Affinage

ERP44

Endoplasmic reticulum resident protein 44 · UniProt Q9BS26

Length
406 aa
Mass
47.0 kDa
Annotated
2026-06-09
46 papers in source corpus 26 papers cited in narrative 27 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

ERp44 is a thioredoxin-family chaperone that enforces thiol-mediated quality control in the early secretory pathway, retaining or retrieving incompletely assembled or oxidatively immature clients before they can be secreted (PMID:11847130, PMID:14517240). Through its CRFS active-site Cys29 it forms reversible mixed disulfides with clients that lack canonical ER retention signals—including the oxidases Ero1α/Ero1β, peroxiredoxin 4, the formylglycine-generating enzyme SUMF1/FGE, and TMX5—and recycles them to the ER via its C-terminal RDEL motif (PMID:11847130, PMID:18178549, PMID:27642162, PMID:39348940), while also clamping unpaired cysteines on maturing cargo such as immature IgM, the serotonin transporter SERT, and the ryanodine receptor RyR2 (PMID:22451649, PMID:34957576, PMID:35086342). Structurally, ERp44 comprises three thioredoxin-like domains (a, b, b') with a flexible C-terminal tail that folds back to shield the CRFS site and an adjacent hydrophobic pocket, gating substrate access (PMID:18552768). This tail is conformationally regulated by the acidic, Zn2+-rich downstream Golgi milieu: protonation of a histidine cluster and high-affinity Zn2+ binding displace the tail to simultaneously expose the client-binding surface and the RDEL motif, coupling client capture to retrieval (PMID:25097228, PMID:28373561, PMID:30723194). ERp44 cycling depends on the cargo receptor ERGIC-53 for COPII loading and ER exit and on KDEL receptors for retrieval, with Golgi ZnT transporters tuning its activity through subregional Zn2+ fluxes (PMID:33763635, PMID:37160917). ERp44 senses the ER lumenal redox/Ca2+/pH state to control IP3R and RyR2 channel activity and intracellular Ca2+ release (PMID:15652484, PMID:35086342), and its loss causes embryonic lethality with cardiac developmental and Ca2+ homeostasis defects (PMID:25332179). ERp44 additionally governs secretion of clients including adiponectin, VEGFA, and procollagen, linking it to metabolic, cardiac, and skeletal development (PMID:20484463, PMID:35088919, PMID:42100748). Its stability and client-binding capacity are modulated by SUMOylation at Lys76 (PMID:36427672).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2002 High

    Establishing that a thioredoxin-family ER protein physically couples to the oxidase machinery and folding intermediates defined ERp44 as a participant in oxidative protein folding rather than a passive resident.

    Evidence Co-IP and mixed-disulfide trapping showing ERp44 forms disulfides with Ero1-Lα/β and Ig chains via its CRFS motif

    PMID:11847130

    Open questions at the time
    • Did not define the retrieval signal or trafficking route
    • Structural basis of CRFS-mediated client selection unknown
  2. 2003 High

    Showing that ERp44 retains Ero1α—which lacks an ER retention motif—and blocks secretion of cargo with unpaired cysteines established thiol-mediated ER retention as ERp44's core function.

    Evidence Mixed-disulfide trapping and secretion assays with ERp44 overexpression/knockdown

    PMID:14517240

    Open questions at the time
    • Mechanism of retrieval signal exposure not resolved
    • How ERp44 distinguishes mature from immature clients unclear
  3. 2005 High

    Demonstrating direct binding to the IP3R1 lumenal loop with inhibition of channel activity revealed ERp44 as a redox/pH/Ca2+ sensor that links ER lumenal state to Ca2+ release.

    Evidence Co-IP, Ca2+ imaging, single-channel lipid bilayer recording, and mutagenesis of lumenal cysteines

    PMID:15652484

    Open questions at the time
    • Physiological setting of IP3R1 regulation not defined in vivo
    • Relationship between channel binding and oxidase binding modes unclear
  4. 2006 High

    Defining covalent, RDEL-dependent retention of Ero1 and competition with PDI clarified the division of labor in oxidase localization and prevention of aggregation.

    Evidence Secretion assays, Co-IP, and KDEL/RDEL deletion mutants

    PMID:16677073

    Open questions at the time
    • Stoichiometry of the PDI/ERp44/Ero1 competition not quantified
    • Conditions favoring covalent vs non-covalent binding unresolved
  5. 2008 High

    Crystallizing ERp44 and mapping the autoinhibitory C-terminal tail over the CRFS site and hydrophobic pocket provided the structural logic for gated, regulated client capture.

