EDEM2

UniProt ID: Q9BV94
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

EDEM2 (ER degradation-enhancing alpha-mannosidase-like protein 2) is a soluble, N-glycosylated endoplasmic reticulum lumenal protein of glycoside hydrolase family 47 (GH47), one of three mammalian Htm1/Mns1 homologues (EDEM1, EDEM2, EDEM3) acting in ER-associated degradation of glycoproteins (gpERAD). EDEM2 catalyzes the initiating mannose-trimming step of mammalian gpERAD, converting Man9GlcNAc2 to Man8GlcNAc2 isomer B, an activity that requires the conserved EF-hand glutamate (E117) and is thought to operate within a disulfide-linked complex with the thioredoxin-domain protein TXNDC11. By generating Man8GlcNAc2, EDEM2 acts upstream of EDEM1 and EDEM3, which further trim the glycan to expose the alpha-1,6-mannose recognized by the downstream lectin OS-9. EDEM2 recognizes and binds misfolded glycoproteins (e.g. misfolded alpha-1-antitrypsin), accelerates their degradation, and promotes ER-to-cytosol retrotranslocation of substrates such as the ricin A chain; unlike EDEM1 and EDEM3 it does not bind the HRD1 adaptor SEL1L. It is induced by the IRE1-XBP1 branch of the unfolded protein response and is broadly expressed. Its catalytic mannosidase activity was historically controversial, with early recombinant assays detecting no activity before endogenous-knockout analysis established its role as the first-step mannosidase.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0030968 endoplasmic reticulum unfolded protein response
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: EDEM2 is induced by the IRE1-XBP1 branch of the unfolded protein response and functions in the ERAD arm of the ER stress response; phylogenetic assignment of involvement in the UPR is consistent with this.
Reason: EDEM2 is a UPR-induced effector acting in ERAD rather than a UPR signaling/sensing component; the informative function is the ERAD/mannose-trimming role.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
Belongs to the glycosyl hydrolase 47 family
GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: EDEM2 functions in N-glycan-dependent (glycoprotein) ERAD, in which misfolded glycoproteins are ubiquitinated and degraded by the proteasome; this is an accurate, specific process for EDEM2.
Reason: Correct, specific core biological process; redundant with the experimental ERAD/mannose-trimming evidence.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
targets misfolded glycoproteins for degradation in an N-glycan-dependent manner
GO:0005509 calcium ion binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: GH47-family mannosidases use a calcium ion in the active site; EDEM2 retains this fold and binds calcium as a structural/catalytic cofactor of its mannosidase activity.
Reason: Accurate structural cofactor attribute of the GH47 fold but not a standalone core function; the catalytic mannosidase activity is the informative function.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
Belongs to the glycosyl hydrolase 47 family
GO:0005788 endoplasmic reticulum lumen
IEA
GO_REF:0000044 		ACCEPT
Summary: EDEM2 is a soluble ER lumenal protein (signal peptide, no transmembrane domain); electronic transfer of ER lumen localization is correct.
Reason: Correct compartment; redundant with the EXP ER lumen annotation and UniProt subcellular location.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005975 carbohydrate metabolic process
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: Generic carbohydrate metabolic process from InterPro; far less informative than the specific ER mannose trimming and ERAD processes EDEM2 participates in.
Reason: Over-general parent; the specific ER mannose trimming (GO:1904380) and glycoprotein ERAD terms better capture the biology.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
Belongs to the glycosyl hydrolase 47 family
GO:0009100 glycoprotein metabolic process
IEA
GO_REF:0000117 		MARK AS OVER ANNOTATED
Summary: Generic glycoprotein metabolic process from ARBA; correct in essence but far less informative than the specific N-glycan trimming and ERAD annotations.
Reason: Over-general parent process; the specific glycan-trimming/ERAD terms are preferred.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
targets misfolded glycoproteins for degradation in an N-glycan-dependent manner
GO:0016020 membrane
IEA
GO_REF:0000002 		MARK AS OVER ANNOTATED
Summary: Generic membrane localization from InterPro. EDEM2 is in fact a soluble ER lumenal protein, not a membrane protein, so this term is both uninformative and a poor fit.
Reason: Uninformative and inaccurate parent from a domain-based inference; EDEM2 is a soluble ER lumenal protein, better captured by ER lumen.
Proposed replacements: endoplasmic reticulum lumen
