Affinage

EDEM1

ER degradation-enhancing alpha-mannosidase-like protein 1 · UniProt Q92611

Length
657 aa
Mass
73.8 kDa
Annotated
2026-06-09
51 papers in source corpus 29 papers cited in narrative 28 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

EDEM1 is an endoplasmic reticulum-resident mannosidase-like protein that commits terminally misfolded glycoproteins to ER-associated degradation (ERAD) by extracting them from the calnexin folding cycle and routing them to the dislocation machinery (PMID:12610306, PMID:12610305). It physically associates with calnexin and acts as an acceptor that releases folding-incompetent substrates, accelerating their degradation while sparing productively folding clients (PMID:12610306, PMID:12610305). EDEM1 possesses intrinsic alpha-1,2-mannosidase activity, trimming the C branch of N-glycans and catalyzing the second mannose-trimming step (M8B to M7/M6/M5) that exposes the alpha-1,6-mannose recognized by downstream ERAD lectins; this activity is modest on native substrates but strongly enhanced on unfolded glycoproteins and by association with oxidoreductases such as TXNDC11 (PMID:20065073, PMID:30374462, PMID:34698634). Substrate recognition is genetically separable from catalysis: EDEM1 binds nonnative proteins through its N-terminal intrinsically disordered region and through hydrophobicity- and thiol-dependent contacts, independently of glycan trimming, allowing it to engage both glycosylated and nonglycosylated clients and to prevent their covalent disulfide-linked aggregation during release from calnexin (PMID:16987498, PMID:19524542, PMID:23233672, PMID:22905195, PMID:25655076, PMID:30021839). EDEM1 then delivers clients to the SEL1L/HRD1 dislocation and ubiquitination complex, positioning it upstream of the mannose-dependent lectins XTP3-B and OS9 (PMID:19524542, PMID:21062743, PMID:21917589). Two isoforms arising from inefficient signal-sequence cleavage partition this activity: a soluble form associates with the oxidoreductase ERdj5 to handle soluble substrates and a type-II membrane form associates with SEL1L for membrane substrates (PMID:21632540). EDEM1 promotes retrotranslocation of physiological and toxin clients including ricin A-chain, APP, and EGFR, and is itself turned over by selective autophagy following PNGase deglycosylation and p62/NBR1 targeting, as well as by the SEL1L/HRD1 ERAD pathway (PMID:16452630, PMID:21388347, PMID:24664425, PMID:35008544, PMID:37569550, PMID:38682256). Beyond degradation, EDEM1 modulates the unfolded protein response by negatively regulating ATF6 stability and by tuning IRE1 signaling (PMID:30281916, PMID:37822496).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 High

    Established EDEM1's core role by showing it extracts terminally misfolded glycoproteins from the calnexin cycle, answering how doomed clients are diverted from futile folding into degradation.

    Evidence Overexpression/knockdown with pulse-chase of misfolded glycoprotein fate and reciprocal co-IP mapping calnexin binding to the transmembrane region

    PMID:12610305 PMID:12610306

    Open questions at the time
    • Did not establish the biochemical signal distinguishing misfolded from folding-competent clients
    • Catalytic activity not yet demonstrated
  2. 2004 Medium

    Resolved that EDEM1 also exists as a soluble ER-lumenal species and defined a stress-regulated paralog EDEM2, clarifying that EDEM function is not restricted to a membrane-anchored form.

    Evidence Subcellular fractionation, pulse-chase ERAD assays, and XBP1 reporter assays

    PMID:15579471

    Open questions at the time
    • Relationship between soluble and membrane forms unresolved
    • Functional distinction between EDEM1 and EDEM2 substrates unaddressed
  3. 2006 High

    Dissected two separable EDEM1 activities by catalytic-site mutagenesis, showing de-mannosylation and anti-aggregation chaperone function are mechanistically distinct.

    Evidence Site-directed mutagenesis of the conserved alpha-1,2-mannosidase catalytic residue (E220Q) with N-glycan analysis and non-reducing SDS-PAGE; comparison against control ER proteins

    PMID:16629899 PMID:16987498

    Open questions at the time
    • Direct enzymatic activity of purified protein not shown
    • Molecular basis of anti-aggregation function undefined
  4. 2007 High

    Revealed a non-canonical ER exit route by localizing endogenous EDEM1 to non-COPII ~150 nm vesicles (EDEMosomes) shared with Derlin-2 and misfolded substrate.