    Evidence X-ray crystallography at 2.6 Å with mutagenesis and functional retention assays

    PMID:18552768

    Open questions at the time
    • The trigger releasing the tail was not yet identified
    • No client-bound structure available at this stage
  6. 2008 High

    Identifying SUMF1/FGE as a client retrieved by ERp44, with non-covalent interactions sufficient for retention, broadened the client repertoire and showed disulfide bonding is not strictly required for ER retrieval.

    Evidence Reciprocal Co-IP, cysteine mutagenesis, knockdown, and sulfatase activity/secretion assays

    PMID:18178549 PMID:18508857

    Open questions at the time
    • How ERp44 and ERGIC-53 partition the same client temporally not fully resolved
    • Contribution of covalent vs non-covalent binding to retention efficiency unquantified
  7. 2012 High

    Extending ERp44 to a plasma-membrane transporter (SERT) via specific external-loop cysteines showed it controls disulfide maturation and surface trafficking of multipass membrane clients.

    Evidence Co-IP, shRNA knockdown, MTSEA-biotin surface labeling, mutagenesis, and 5-HT uptake assays

    PMID:22451649

    Open questions at the time
    • Signal that normally releases SERT from ERp44 not yet defined here
    • Physiological consequence of altered surface SERT incompletely characterized
  8. 2014 High

    Resolving that pH-driven conformational change of the C-terminal histidine-containing tail couples client capture to RDEL exposure explained how ERp44 acts only in the appropriate compartment.

    Evidence Mutagenesis of conserved histidines, O-glycosylation and co-expression secretion assays in vivo

    PMID:25097228

    Open questions at the time
    • Whether pH alone fully accounts for tail displacement was unresolved
    • Quantitative pH thresholds for switching not defined
  9. 2014 Medium

    Genetic deletion in mice and zebrafish established ERp44 as essential for cardiac development and Ca2+ homeostasis, moving it from a biochemical regulator to a developmentally required gene.

    Evidence ERp44 KO/morphant models with Ca2+ and ROS imaging and ER stress markers

    PMID:25332179

    Open questions at the time
    • Which client(s) mediate the cardiac phenotype not pinpointed
    • Embryonic lethality complicates dissection of tissue-specific roles
  10. 2014 Medium

    Linking insulin signaling to SERT-ERp44 dissociation, and its failure in gestational diabetes, connected ERp44 client release to physiological signaling and disease.

    Evidence Co-IP, insulin receptor blockade, mutagenesis, and 5-HT uptake assays

    PMID:25512553

    Open questions at the time
    • Molecular mechanism by which insulin signaling triggers dissociation unknown
    • Single-lab finding without independent confirmation
  11. 2016 High

    A client-bound crystal structure (ERp44-Prx4) plus glutathione/PDI-mediated reduction defined the thiol-disulfide interchange interface and the recycling step that regenerates free ERp44.

    Evidence X-ray crystallography of the complex, mutagenesis, and in vitro disulfide exchange assays

    PMID:27642162

    Open questions at the time
    • Generality of the interface across diverse clients not established
    • In vivo reductant responsible for recycling not pinned down
  12. 2016 Medium

    Isoform-selective IP3R2 regulation governing cancer cell migration extended ERp44's Ca2+ control function to a disease-relevant cellular behavior.

    Evidence ERp44 overexpression, IP3R-isoform-specific siRNA, Ca2+ imaging, and wound-healing assays

    PMID:27347718

    Open questions at the time
    • Direct binding to IP3R2 vs indirect effect not distinguished
    • Single cell-line context limits generality
  13. 2017 High

    High-resolution structures at two pH values identified His157 and a C-terminal His cluster as the protonation switch driving domain rearrangement and client-site exposure, giving atomic detail to pH gating.

    Evidence X-ray crystallography at neutral and acidic pH, MD simulations, and mixed-disulfide mutagenesis

    PMID:28373561

    Open questions at the time
    • pH and metal contributions not yet integrated
    • Dynamics in the native Golgi lumen inferred from crystals
  14. 2019 High

    Demonstrating high-affinity Zn2+ binding to the histidine cluster that displaces the tail and the existence of Zn2+-bridged homodimers established Zn2+ as a second physiological switch coordinating ERp44 activity with the Golgi metal environment.