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:1904380 endoplasmic reticulum mannose trimming
IEA
GO_REF:0000002 		ACCEPT
Summary: EDEM2 performs the first ER mannose-trimming step (Man9 to Man8B); electronic assignment is consistent with the IMP evidence.
Reason: Correct core biological process; redundant with the IMP annotation from endogenous knockout analysis.
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:1904154 positive regulation of retrograde protein transport, ER to cytosol
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: EDEM2 promotes retrotranslocation of ERAD substrates from the ER to the cytosol; electronic assignment is consistent with the experimental ricin retrotranslocation data.
Reason: Real, specific aspect of EDEM2 function (substrate dislocation) but subordinate to the core mannose-trimming/ERAD role; redundant with the IMP/IGI annotations.
Supporting Evidence:
PMID:24200403
EDEM2 is also involved in ricin retrotranslocation out of the ER
GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
TAS
Reactome:R-HSA-901024 		ACCEPT
Summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
Reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
TAS
Reactome:R-HSA-901036 		ACCEPT
Summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
Reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
TAS
Reactome:R-HSA-901039 		ACCEPT
Summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
Reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
TAS
Reactome:R-HSA-901074 		ACCEPT
Summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
Reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
TAS
Reactome:R-HSA-9696807 		ACCEPT
Summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
Reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:1904380 endoplasmic reticulum mannose trimming
IMP
PMID:25092655
EDEM2 initiates mammalian glycoprotein ERAD by catalyzing th... 		ACCEPT
Summary: Endogenous EDEM2 knockout in human and chicken cells blocked conversion of Man9 to Man8B as effectively as the mannosidase inhibitor kifunensine, demonstrating EDEM2 performs the first ER mannose-trimming step.
Reason: Core biological process with direct experimental (IMP) support from endogenous gene knockout.
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:1904380 endoplasmic reticulum mannose trimming
TAS
Reactome:R-HSA-901032 		ACCEPT
Summary: Reactome curation of EDEM2 ER mannose trimming in the ER Quality Control Compartment pathway.
Reason: Correct core biological process; redundant with the IMP evidence.
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:0036503 ERAD pathway
IMP
PMID:15537790
Human EDEM2, a novel homolog of family 47 glycosidases, is i... 		ACCEPT
Summary: Overexpression of EDEM2 accelerated degradation of misfolded alpha-1-antitrypsin, directly implicating EDEM2 in the ERAD pathway.
Reason: Core biological process with direct experimental (IMP) support.
Supporting Evidence:
PMID:15537790
Overexpression of EDEM2 accelerates the degradation of misfolded alpha1-antitrypsin, indicating that the protein is involved in ERAD
GO:0036503 ERAD pathway
IMP
PMID:25092655
EDEM2 initiates mammalian glycoprotein ERAD by catalyzing th... 		ACCEPT
Summary: Endogenous EDEM2 knockout most effectively blocked gpERAD of ATF6alpha, and the E117Q catalytic mutant failed to rescue, demonstrating EDEM2's central role in the ERAD pathway.
Reason: Core biological process with direct experimental (IMP) support.
Supporting Evidence:
PMID:25092655
stable introduction of Flag-tagged hEDEM2, but not Flag-tagged hEDEM2-E117Q, into hEDEM2-KO cells restored degradation of endogenous hATF6
GO:0019082 viral protein processing
TAS
Reactome:R-HSA-9694548 		KEEP AS NON CORE
Summary: Reactome annotation of EDEM2 in N-glycan mannose trimming of the SARS-CoV-2 spike glycoprotein. This is the generic mannosidase activity acting on a viral glycoprotein substrate, not a distinct viral function.
Reason: Real but peripheral; reflects the core mannosidase activity applied to a viral substrate rather than a dedicated viral-processing role.
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:0036510 trimming of terminal mannose on C branch
TAS
Reactome:R-HSA-901039 		KEEP AS NON CORE
Summary: Reactome curation of a specific terminal-mannose trimming sub-step. EDEM2 mainly initiates trimming on the B branch (Man9 to Man8B); this C-branch sub-step annotation is a Reactome-curated refinement.
Reason: Specific Reactome-curated trimming sub-step; retained as a non-core refinement of the mannosidase activity, whose principal demonstrated action is Man9 to Man8B.
Supporting Evidence:
PMID:25092655
the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
GO:0005788 endoplasmic reticulum lumen
EXP
PMID:15537790
Human EDEM2, a novel homolog of family 47 glycosidases, is i... 		ACCEPT