    Evidence Quantitative immunogold electron microscopy with serial sections and subcellular fractionation

    PMID:17360537

    Open questions at the time
    • Machinery generating these vesicles unidentified
    • Destination and functional purpose of vesicular EDEM1 unresolved
  5. 2009 High

    Decoupled substrate recognition from glycan chemistry, showing EDEM1 binds nonnative proteins glycan-independently while its mannosidase-like domain targets clients to SEL1L.

    Evidence Co-IP under kifunensine, mannosidase-domain mutants, and SEL1L pulldowns; extended by an opsin chaperone study and the first demonstration of basal autophagic turnover of EDEM1

    PMID:19266160 PMID:19524542 PMID:19934218

    Open questions at the time
    • The protein determinant recognized by EDEM1 not yet defined
    • How recognition and SEL1L handoff are coordinated unclear
  6. 2011 Medium

    Placed EDEM1 upstream of mannose-dependent lectins and showed its overexpression can bypass the ER mannosidase I requirement, refining the ERAD step order.

    Evidence ERManI knockdown with EDEM1 overexpression, deletion mutants lacking the carbohydrate-recognition domain, and colocalization at the pericentriolar ERQC; isoform analysis defining soluble-ERdj5 vs membrane-SEL1L partitioning

    PMID:21062743 PMID:21632540 PMID:21917589

    Open questions at the time
    • Quantitative contribution of mannose-dependent vs -independent routing in vivo unresolved
    • Regulation of isoform ratio not defined
  7. 2015 Medium

    Generalized EDEM1's client repertoire to nonglycosylated proteins and toxin chains, and identified hydrophobicity and a disordered N-terminal region as the recognition basis.

    Evidence Domain deletion and substrate-hydrophobicity mutagenesis with co-IP and ERAD/retrotranslocation assays across multiple substrates (NHK, H2a, ricin A-chain, BACE457, tyrosinase)

    PMID:21388347 PMID:22905195 PMID:23233672 PMID:25655076

    Open questions at the time
    • Structural details of disordered-region engagement unresolved
    • Whether the same surface binds glycosylated and nonglycosylated clients unclear
  8. 2018 High

    Demonstrated intrinsic mannosidase activity directly in vitro and showed it is substrate-state dependent and enhanced by oxidoreductase partners, and that client capture involves redox-sensitive thiol contacts.

    Evidence In vitro mannosidase assays with purified EDEM1/2 on native vs denatured substrates, co-IP with TXNDC11; reducing/non-reducing co-IP with client Cys256 mutants and IDR/MLD constructs

    PMID:30021839 PMID:30374462

    Open questions at the time
    • Stoichiometry and dynamics of oxidoreductase coupling in cells unresolved
    • How redox state gates substrate release undefined
  9. 2021 High

    Defined the precise enzymatic step EDEM1 catalyzes (M8B to M7/M6/M5) using reconstituted purified enzyme, situating it alongside EDEM3 in N-glycan trimming.

    Evidence In vitro mannosidase assay with purified EDEM1 and EDEM3 on pyridylamine-labeled M8B and glycoprotein substrates with HPLC profiling

    PMID:34698634

    Open questions at the time
    • Functional division of labor between EDEM1 and EDEM3 in vivo unresolved
    • Kinetic parameters on physiological clients undefined
  10. 2023 Medium

    Extended EDEM1 to physiological and disease-relevant clients (APP, EGFR, TSP1) and to UPR regulation, showing roles beyond bulk misfolded-protein clearance.

    Evidence Knockdown/overexpression with co-IP, pulse-chase, Abeta ELISA, and maturation/localization readouts; ATF6 export/cleavage assays and IRE1/JNK/c-Jun pathway analysis with insulin secretion in beta cells and islets

    PMID:30281916 PMID:35008544 PMID:37569550 PMID:37822496

    Open questions at the time
    • Direct vs indirect effects on UPR transducers not fully separated
    • Physiological significance of individual substrate effects in tissue not established
  11. 2024 Medium

    Mapped how EDEM1 itself is degraded, showing dual ERAD (SEL1L/HRD1, YOD1, XTP3-B, ERdj3, VIMP, BAG6, JB12) and selective autophagy routes, establishing autoregulation of the ERAD machinery.