    Evidence Crystallography of Zn2+-bound ERp44, Zn2+ binding assays, ZnT knockdown, secretion assays, and mutagenesis

    PMID:30723194

    Open questions at the time
    • Interplay between pH and Zn2+ switches not fully deconvolved
    • Function of the homodimer beyond client sequestration unclear
  15. 2021 High

    Showing ERp44 binds ERGIC-53 for COPII loading and ER exit, then is released downstream to engage KDEL receptors, completed the trafficking itinerary that lets ERp44 keep pace with its clients.

    Evidence Co-IP, ERGIC-53 knockdown, 4-PBA competition, secretion assays, and cargo-appending experiments

    PMID:33763635

    Open questions at the time
    • Quantitative kinetics of the handoff between receptors not measured
    • Selectivity of ERGIC-53 for ERp44 vs other cargo not fully defined
  16. 2021 High

    Defining ERp44's attack on non-native C575 disulfides in the IgM µs tailpiece showed it actively remodels client disulfides to drive correct polymerization, not merely retains clients.

    Evidence Disulfide trapping, mutagenesis of specific cysteines, Co-IP, and non-reducing SDS-PAGE

    PMID:34957576

    Open questions at the time
    • Generality of disulfide-isomerase-like activity to other clients untested
    • Order of polymerization steps not fully temporally resolved
  17. 2022 High

    Identifying redox-gated ERp44-RyR2 association via Cys4806, dissociated by Ero1α-driven SR oxidation, extended ERp44's Ca2+ channel control to RyR2 with arrhythmia relevance.

    Evidence Mutagenesis, MD simulations, Co-IP, Ca2+ imaging, and Ero1α inhibition

    PMID:35086342

    Open questions at the time
    • In vivo contribution to cardiac rhythm not fully established
    • How ERp44 reaches the SR lumen mechanistically unspecified
  18. 2022 Medium

    Mapping SUMOylation at Lys76 by Ubc9 that stabilizes ERp44 and promotes Ero1α binding revealed a post-translational layer linking ERp44 activity to metabolic ER stress control.

    Evidence LC-MS, Ubc9 conditional KO mice, Co-IP, and site-specific mutagenesis

    PMID:36427672

    Open questions at the time
    • Enzymes removing the SUMO mark not identified
    • Single-lab finding requiring independent validation
  19. 2022 Medium

    Showing direct VEGFA binding and cardiac-specific knockout phenotypes connected ERp44 client release to endocardial cushion formation through EndMT.

    Evidence Conditional KO mice, binding assays, immunofluorescence, transcriptomics, and EndMT assays

    PMID:35088919

    Open questions at the time
    • Whether VEGFA binding is disulfide-mediated not defined
    • Direct vs indirect control of VEGFA release not fully separated
  20. 2022 Medium

    Identifying ERp44 as the active-site target of disulfide-bond-disrupting agents that modulate DR4/5 receptor oligomerization opened a pharmacological route to perturbing ERp44 client disulfides.

    Evidence Affinity purification with biotinylated DDAs, shRNA knockdown, active-site mutant expression, and DR5 oligomerization assays

    PMID:35247515

    Open questions at the time
    • Direct vs indirect effect on DR4/5 disulfides not fully resolved
    • Specificity of DDAs for ERp44 over other Trx proteins incomplete
  21. 2023 High

    Mapping ZnT4, ZnT5/6, and ZnT7 to distinct Golgi subregions that set local Zn2+ refined the model in which subregional metal gradients spatially tune ERp44 localization and retrieval activity.

    Evidence Super-resolution Zn2+ imaging, systematic ZnT knockdowns, and time-course trafficking assays

    PMID:37160917

    Open questions at the time
    • Direct measurement of ERp44 conformational state in each subregion lacking
    • How Zn2+ gradients are maintained dynamically not detailed
  22. 2024 Medium

    Adding TMX5 to the covalent/non-covalent client repertoire via Cys29-Cys114/124 mixed disulfides reinforced the unified mode of pre-Golgi client localization control.

    Evidence Co-IP, disulfide trapping, mutagenesis, and localization assays

    PMID:39348940

    Open questions at the time
    • Functional consequence of TMX5 retention not characterized
    • Single-lab characterization
  23. 2024 Medium

    Defining ERp44 as a primary mediator of selective ER retention of glycoproteins under ER stress, opposed by PDIA6, framed ERp44 within a stress-responsive trafficking checkpoint.

