of cell science 26 11017878
2020 PDIA3 regulates trophoblast apoptosis and proliferation in preeclampsia via the MDM2/p53 pathway. Reproduction (Cambridge, England) 25 32585639
2018 Punicalagin, an active pomegranate component, is a new inhibitor of PDIA3 reductase activity. Biochimie 25 29425676
2015 MicroRNA-148a inhibits the proliferation and promotes the paclitaxel-induced apoptosis of ovarian cancer cells by targeting PDIA3. Molecular medicine reports 25 26004124
2021 Insights into the role of ERp57 in cancer. Journal of Cancer 24 33758622
2013 AGR2, ERp57/GRP58, and some other human protein disulfide isomerases. Biochemistry. Biokhimiia 24 24490732
2007 Aggregate formation by ERp57-deficient MHC class I peptide-loading complexes. Traffic (Copenhagen, Denmark) 24 17822402
2014 Impaired bone formation in Pdia3 deficient mice. PloS one 23 25405762
1999 Mapping of structural determinants for the oligomerization of p58, a lectin-like protein of the intermediate compartment and cis-Golgi. European journal of biochemistry 23 10095773
2021 Identification of dihydrotanshinone I as an ERp57 inhibitor with anti-breast cancer properties via the UPR pathway. Biochemical pharmacology 22 34062127
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
2011 Polypyrimidine tract-binding protein regulates the cell cycle through IRES-dependent translation of CDK11(p58) in mouse embryonic stem cells. Cell cycle (Georgetown, Tex.) 22 22037210
2019 Influence of Ellagitannins Extracted by Pomegranate Fruit on Disulfide Isomerase PDIA3 Activity. Nutrients 21 30658391
2012 Protective role for the disulfide isomerase PDIA3 in methamphetamine neurotoxicity. PloS one 21 22715419
2021 Cancer Biology of the Endoplasmic Reticulum Lectin Chaperones Calreticulin, Calnexin and PDIA3/ERp57. Progress in molecular and subcellular biology 20 34050867
2021 A fusion peptide in preS1 and the human protein disulfide isomerase ERp57 are involved in hepatitis B virus membrane fusion process. eLife 20 34190687
2024 PDIA3 defines a novel subset of adipose macrophages to exacerbate the development of obesity and metabolic disorders. Cell metabolism 19 39293433
2013 Chaperone properties of pdia3 participate in rapid membrane actions of 1α,25-dihydroxyvitamin d3. Molecular endocrinology (Baltimore, Md.) 19 23660595
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
2005 Cyclin-dependent kinase 11(p58) interacts with HBO1 and enhances its histone acetyltransferase activity. FEBS letters 19 15963510
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