    Evidence Sibling knockdowns of ERAD components, proteasome and autophagy inhibitors, pulse-chase; PNGase-dependent p62/NBR1 routing imaging and autoregulatory complex mass spectrometry

    PMID:24664425 PMID:32423001 PMID:38682256

    Open questions at the time
    • Trigger selecting ERAD vs autophagy for EDEM1 turnover unresolved
    • Physiological consequences of dysregulated EDEM1 levels undefined
  12. 2025 Medium

    Provided the first structural model of EDEM client engagement, showing the EDEM catalytic domain nesting in a PDI arc with disulfide-mediated client capture and a redox relay priming PDI as the ERAD reductase.

    Evidence Cryo-EM of EDEM:PDI heterodimer with/without A1AT-NHK client (thermophilic orthologs), mass spectrometry of disulfide bonds, and in vitro redox assays (preprint)

    PMID:bio_10.1101_2025.01.29.635535

    Open questions at the time
    • Awaits peer review and confirmation in human EDEM1
    • How redox cycling couples to retrotranslocation in the full dislocon unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how EDEM1 integrates substrate recognition, catalytic trimming, redox chemistry, and isoform/vesicle partitioning into a single regulated decision to commit a client to degradation in vivo.
  • No quantitative model linking mannose-dependent and -independent routing
  • Physiological regulation of EDEMosome formation and EDEM1 turnover unknown
  • No high-resolution human EDEM1 structure with client