    Evidence Pulse-chase, ERp44/PDIA6 KO cells, Co-IP, and complex-size analysis

    PMID:39621446

    Open questions at the time
    • Molecular basis of opposing ERp44/PDIA6 effects unresolved
    • Identity of retained tyrosine kinase receptor clients not fully enumerated
  24. 2026 Medium

    Genetic loss of ERp44 causing impaired collagen secretion and skeletal malformations across mouse, zebrafish, and cell models extended its quality-control role to procollagen and bone development.

    Evidence ERp44 KO mice, zebrafish morphants, cellular knockdown, immunofluorescence, and collagen deposition assays

    PMID:42100748

    Open questions at the time
    • Direct ERp44-procollagen interaction not biochemically defined
    • Mechanism distinguishing collagen retention from other clients unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ERp44's pH and Zn2+ switches, SUMOylation, and partner receptors are integrated to select among its broad client set in different tissues and disease states remains unresolved.
  • No unified model of client selectivity across the diverse repertoire
  • Tissue-specific client priorities not mapped
  • Whether a defined human Mendelian disease arises from ERp44 mutation not established in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 3
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9609507 Protein localization 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ERO1AERO1BITPR1LMAN1PDIA6PRDX4SUMF1TMX5

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ERp44 is an ER-resident protein of the thioredoxin family containing a CRFS motif that forms mixed disulfides with both Ero1-Lα/Ero1-Lβ (hEROs) and cargo folding intermediates. It binds stably with J chains retained in the ER and transiently with transport-competent Ig-κ chains. Overexpression of ERp44 alters the equilibrium of Ero1-Lα redox isoforms, implicating it in oxidative protein folding control. Co-immunoprecipitation, mixed disulfide trapping, redox isoform analysis by SDS-PAGE The EMBO journal High 11847130
2003 ERp44 mediates ER localization of Ero1α through formation of reversible mixed disulfides, retaining Ero1α (which lacks canonical ER retention motifs) in the ER. ERp44 also prevents secretion of unassembled cargo proteins with unpaired cysteines, establishing it as a key element in thiol-mediated ER retention. Mixed disulfide trapping, secretion assays, ERp44 overexpression/knockdown The EMBO journal High 14517240
2005 ERp44 directly interacts with the third lumenal loop of IP3R type 1 (IP3R1) and inhibits IP3R1 channel activity. The interaction is dependent on pH, Ca2+ concentration, and redox state; free cysteine residues in the lumenal loop are required. ERp44 thereby senses the ER lumenal environment and modulates IP3R1-mediated Ca2+ release. Co-immunoprecipitation, Ca2+ imaging, planar lipid bilayer single-channel recording, mutational analysis Cell High 15652484
2006 ERp44 dynamically retains Ero1α and Ero1β in the ER through covalent (disulfide) interactions in a KDEL/RDEL-dependent manner. PDI and ERp44 compete for Ero1 binding; covalent interactions between ERp44 and Ero1 are essential for retention, whereas PDI also prevents Ero1 aggregation/dimerization. Overexpression secretion assays, co-immunoprecipitation, KDEL/RDEL deletion mutants Antioxidants & redox signaling High 16677073
2008 Crystal structure of human ERp44 at 2.6 Å resolution reveals three thioredoxin domains (a, b, b') in a clover-like arrangement. A flexible C-terminal tail turns back over domains b' and a, shielding a hydrophobic pocket and the CRFS active site. Mutational and functional studies show the C-terminal tail dynamically gates the CRFS area and adjacent hydrophobic pocket to regulate protein quality control. X-ray crystallography (2.6 Å), site-directed mutagenesis, functional retention assays EMBO reports High 18552768