Summary: Recombinant EDEM2 is localized to the ER, consistent with its signal peptide and soluble lumenal topology.
Reason: Correct compartment with experimental support.
Supporting Evidence:
PMID:15537790
recombinant EDEM2 is localized to the ER where it can associate with misfolded alpha1-antitrypsin
GO:0005783 endoplasmic reticulum
IDA
PMID:24200403
The role of EDEM2 compared with EDEM1 in ricin transport fro... 		ACCEPT
Summary: Direct evidence for ER localization of EDEM2 in the ricin retrotranslocation study.
Reason: Correct site of action with direct experimental support.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:1904154 positive regulation of retrograde protein transport, ER to cytosol
IMP
PMID:24200403
The role of EDEM2 compared with EDEM1 in ricin transport fro... 		KEEP AS NON CORE
Summary: EDEM2 promotes ER-to-cytosol retrotranslocation of the ricin A chain irrespective of translocon accessibility, supporting a role in substrate dislocation.
Reason: Specific, experimentally supported aspect of EDEM2's ERAD/dislocation activity, but subordinate to the core mannose-trimming/ERAD role.
Supporting Evidence:
PMID:24200403
EDEM2 promotes ricin retrotranslocation irrespectively of ER translocon accessibility
GO:1904154 positive regulation of retrograde protein transport, ER to cytosol
IGI
PMID:24200403
The role of EDEM2 compared with EDEM1 in ricin transport fro... 		KEEP AS NON CORE
Summary: Genetic-interaction evidence (with EDEM1, UniProtKB:Q92611) that EDEM2 promotes ricin A-chain retrotranslocation from the ER to the cytosol.
Reason: Consistent with the IMP retrotranslocation annotation; a specific aspect of the dislocation function rather than the core role.
Supporting Evidence:
PMID:24200403
more ricin can interact with EDEM2 in comparison with EDEM1
GO:0044322 endoplasmic reticulum quality control compartment
TAS
Reactome:R-HSA-901024 		ACCEPT
Summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
Reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0044322 endoplasmic reticulum quality control compartment
TAS
Reactome:R-HSA-901036 		ACCEPT
Summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
Reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0044322 endoplasmic reticulum quality control compartment
TAS
Reactome:R-HSA-901039 		ACCEPT
Summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
Reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0044322 endoplasmic reticulum quality control compartment
TAS
Reactome:R-HSA-901074 		ACCEPT
Summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
Reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0044322 endoplasmic reticulum quality control compartment
TAS
Reactome:R-HSA-9696807 		ACCEPT
Summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
Reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
Supporting Evidence:
file:human/EDEM2/EDEM2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
IMP
PMID:25092655
EDEM2 initiates mammalian glycoprotein ERAD by catalyzing th... 		ACCEPT
Summary: Endogenous gene knockout and the catalytically inactivating E117Q mutation established that EDEM2 possesses alpha-1,2-mannosidase activity catalyzing the first trimming step (Man9 to Man8B), resolving the long-standing controversy over its catalytic activity.
Reason: Core molecular function with direct experimental (IMP) support; EDEM2 is the first-step mannosidase of mammalian gpERAD.
Supporting Evidence:
PMID:25092655
EDEM2, a novel-type Htm1 homologue that catalyzes the first mannose trimming step from Man9GlcNAc2
GO:0005783 endoplasmic reticulum
IDA
PMID:15537790
Human EDEM2, a novel homolog of family 47 glycosidases, is i... 		ACCEPT
Summary: Direct evidence that recombinant EDEM2 localizes to the ER.
Reason: Correct compartment with direct experimental support.
Supporting Evidence:
PMID:15537790
recombinant EDEM2 is localized to the ER where it can associate with misfolded alpha1-antitrypsin
GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
IDA NOT
PMID:15537790
Human EDEM2, a novel homolog of family 47 glycosidases, is i... 		KEEP AS NON CORE
Summary: A negated (NOT) experimental annotation reflecting the original characterization, in which recombinant EDEM2 showed no alpha-1,2-mannosidase activity, leading to a proposed lectin role. Endogenous-knockout analysis (PMID:25092655) and the E117Q mutant later established that EDEM2 does possess mannosidase activity, so this negation is superseded but retained as the curated record of the early finding.
Reason: Genuine historical experimental (IDA) annotation that conflicts with later endogenous-KO evidence; per guidelines an experimental annotation is not removed on weak grounds. Flagged as superseded by PMID:25092655 (UniProt CAUTION documents both views).
Supporting Evidence:
PMID:15537790
Using recombinantly generated EDEM2, no alpha-1,2 mannosidase activity was observed