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0060090 molecular adaptor activity 3 GO:0140098 catalytic activity, acting on RNA 3 GO:0044183 protein folding chaperone 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CANXDNAJC10NBR1PDIASEL1LSQSTM1TXNDC11
Complex memberships
EDEM:PDI heterodimerSEL1L/HRD1 ERAD dislocation complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 EDEM extracts misfolded glycoproteins (but not productively folding glycoproteins) from the calnexin cycle, promoting their release and accelerating ERAD. EDEM overexpression caused faster release of folding-incompetent proteins from calnexin and earlier onset of degradation; EDEM down-regulation prolonged folding attempts and delayed ERAD. Overexpression and down-regulation of EDEM combined with pulse-chase analysis of misfolded glycoprotein fate and calnexin association Science High 12610305 12610306
2003 EDEM interacts physically with calnexin through its transmembrane region (not with calreticulin). Both binding of substrates to calnexin and their release from calnexin are required for ERAD; EDEM overexpression promoted release of terminally misfolded proteins from calnexin, functioning as an acceptor of calnexin substrates. Co-immunoprecipitation; overexpression studies with pulse-chase analysis; domain deletion mapping (transmembrane region) Science High 12610305
2004 EDEM is a soluble protein of the ER lumen (in HEK293 cells), not exclusively an ER membrane protein; it functions as a mannosidase-like chaperone. A second homolog EDEM2 was identified that is also a stress-regulated mannosidase-like protein operating in the ER lumen and accelerates ERAD of terminally misfolded glycoproteins by facilitating their extraction from the calnexin cycle; EDEM2 transcriptional up-regulation depends on the ER stress-activated transcription factor XBP1. Subcellular fractionation; overexpression and pulse-chase ERAD assays; reporter assays for XBP1-dependent transcription The Journal of Biological Chemistry Medium 15579471
2006 EDEM1 overexpression accelerates de-mannosylation of terminally misfolded glycoproteins (Man9 or Man5 N-glycans) and inhibits formation of covalent (disulfide-linked) aggregates upon their release from calnexin. Substitution of one conserved catalytic residue in the alpha-1,2-mannosidase active site (E220Q equivalent) fully blocked accelerated de-mannosylation but did not affect the anti-aggregation (chaperone) function of EDEM1, indicating two separable activities. Pulse-chase with N-glycan analysis; site-directed mutagenesis of conserved catalytic residue; non-reducing SDS-PAGE to detect aggregates Biochemical and Biophysical Research Communications High 16987498
2006 EDEM prevents aberrant covalent dimer formation of misfolded alpha1-antitrypsin NHK, maintaining its retrotranslocation competence. EDEM overexpression selectively prevented accumulation of covalent NHK dimers; this anti-aggregation effect was specific to EDEM and not observed with calnexin or H+/K+-ATPase beta subunit overexpression. Overexpression of EDEM and control ER membrane proteins; non-reducing SDS-PAGE; pulse-chase degradation assays Genes to Cells Medium 16629899
2007 Endogenous EDEM1 is sequestered in ~150 nm vesicles that bud from rough ER cisternae outside of transitional ER exit sites, lacking a recognizable COPII coat (~87% of immunogold label on vesicles). These vesicles also contain Derlin-2 and misfolded alpha-1-antitrypsin (NHK), indicating a non-canonical ER exit pathway for quality control components and substrates. High-resolution immunogold electron microscopy and serial section analysis; subcellular fractionation Proceedings of the National Academy of Sciences of the USA High 17360537