2008 ERp44 interacts with the formylglycine-generating enzyme (FGE/SUMF1) forming heterodimeric and higher-order complexes stabilized through disulfide bonds between ERp44 Cys29 and FGE Cys50/Cys52. ERp44 mediates FGE retrieval to the ER via its C-terminal RDEL signal. Notably, mutating critical cysteines does not abrogate ERp44-FGE complex formation, indicating non-covalent interactions are sufficient for ER retention. Co-immunoprecipitation, site-directed mutagenesis, ERp44 overexpression/knockdown, secretion assays The Journal of biological chemistry High 18178549
2008 ERp44 interacts with SUMF1 (formylglycine-generating enzyme) to retrieve it to the ER, while ERGIC-53 favors SUMF1 export. PDI couples SUMF1 retention and activation in the ER. Silencing ERp44 promotes SUMF1 secretion; silencing ERGIC-53 causes proteasomal SUMF1 degradation. This reveals a multistep sequential control of SUMF1 trafficking. Co-immunoprecipitation, siRNA knockdown, secretion assays, functional sulfatase activity assays Human molecular genetics High 18508857
2012 ERp44 binds to Cys200 and Cys209 on the second external loop of the serotonin transporter (SERT) through its thioredoxin-like domain (Cys29 required). ERp44 together with Ero1-Lα regulates disulfide bond formation in SERT, and ERp44 retention prevents premature plasma membrane trafficking. Knockdown of ERp44 increases SERT surface localization but decreases 5-HT uptake efficiency. Co-immunoprecipitation, shRNA knockdown, MTSEA-biotin labeling, site-directed mutagenesis The Journal of biological chemistry High 22451649
2014 ERp44 interacts with SERT at Cys200/Cys209 to build a disulfide bond during maturation. Insulin signaling facilitates dissociation of SERT from ERp44 for trafficking to the plasma membrane. In gestational diabetes mellitus, defective insulin signaling traps SERT with ERp44, impairing SERT glycosylation at Asn208 (between Cys200 and Cys209) and reducing 5-HT uptake. Co-immunoprecipitation, insulin receptor blockade, mutational analysis, 5-HT uptake assays Proceedings of the National Academy of Sciences of the United States of America Medium 25512553
2014 Deletion of ERp44 in mice causes embryonic lethality, abnormal heart development, altered Ca2+ dynamics, ROS generation, ER stress activation, and apoptosis. ERp44+/- mice under pressure overload show enhanced ER stress and cardiac dysfunction. ERp44-/- ESC-derived cardiomyocytes recapitulate Ca2+ signaling and ER stress defects, demonstrating ERp44 is required for cardiac development and Ca2+ homeostasis. ERp44 knockout/morphant mouse and zebrafish models, confocal Ca2+ imaging, ROS imaging, ER stress marker analysis Journal of the American Heart Association Medium 25332179
2014 ERp44 cycles between ER and Golgi in a pH-regulated manner. In the acidic Golgi milieu, its C-terminal tail changes conformation, simultaneously exposing the substrate-binding site and RDEL motif for client capture and ER retrieval. Conserved histidine residues in the C-terminal tail regulate ERp44 activity in vivo; histidine mutants retain substrates more efficiently but are O-glycosylated and partially secreted. Client binding prevents secretion of histidine mutants by forcing RDEL exposure. Mutagenesis, O-glycosylation assays, co-expression secretion assays, in vivo functional studies Journal of cell science High 25097228
2016 Crystal structure of ERp44 bound to its client peroxiredoxin 4 (Prx4) reveals that ERp44 binds oxidized Prx4 via thiol-disulfide interchange. The structure defines essential non-covalent interactions at the interface. The ERp44-Prx4 covalent complex can be reduced by glutathione and PDI family members, allowing recycling of both components. X-ray crystallography (structure of ERp44-Prx4 complex), mutagenesis, in vitro disulfide exchange assays Structure (London, England : 1993) High 27642162