Core Functions

Catalyzes the initiating mannose-trimming step of mammalian glycoprotein ERAD, converting Man9GlcNAc2 to Man8GlcNAc2 isomer B (requiring the EF-hand glutamate E117), thereby committing misfolded glycoproteins to the gpERAD pathway upstream of EDEM1/EDEM3.

Molecular Function:
mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
Directly Involved In:
endoplasmic reticulum mannose trimming ERAD pathway
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • PMID:25092655
    EDEM2, a novel-type Htm1 homologue that catalyzes the first mannose trimming step from Man9GlcNAc2
  • PMID:25092655
    the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
  • PMID:32065582

Recognizes and binds misfolded glycoproteins in the ER lumen and accelerates their ER-associated degradation, including promoting their retrotranslocation from the ER to the cytosol.

Molecular Function:
mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
Directly Involved In:
ubiquitin-dependent glycoprotein ERAD pathway
Cellular Locations:
endoplasmic reticulum lumen
Supporting Evidence:
  • PMID:15537790
    Overexpression of EDEM2 accelerates the degradation of misfolded alpha1-antitrypsin, indicating that the protein is involved in ERAD

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:15537790
Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins.
  • Recombinant EDEM2 showed no alpha-1,2-mannosidase activity, localized to the ER, associated with misfolded alpha-1-antitrypsin, and its overexpression accelerated ERAD of misfolded alpha-1-antitrypsin.
PMID:24200403
The role of EDEM2 compared with EDEM1 in ricin transport from the endoplasmic reticulum to the cytosol.
  • EDEM2 promotes ER-to-cytosol retrotranslocation of the ricin A chain irrespective of translocon accessibility, and binds ricin more efficiently than EDEM1.
PMID:25092655
EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step.
  • Endogenous EDEM2 catalyzes the first mannose-trimming step Man9 to Man8B; EDEM2 is a novel-type Htm1 homologue, resolving the controversy over its catalytic activity.
  • The catalytically inactivating E117Q mutant failed to restore gpERAD of ATF6alpha in EDEM2-KO cells, tying EDEM2's mannosidase activity to ERAD; SEL1L binds EDEM1 and EDEM3 but not EDEM2.
PMID:32065582
EDEM2 stably disulfide-bonded to TXNDC11 catalyzes the first mannose trimming step in mammalian glycoprotein ERAD.
  • EDEM2 is stably disulfide-bonded to the thioredoxin-domain protein TXNDC11 (EDEM2 Cys558 to TXNDC11 Cys692 in the Trx5 CXXC motif); this covalent bond is essential for mannose trimming and gpERAD, and the purified EDEM2-TXNDC11 complex converts Man9GlcNAc2 to Man8GlcNAc2 isomer B in vitro - the first clear demonstration of in vitro mannosidase activity for an EDEM-family protein.
PMID:30374462
Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates.
  • Immunoprecipitated EDEM2 has bona fide alpha-mannosidase activity that is modest on free glycans and native glycoproteins but markedly higher on denatured/unfolded glycoproteins, providing a mechanism for preferential trimming of misfolded ERAD clients; oxidoreductases including TXNDC11 and PDI associate with EDEM2.
PMID:39654396
UGGT1-mediated reglucosylation of N-glycan competes with ER-associated degradation of unstable and misfolded glycoproteins.
  • Glycoprotein fate in the ER reflects a tug-of-war between UGGT1-mediated reglucosylation (favoring calnexin/calreticulin folding cycles) and EDEM-mediated mannose trimming (committing substrates to gpERAD); EDEM2 provides the initiating Man9-to-Man8B step upstream of EDEM1/EDEM3 and OS-9/XTP3-B delivery to SEL1L-HRD1.
Reactome:R-HSA-901024
MAN1B1 hydrolyses 1,2-linked mannose (a branch)
Reactome:R-HSA-901032
ER Quality Control Compartment (ERQC)
Reactome:R-HSA-901036
MAN1B1 hydrolyses a second 1,2-linked mannose (a branch)
Reactome:R-HSA-901039
MAN1B1 hydrolyses 1,2-linked mannose (c branch)
Reactome:R-HSA-901074
MAN1B1,EDEM2 hydrolyse 1,2-linked mannose (b branch)
Reactome:R-HSA-9694548
Maturation of spike protein
Reactome:R-HSA-9696807
N-glycan mannose trimming of Spike
file:human/EDEM2/EDEM2-uniprot.txt
UniProt entry Q9BV94 (EDEM2_HUMAN), ER degradation-enhancing alpha-mannosidase-like protein 2
  • Soluble ER lumenal GH47 protein involved in N-glycan-dependent gpERAD; initiates ERAD by trimming Man9GlcNAc2 to Man8GlcNAc2 (E117-dependent); catalytic activity historically controversial; UPR-induced.