2009 EDEM1 specifically binds nonnative proteins in a glycan-independent manner. Inhibition of mannosidase activity with kifunensine or mutation of the mannosidase-like domain had no effect on substrate binding but diminished EDEM1 association with the ER membrane adaptor protein SEL1L. EDEM1 thus uses its mannosidase-like domain to target aberrant proteins to the SEL1L-containing dislocation/ubiquitination complex. Co-immunoprecipitation under glycan-inhibited conditions (kifunensine); mannosidase domain mutants; pulldown assays with SEL1L Molecular Cell High 19524542
2009 EDEM1 functions as a chaperone for rod opsin: it promotes degradation of misfolded P23H rod opsin via ERAD and decreases its aggregation into inclusions. shRNA knockdown of EDEM1 increased P23H rod opsin levels and aggregation. Unexpectedly, EDEM1 binding to rod opsin was independent of mannose trimming, and EDEM1 also promoted cell-surface expression of mutant rod opsin. shRNA knockdown; overexpression; co-immunoprecipitation; pulse-chase assays; immunofluorescence; endoglycosidase H sensitivity assays Journal of Cell Science Medium 19934218
2009 Endogenous EDEM1 is degraded by basal autophagy (not by the proteasome under non-starved conditions). EDEM1 was detected in autophagosomes biochemically (LC3 immuno-purification) and by immunocytochemistry. Inhibition of the lysosome-autophagy pathway or knockdown of ATG genes stabilized EDEM1. Autophagosome immunopurification; immunocytochemistry; pharmacological inhibitors (vinblastine, pepstatin A/E64d, 3-methyladenine); siRNA knockdown of ATGs Cellular and Molecular Life Sciences Medium 19266160
2010 EDEM1 overexpression specifically accelerates trimming of alpha-1,2-linked mannose from the C branch of N-glycans, producing Glc1Man8GlcNAc2 isomer C and increasing Man7GlcNAc2 isomer A. The EDEM1 E220Q catalytic mutant did not produce this isomer, confirming alpha-1,2-mannosidase catalytic activity on the C branch. However, ERAD enhancement by wild-type and E220Q EDEM1 was equivalent, attributed to inhibition of aberrant NHK dimer formation. Radiolabeled N-glycan structural analysis (3H-mannose pulse-chase); site-directed mutagenesis (E220Q); stable cell line overexpression Glycobiology High 20065073
2010 Mannose trimming is not required for EDEM1 binding to an ERAD substrate glycoprotein (binding persists with kifunensine treatment or ERManI knockdown). In contrast, substrate association with XTP3-B and E3 ubiquitin ligases HRD1 and SCF(Fbs2) required mannose trimming, placing EDEM1 upstream of these factors in the ERAD pathway. Co-immunoprecipitation under mannosidase inhibitor (kifunensine) treatment; ERManI siRNA knockdown; colocalization by immunofluorescence at the ERQC The Journal of Biological Chemistry Medium 21062743
2011 EDEM1 overexpression or its up-regulation via IRE1 (unfolded protein response) overrides the mannose-trimming requirement for ERAD, rendering ER mannosidase I dispensable. An EDEM1 deletion mutant lacking most of the carbohydrate-recognition domain still accelerated ERAD and delivered substrate to XTP3-B and OS9. Upon proteasomal inhibition, EDEM1 concentrated with ERAD substrate in the pericentriolar ERQC compartment containing OS9. ERManI knockdown combined with EDEM1 overexpression; EDEM1 deletion mutants; co-immunoprecipitation; immunofluorescence colocalization at ERQC Molecular Biology of the Cell Medium 21917589
2011 Signal sequence cleavage of EDEM1 is slow and inefficient, producing two isoforms: a soluble form and a type-II membrane form (when signal sequence is uncleaved, creating an N-terminal transmembrane segment). The soluble form efficiently associates with the oxidoreductase ERdj5 and accelerates turnover of soluble ERAD substrates, while the membrane form efficiently associates with SEL1L and accelerates turnover of membrane-associated ERAD substrates. Signal sequence cleavage analysis; glycosylation site mapping; co-immunoprecipitation with ERdj5 and SEL1L; pulse-chase ERAD assays with isoform-specific constructs The Journal of Biological Chemistry Medium 21632540