2016 ERp44 inhibits lung cancer cell migration via regulation of IP3R2-dependent intracellular Ca2+ release. Overexpression of ERp44 reduces Ca2+ release via IP3Rs, alters cell morphology, and inhibits A549 cell migration primarily through IP3R2 (not IP3R1 or IP3R3), as demonstrated by selective siRNA knockdown. ERp44 overexpression, IP3R-specific siRNA knockdown, Ca2+ imaging, wound healing migration assay Aging Medium 27347718
2017 High-resolution crystal structures of ERp44 at neutral and weakly acidic pH reveal that pH-dependent conformational changes are driven by protonation of His157 at the a-b domain interface and a histidine-rich regulatory region (His cluster) in the C-terminal tail. At low pH, the three Trx-like domains rearrange, the α16-helix partially unwinds, and positively charged regions around the client-binding site are enlarged. Mutational analyses show ERp44 forms mixed disulfides with specific negatively charged cysteines on Ero1α. X-ray crystallography at multiple pH values, molecular dynamics simulations, site-directed mutagenesis, mixed disulfide trapping Proceedings of the National Academy of Sciences of the United States of America High 28373561
2019 Zinc ions (Zn2+) bind with high affinity to a conserved histidine cluster in ERp44, causing large displacements of the regulatory C-terminal tail that expose the substrate-binding surface and RDEL motif, thereby enabling client capture and ER retrieval. ERp44 also forms Zn2+-bridged homodimers that dissociate upon client binding. Silencing Golgi Zn2+ transporters causes ERp44 dysfunction and increased secretion of Ero1α and ERAP1. Histidine mutations at Zn2+-binding sites compromise ERp44 activity and localization. High-resolution X-ray crystallography of Zn2+-bound ERp44, Zn2+ binding assays, ZnT transporter knockdown, secretion assays, mutagenesis Nature communications High 30723194
2010 PPARγ transcriptionally represses ERp44 by binding to a peroxisome proliferator response element at positions -981 to -1004 in the ERp44 5'-flanking region, thereby reducing ERp44-mediated retention of adiponectin and increasing adiponectin secretion. Chromatin immunoprecipitation, luciferase reporter assay, PPARγ overexpression, rosiglitazone treatment Endocrinology Medium 20484463
2021 ERp44 binds the cargo receptor ERGIC-53 in the ER to negotiate preferential loading into COPII vesicles, enabling ERp44 to exit the ER as rapidly as its clients. In more acidic, Zn2+-rich downstream compartments, ERGIC-53 releases ERp44, which then captures non-native conformers via KDEL receptors. Silencing ERGIC-53 or competing for COPII binding causes secretion of the ERp44 client Prx4. Co-immunoprecipitation, ERGIC-53 siRNA knockdown, 4-phenylbutyrate competition, secretion assays, cargo appending experiments iScience High 33763635
2021 During biogenesis of secretory IgM, ERp44 attacks non-native intra-subunit disulfide bonds at C575 in the µs tailpiece, rearranging C-terminal tails into native quaternary structure and promoting IgM polymerization and formation of C414 disulfide linkages. Disulfide bond trapping, mutational analysis, co-immunoprecipitation, SDS-PAGE under non-reducing conditions The EMBO journal High 34957576
2022 ERp44 forms a redox-sensitive association with the ryanodine receptor RyR2 mediated by RyR2 intraluminal Cys4806. Ero1α-mediated increase in SR oxidation dissociates ERp44 from RyR2, increasing RyR2 Ca2+ channel activity. Site-directed mutagenesis and molecular dynamics simulations confirmed the Cys4806-dependent ERp44-RyR2 interaction. Ero1α inhibition restores ERp44-RyR2 association and reduces spontaneous Ca2+ release and arrhythmias. Site-directed mutagenesis, molecular dynamics simulations, co-immunoprecipitation, Ca2+ imaging, pharmacological and genetic Ero1α inhibition Circulation research High 35086342