2012 EDEM1 participates in a shared ERAD pathway for both glycosylated and nonglycosylated proteins. Nonglycosylated ERAD substrates (including nonglycosylated H2a, NS-1κ light chain, truncated Igγ heavy chain) co-immunoprecipitate with EDEM1, and require EDEM1 for their degradation. EDEM1 associates with nonglycosylated proteins through a region outside its mannosidase-like domain. Co-immunoprecipitation; siRNA knockdown of EDEM1; pulse-chase degradation assays; domain deletion analysis The Journal of Biological Chemistry Medium 23233672
2012 The intrinsically disordered (ID) N-terminal region of EDEM1 (residues ~40–119) mediates binding to both glycosylated and non-glycosylated misfolded proteins. Deletion of this ID region abolished co-immunoprecipitation with misfolded tyrosinase (glycosylated and non-glycosylated mutants), while the intact mannosidase-like domain was not required for substrate binding. EDEM1 overexpression enhanced degradation of wild-type and misfolded tyrosinase. Co-immunoprecipitation with EDEM1 deletion mutants; homology modeling of mannosidase domain; pulse-chase degradation assays PLOS ONE Medium 22905195
2014 EDEM1 promotes retrotranslocation of ricin A-chain (RTA) from the ER to the cytosol. EDEM1 overexpression increased RTA retrotranslocation (demonstrated with kifunensine to block competition from misfolded proteins), while RNAi-mediated knockdown decreased RTA retrotranslocation. Co-immunoprecipitation showed that ricin interacts with EDEM1 and with Sec61alpha. Overexpression and siRNA knockdown of EDEM1; cytosol/ER fractionation to measure retrotranslocation; co-immunoprecipitation Molecular Biology of the Cell Medium 16452630 21388347
2014 EDEM1 is degraded by selective autophagy. It colocalizes with selective autophagy cargo receptors p62/SQSTM1, NBR1, and Alfy, and is engulfed by autophagic isolation membranes. p62/SQSTM1 and NBR1 knockdown blocked EDEM1 routing to autophagosomes. p62/SQSTM1 interacts only with deglycosylated (and ubiquitinated) EDEM1; deglycosylation by cytosolic peptide N-glycanase (PNGase) is a prerequisite for p62/SQSTM1 interaction and aggregate formation. Immunofluorescence colocalization; siRNA knockdown of cargo receptors; PNGase inhibitors; ubiquitination assays Histochemistry and Cell Biology Medium 24664425
2015 Recognition of ERAD substrates by EDEM1 is determined by the hydrophobicity of protein determinants. Mutations increasing or decreasing hydrophobicity in misfolded substrates (ricin A-chain, BACE457) correspondingly altered their interaction with EDEM1. EDEM1 can bind hydrophobic transmembrane regions of misfolded ERAD substrates, and this binding does not require substrate glycosylation. Site-directed mutagenesis to alter substrate hydrophobicity; co-immunoprecipitation; ERAD assays BMC Cell Biology Medium 25655076
2018 EDEM1 and EDEM2 possess intrinsic mannosidase activity in vitro, demonstrated directly. Their activity on free N-glycans and intact glycoproteins is modest, but is significantly enhanced on denatured (unfolded) glycoproteins. EDEM1/2 associate with oxidoreductases including TXNDC11, which enhances their mannosidase activity on glycoproteins but not on free N-glycans. In vitro mannosidase assay with purified proteins; denatured vs. native substrate comparisons; co-immunoprecipitation with oxidoreductases Communications Biology High 30374462
2018 EDEM1 binds ERAD clients (Z and NHK alpha1-antitrypsin) through a thiol-dependent (redox-sensitive) interaction via Cys256 of the client, as well as through weaker protein-protein interactions (bipartite binding). The EDEM1 mannosidase-like domain (MLD) alone retains both thiol-dependent binding and glycan-trimming activity. Two intrinsically disordered regions (IDRs), one N-terminal and one C-terminal, are both required for ERdj5 binding. Co-immunoprecipitation under reducing/non-reducing conditions; Cys-to-Ala point mutation in client; MLD domain construct; IDR deletion mutants The Journal of Biological Chemistry Medium 30021839
2020 EDEM1 is found in auto-regulatory complexes with ERAD components (identified by mass spectrometry). The N-terminal disordered region of EDEM1 mediates protein-protein interaction with misfolded proteins; deletion of this domain significantly impairs their degradation. When proteasomal activity is severely impaired, EDEM1 overexpression can still promote degradation by promoting aggregate formation, which is then cleared by autophagy (ER-phagy as a back-up). Mass spectrometry; co-immunoprecipitation; EDEM1 domain deletion mutants; proteasome inhibition with MG132; autophagy assays International Journal of Molecular Sciences Medium 32423001
2021 EDEM1 and EDEM3 are responsible for the second step of N-glycan mannose trimming in ERAD (from M8B to M7, M6, M5, exposing the alpha-1,6-linked mannosyl residue). Purified EDEM3 alone converted pyridylamine-labeled M8B to M7A, M7C, M6, and M5; purified EDEM1 showed similar but weaker activity (less M6/M5). Both efficiently trimmed M8B from a glycoprotein substrate. In vitro mannosidase assay with purified EDEM1 and EDEM3 proteins; pyridylamine-labeled M8B oligosaccharide and glycoprotein substrates; HPLC N-glycan profiling eLife High 34698634
2021 EDEM1 physically interacts with amyloid precursor protein (APP) and promotes APP degradation via ERAD retrotranslocation to the cytosol. EDEM1 overexpression reduced APP cellular levels and decreased Abeta40/Abeta42 secretion; EDEM1 knockdown increased APP levels. Co-immunoprecipitation; overexpression and siRNA knockdown; pulse-chase assays; Abeta ELISA International Journal of Molecular Sciences Medium 35008544
2023 EDEM1 physically associates with EGFR and enhances EGFR degradation via ERAD. EGFR and thrombospondin-1 (TSP1) were identified as endogenous EDEM1 substrate proteins; their protein maturation status and cellular localization were markedly affected by EDEM1 knockdown. siRNA knockdown of EDEM1; co-immunoprecipitation; pulse-chase and protein stability assays; immunofluorescence International Journal of Molecular Sciences Medium 37569550
2024 EDEM1 is itself turned over by both ERAD and autophagy. ERAD-dependent degradation of EDEM1 involves the SEL1L/HRD1 complex, YOD1, XTP3-B, ERdj3, VIMP, BAG6, and JB12, but not OS9, and occurs in both mannose-trimming-dependent and -independent manners. Sibling knockdowns of ERAD components; proteasome and autophagy inhibitors; pulse-chase assays Genes to Cells Medium 38682256
2018 Silencing of EDEM1 increased bioavailability of ATF6 for Golgi export and cleavage upon ER stress, by stabilizing the natively unstable ATF6 protein. A somatic cancer variant of EDEM1 (N198I) altered ATF6 signaling. This places EDEM1 as a negative regulator of ATF6 stability/activity. siRNA screening; ATF6 export and cleavage assays; overexpression of EDEM1 variants The FEBS Journal Medium 30281916
2023 EDEM1 inhibits the IRE1/JNK/c-Jun signaling pathway, leading to increased insulin mRNA levels. EDEM1 overexpression in INS-1E beta cells and human islets increased insulin secretion upon glucose stimulation; EDEM1 modulates UPR via both IRE1/XBP1s and IRE1/JNK/c-Jun cascades. Overexpression in INS-1E cells and human islets; western blotting of IRE1/JNK/c-Jun pathway; qRT-PCR for insulin mRNA; glucose-stimulated insulin secretion assay; in vivo diabetic rat model iScience Medium 37822496
2025 Cryo-EM structures of the EDEM:PDI heterodimer (from Chaetomium thermophilum orthologs) were solved, with and without an alpha1-antitrypsin NHK client. The EDEM catalytic domain nests within the PDI arc; the client (A1AT-NHK) binds EDEM's C-terminal flexible domains. A disulfide bond forms between A1AT-NHK and an exposed Cys in the EDEM PAD domain. Redox chemistry between EDEM and PDI generates oxidized (demannosylation-competent) EDEM and reduced PDI, priming PDI to act as the ERAD reductase facilitating client retrotranslocation. Cryo-EM structure determination; mass spectrometry (disulfide bond identification); non-reducing SDS-PAGE after co-transfection; in vitro redox assays bioRxiv (preprint)preprint Medium bio_10.1101_2025.01.29.635535