2022 SUMOylation of ERp44 at lysine 76 (within the thioredoxin-like domain) by Ubc9 stabilizes ERp44 and promotes its covalent binding to Ero1α, enhancing Ero1α ER retention. Adipocyte-specific Ubc9 deficiency reduces ERp44 SUMOylation, enhances ERp44 degradation, suppresses covalent ERp44-Ero1α binding, and promotes Ero1α secretion, alleviating ER stress. LC-MS proteomics, Ubc9 conditional KO mice, co-immunoprecipitation, site-specific mutational analysis Metabolism: clinical and experimental Medium 36427672
2022 ERp44 knockout or expression of ERp44 active site mutants enhances basal DR5 oligomerization. Disulfide Bond Disrupting Agents (DDAs) bind ERp44 as an active site target, disrupting its mixed disulfide bonds with client proteins and affecting DR4/5 activity, stability, and localization. Affinity purification with biotinylated DDAs, shRNA knockdown, ERp44 mutant expression, DR5 oligomerization assays Cancer letters Medium 35247515
2023 ZnT4, ZnT5/ZnT6, and ZnT7 regulate labile Zn2+ concentration in distinct Golgi subregions (distal, medial, proximal respectively). ZnT-mediated Zn2+ fluxes tune ERp44 localization, trafficking, and client-retrieval activity. Systematic ZnT knockdowns reveal that disruption of Zn2+ homeostasis at specific Golgi subregions impairs ERp44-dependent quality control. Quantitative Zn2+ imaging (super-resolution microscopy with targeted probes), ZnT knockdowns, time-course secretory trafficking assays Nature communications High 37160917
2024 TMX5 interacts with ERp44 both non-covalently and covalently via a mixed disulfide between ERp44 Cys29 (catalytic) and TMX5 non-catalytic Cys114 and/or Cys124. This ERp44-TMX5 association controls the ER localization of TMX5 in pre-Golgi compartments, analogous to other ERp44 clients (Ero1α, Ero1β, Prx4, ERAP1, SUMF1). Co-immunoprecipitation, disulfide trapping, site-directed mutagenesis, localization assays Life science alliance Medium 39348940
2024 ERp44 promotes selective ER retention (sERr) of glycoproteins including tyrosine kinase receptors under ER stress conditions by forming large disulfide-bonded complexes. ERp44 constitutively interacts with PDIA6 via disulfides, and they have opposing effects: ERp44 deletion accelerates trafficking recovery after sERr conditions while PDIA6 deletion slows it. ERp44 is a primary interactor with sERr clients. Pulse-chase analysis, ERp44/PDIA6 knockout cell lines, co-immunoprecipitation, sERr complex size analysis by SDS-PAGE The Biochemical journal Medium 39621446
2022 ERp44 directly binds VEGFA and controls its release, thereby regulating endothelial-mesenchymal transition (EndMT). Conditional cardiac-specific knockout of ERp44 (cTNT-Cre; ERp44fl/fl) shows reduced cushion cell proliferation, impaired EndMT, and endocardial cushion dysplasia, demonstrating that myocardial ERp44 controls endocardial cushion formation through VEGFA. Conditional knockout mice, co-immunoprecipitation/binding assay, immunofluorescence, transcriptome analysis, functional EndMT assays Cell proliferation Medium 35088919
2026 ERp44 deficiency causes impaired collagen type 1 deposition and intracellular procollagen 1 accumulation in cellular models. ERp44 KO mice show skeletal malformations, delayed bone development, and reduced collagen deposition. Zebrafish with ERp44 knockdown display similar skeletal defects, indicating a conserved role for ERp44 in collagen secretion and skeletal development. ERp44 KO mice, zebrafish morphants, cellular ERp44 knockdown models, immunofluorescence, collagen deposition assays iScience Medium 42100748
2025 Silencing ERp44 phenocopies KDELR3 knockdown in upregulating AGR2 transcripts, suggesting that ERp44-KDELR3 interactions regulate AGR2 production. ERp44 but not other ER residents mediates this effect, identifying ERp44 as part of a regulatory circuit controlling molecular composition of the early secretory pathway through specific KDELR interactions. siRNA knockdown of ERp44 and KDELR isoforms, AGR2 transcript quantification, functional secretion assays bioRxivpreprint Low