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science (New York, N.Y.) 356 12610306
2003 EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science (New York, N.Y.) 353 12610305
2006 EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. The Journal of biological chemistry 199 16431915
2006 EDEM1 regulates ER-associated degradation by accelerating de-mannosylation of folding-defective polypeptides and by inhibiting their covalent aggregation. Biochemical and biophysical research communications 144 16987498
2004 A novel stress-induced EDEM variant regulating endoplasmic reticulum-associated glycoprotein degradation. The Journal of biological chemistry 128 15579471
2009 EDEM1 recognition and delivery of misfolded proteins to the SEL1L-containing ERAD complex. Molecular cell 112 19524542
2007 Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins. FEBS letters 112 17499246
2014 Japanese encephalitis virus replication is negatively regulated by autophagy and occurs on LC3-I- and EDEM1-containing membranes. Autophagy 97 25046112
2010 EDEM1 accelerates the trimming of alpha1,2-linked mannose on the C branch of N-glycans. Glycobiology 93 20065073
2004 Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast. Molecular biology of the cell 82 15215312
2007 EDEM1 reveals a quality control vesicular transport pathway out of the endoplasmic reticulum not involving the COPII exit sites. Proceedings of the National Academy of Sciences of the United States of America 73 17360537
2007 The EDEM and Yos9p families of lectin-like ERAD factors. Seminars in cell & developmental biology 65 17945519
2006 EDEM accelerates ERAD by preventing aberrant dimer formation of misfolded alpha1-antitrypsin. Genes to cells : devoted to molecular & cellular mechanisms 65 16629899
2016 Quality control of glycoprotein folding and ERAD: the role of N-glycan handling, EDEM1 and OS-9. Histochemistry and cell biology 63 27803995
2006 EDEM is involved in retrotranslocation of ricin from the endoplasmic reticulum to the cytosol. Molecular biology of the cell 63 16452630
2011 Bypass of glycan-dependent glycoprotein delivery to ERAD by up-regulated EDEM1. Molecular biology of the cell 52 21917589
2009 A dual role for EDEM1 in the processing of rod opsin. Journal of cell science 52 19934218
2010 Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B and to late endoplasmic reticulum-associated degradation steps. The Journal of biological chemistry 50 21062743
2018 Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates. Communications biology 46 30374462
2012 A shared endoplasmic reticulum-associated degradation pathway involving the EDEM1 protein for glycosylated and nonglycosylated proteins. The Journal of biological chemistry 45 23233672
2009 Basal autophagy is involved in the degradation of the ERAD component EDEM1. Cellular and molecular life sciences : CMLS 40 19266160
2018 Alterations of EDEM1 functions enhance ATF6 pro-survival signaling. The FEBS journal 36 30281916
2010 Identification of an Htm1 (EDEM)-dependent, Mns1-independent Endoplasmic Reticulum-associated Degradation (ERAD) pathway in Saccharomyces cerevisiae: application of a novel assay for glycoprotein ERAD. The Journal of biological chemistry 36 20511219
2011 Characterization of early EDEM1 protein maturation events and their functional implications. The Journal of biological chemistry 35 21632540
2012 Tyrosinase degradation is prevented when EDEM1 lacks the intrinsically disordered region. PloS one 34 22905195
2018 EDEM1's mannosidase-like domain binds ERAD client proteins in a redox-sensitive manner and possesses catalytic activity. The Journal of biological chemistry 33 30021839
2004 EDEM contributes to maintenance of protein folding efficiency and secretory capacity. The Journal of biological chemistry 33 15308654
2011 A single point mutation in ricin A-chain increases toxin degradation and inhibits EDEM1-dependent ER retrotranslocation. The Biochemical journal 29 21388347
2017 EDEM Function in ERAD Protects against Chronic ER Proteinopathy and Age-Related Physiological Decline in Drosophila. Developmental cell 28 28633019
2020 EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired. International journal of molecular sciences 26 32423001
2022 PCV2 and PRV Coinfection Induces Endoplasmic Reticulum Stress via PERK-eIF2α-ATF4-CHOP and IRE1-XBP1-EDEM Pathways. International journal of molecular sciences 25 35562870
2014 MicroRNA-581 promotes hepatitis B virus surface antigen expression by targeting Dicer and EDEM1. Carcinogenesis 21 24913918
2015 Hydrophobicity of protein determinants influences the recognition of substrates by EDEM1 and EDEM2 in human cells. BMC cell biology 19 25655076
2014 ERADication of EDEM1 occurs by selective autophagy and requires deglycosylation by cytoplasmic peptide N-glycanase. Histochemistry and cell biology 19 24664425
2021 Purified EDEM3 or EDEM1 alone produces determinant oligosaccharide structures from M8B in mammalian glycoprotein ERAD. eLife 15 34698634
2022 Targeting EDEM protects against ER stress and improves development and survival in C. elegans. PLoS genetics 13 35192599
2021 EDEM1 Regulates Amyloid Precursor Protein (APP) Metabolism and Amyloid-β Production. International journal of molecular sciences 13 35008544
2014 The role of EDEM2 compared with EDEM1 in ricin transport from the endoplasmic reticulum to the cytosol. The Biochemical journal 13 24200403
2023 EDEM1 regulates the insulin mRNA level by inhibiting the endoplasmic reticulum stress-induced IRE1/JNK/c-Jun pathway. iScience 12 37822496
2021 Long intergenic non-coding RNA LINC00485 exerts tumor-suppressive activity by regulating miR-581/EDEM1 axis in colorectal cancer. Aging 12 33461166
2019 Profiling Optimal Conditions for Capturing EDEM Proteins Complexes in Melanoma Using Mass Spectrometry. Advances in experimental medicine and biology 10 31347047
2021 lncRNA Xist regulates sevoflurane-induced social and emotional impairment by modulating miR-98-5p/EDEM1 signaling axis in neonatal mice. Molecular therapy. Nucleic acids 9 34094712
2021 Edem1 activity in the fat body regulates insulin signalling and metabolic homeostasis in Drosophila. Life science alliance 7 34140347
2024 Turnover of EDEM1, an ERAD-enhancing factor, is mediated by multiple degradation routes. Genes to cells : devoted to molecular & cellular mechanisms 5 38682256
2023 Identification of EGF Receptor and Thrombospondin-1 as Endogenous Targets of ER-Associated Degradation Enhancer EDEM1 in HeLa Cells. International journal of molecular sciences 4 37569550
2022 New insight in algal cell adhesion and cake layer evolution in algal-related membrane processes: Size-fractioned particles, initial foulant seeds and EDEM simulation. Environmental research 4 36580982
2025 The ERN1 signaling pathway of unfolded protein controls the expression of EDEM1 and its hypoxic regulation in glioblastoma cells. Endocrine regulations 2 40073403
2025 The synthetic cannabinoid CUMYL-4CN-BINACA induces hepatic injury in rats via oxidative stress, NF-κB activation, Nrf2 suppression, EDEM-1, ER stress-mediated apoptotic pathways. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2 41109593
2020 Cleavage and degradation of EDEM1 promotes coxsackievirus B3 replication via ATF6a-mediated unfolded protein response signalling. Cellular microbiology 2 32083795
2025 EDEM1 Inhibits Endoplasmic Reticulum Stress to Induce Doxorubicin Resistance through Accelerating ERAD and Activating Keap1/Nrf2 Antioxidant Pathway in Triple-Negative Breast Cancer. Research (Washington, D.C.) 1 40735463
2026 Modelling and optimization of operating parameters of an electronic cell type metering mechanism for urea super granules (USG) using EDEM-RSM approach. Scientific reports 0 41927606

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