Source papers

Stage 0 corpus · 46 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44. Cell 318 15652484
2002 ERp44, a novel endoplasmic reticulum folding assistant of the thioredoxin family. The EMBO journal 231 11847130
2003 Thiol-mediated protein retention in the endoplasmic reticulum: the role of ERp44. The EMBO journal 199 14517240
2006 Dynamic retention of Ero1alpha and Ero1beta in the endoplasmic reticulum by interactions with PDI and ERp44. Antioxidants & redox signaling 90 16677073
2008 Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail. EMBO reports 65 18552768
2008 Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44. Human molecular genetics 59 18508857
2019 Zinc regulates ERp44-dependent protein quality control in the early secretory pathway. Nature communications 53 30723194
2010 Peroxisome proliferator-activated receptor-gamma increases adiponectin secretion via transcriptional repression of endoplasmic reticulum chaperone protein ERp44. Endocrinology 46 20484463
2008 ERp44 mediates a thiol-independent retention of formylglycine-generating enzyme in the endoplasmic reticulum. The Journal of biological chemistry 41 18178549
2023 Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface. Nature communications 38 37160917
2015 Proteostasis and "redoxtasis" in the secretory pathway: Tales of tails from ERp44 and immunoglobulins. Free radical biology & medicine 38 25744412
2014 GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake. Proceedings of the National Academy of Sciences of the United States of America 38 25512553
2016 Crystal Structure of the ERp44-Peroxiredoxin 4 Complex Reveals the Molecular Mechanisms of Thiol-Mediated Protein Retention. Structure (London, England : 1993) 37 27642162
2017 Structural basis of pH-dependent client binding by ERp44, a key regulator of protein secretion at the ER-Golgi interface. Proceedings of the National Academy of Sciences of the United States of America 35 28373561
2014 Progressive quality control of secretory proteins in the early secretory compartment by ERp44. Journal of cell science 33 25097228
2022 Ero1α-Dependent ERp44 Dissociation From RyR2 Contributes to Cardiac Arrhythmia. Circulation research 32 35086342
2020 The pivotal role of ERp44 in patrolling protein secretion. Journal of cell science 30 33173013
2014 Endoplasmic reticulum resident protein 44 (ERp44) deficiency in mice and zebrafish leads to cardiac developmental and functional defects. Journal of the American Heart Association 28 25332179
2021 Exosomal ERp44 derived from ER-stressed cells strengthens cisplatin resistance of nasopharyngeal carcinoma. BMC cancer 27 34493236
2016 ERP44 inhibits human lung cancer cell migration mainly via IP3R2. Aging 27 27347718
2010 From antibodies to adiponectin: role of ERp44 in sizing and timing protein secretion. Diabetes, obesity & metabolism 25 21029299
2021 A virtuous cycle operated by ERp44 and ERGIC-53 guarantees proteostasis in the early secretory compartment. iScience 24 33763635
2022 SUMOylation of ERp44 enhances Ero1α ER retention contributing to the pathogenesis of obesity and insulin resistance. Metabolism: clinical and experimental 22 36427672
2021 Biogenesis of secretory immunoglobulin M requires intermediate non-native disulfide bonds and engagement of the protein disulfide isomerase ERp44. The EMBO journal 22 34957576
2012 The role of ERp44 in maturation of serotonin transporter protein. The Journal of biological chemistry 20 22451649
2022 Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death. Cancer letters 19 35247515
2020 The regulatory network of lncRNA DLX6-AS1/miR-149-5p/ERP44 is possibly related to the progression of preeclampsia. Placenta 17 32250737
2018 ERp44 depletion exacerbates ER stress and aggravates diabetic nephropathy in db/db mice. Biochemical and biophysical research communications 16 30224065
2015 Knockdown of ERp44 leads to apoptosis via activation of ER stress in HeLa cells. Biochemical and biophysical research communications 15 26043695
2011 ERp44 C160S/C212S mutants regulate IP3R1 channel activity. Protein & cell 12 22183808
2022 ERp44 is required for endocardial cushion development by regulating VEGFA secretion in myocardium. Cell proliferation 8 35088919
2019 The role of ERp44 in glucose and lipid metabolism. Archives of biochemistry and biophysics 6 31283909
2022 ERp44 Regulates the Proliferation, Migration, Invasion, and Apoptosis of Gastric Cancer Cells Via Activation of ER Stress. Biochemical genetics 5 36178559
2024 Opposing regulation of endoplasmic reticulum retention under stress by ERp44 and PDIA6. The Biochemical journal 4 39621446
2021 ERp44/CG9911 promotes fat storage in Drosophila adipocytes by regulating ER Ca2+ homeostasis. Aging 4 34031268
2019 Molecular characterization, host defense mechanisms, and functional analysis of ERp44 from big-belly seahorse: A novel member of the teleost thioredoxin family present in the endoplasmic reticulum. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 4 30797055
2011 Molecular cloning and characterization of the porcine Ero1L and ERp44 genes: potential roles in controlling energy metabolism. General and comparative endocrinology 4 21664357
2024 TMX5/TXNDC15, a natural trapping mutant of the PDI family is a client of the proteostatic factor ERp44. Life science alliance 3 39348940
2021 Protein tyrosine phosphatase receptor type O (PTPRO) knockdown enhances the proliferative, invasive and angiogenic activities of trophoblast cells by suppressing ER resident protein 44 (ERp44) expression in preeclampsia. Bioengineered 3 34719307
2023 The differential placental expression of ERp44 and pre-eclampsia; association with placental zinc, the ERAP1 and the renin-angiotensin-system. Placenta 2 36848863
2021 Quantitative proteomics reveals arsenic attenuates stem-loop binding protein stability via a chaperone complex containing heat shock proteins and ERp44. Proteomics 2 34132035
2013 Acidification activates ERp44--a molecular litmus test for protein assembly. Molecular cell 2 23806332
2015 Segmental expression and C-terminal labeling of protein ERp44 through protein trans-splicing. Protein expression and purification 1 25907381
2026 Zinc-mediated structural and functional regulation of ERp44 and ERGIC-53 in protein quality control. Journal of biochemistry 0 42083771
2026 Impaired collagen deposition in the absence of ERp44. iScience 0 42100748
2026 Exosomal miR-376c-3p derived from cardiac fibroblasts triggers cardiac hypertrophy by targeting ERP44. The Journal of pharmacology and experimental therapeutics 0 42242159

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