Suggested Questions for Experts

Q: How does the disulfide-linked partnership with TXNDC11 regulate EDEM2's first-step mannosidase activity and substrate selection in vivo?

Q: Why is the Man9-to-Man8B step inefficient in mammalian cells (M9 and M8B coexist) compared with the highly efficient yeast Mns1 step, and what sets this rate-limiting behavior?

Suggested Experiments

Experiment: Reconstitute purified EDEM2 (wild-type and E117Q) with and without TXNDC11 on defined Man9GlcNAc2 glycoprotein substrates to quantify the first-step trimming activity and the contribution of the disulfide complex.

Experiment: Endogenous knock-in of catalytic and substrate-binding EDEM2 mutants followed by glycomics and substrate-degradation assays to separate EDEM2's mannosidase activity from its misfolded-glycoprotein recognition during gpERAD commitment.

Deep Research

Falcon

(EDEM2-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 20 citations 2 artifacts 2026-06-12T03:39:45.591427
Edison artifact artifact-00 (text/markdown)
Edison artifact artifact-01 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human EDEM2 (UniProt Q9BV94) Functional Annotation

0) Target verification (mandatory)

The retrieved primary and review literature consistently uses EDEM2 to refer to endoplasmic reticulum (ER) degradation-enhancing alpha-mannosidase-like protein 2 in Homo sapiens, functioning in N-glycan–dependent ER quality control and ER-associated degradation (ERAD), and requiring TXNDC11 for full functionβ€”matching the UniProt Q9BV94 description (george2020edem2stablydisulfidebonded pages 1-2, george2020edem2stablydisulfidebonded pages 2-4).

1) Key concepts and definitions (current understanding)

1.1 ER quality control (ERQC) and ER-associated degradation (ERAD)

Secretory-pathway proteins acquire N-linked glycans in the ER and undergo folding with help from lectin chaperones (calnexin/calreticulin). Proteins that fail to fold productively are routed to ERAD, in which they are recognized in the ER lumen, retrotranslocated, ubiquitinated, and degraded by the proteasome (sΕ‚ominskawojewodzka2015theroleof pages 1-4).

1.2 Mannose trimming as a degradation β€œtimer” and signal

A widely cited model is that progressive demannosylation of oligomannose N-glycans generates β€œdegradation-competent” glycoforms. Demannosylation can (i) promote exit from calnexin/calreticulin cycling and (ii) generate glycan structures that are recognized by ERAD lectins (e.g., OS9/XTP3B) that deliver substrates to the SEL1L–HRD1 ERAD machinery (sΕ‚ominskawojewodzka2015theroleof pages 10-12, adams2019proteinqualitycontrol pages 6-7).

1.3 EDEM proteins

EDEM1/2/3 are GH47 (class I) Ξ±-mannosidase-like proteins (homologous to the yeast ERAD mannosidase Htm1/Mnl1) that participate in ERAD substrate selection and demannosylation. Reviews emphasize that EDEMs contribute both via glycan-dependent recognition/processing and glycan-independent (chaperone-like) interactions with misfolded regions (sΕ‚ominskawojewodzka2015theroleof pages 16-19, sΕ‚ominskawojewodzka2015theroleof pages 10-12, adams2019proteinqualitycontrol pages 6-7).

2) Core molecular function of EDEM2 (biochemical activity and substrate specificity)

2.1 Reaction catalyzed and glycan branch specificity

A key mechanistic study in human cells established that EDEM2 is required for the first mannose-trimming step in mammalian glycoprotein ERAD: Man9GlcNAc2 (M9) β†’ Man8GlcNAc2 (M8B isomer) (george2020edem2stablydisulfidebonded pages 1-2, george2020edem2stablydisulfidebonded pages 4-5, george2020edem2stablydisulfidebonded pages 2-4). This is presented as removal of the outermost mannose on the B-branch, producing M8B as the product glycoform that enters subsequent trimming steps (george2020edem2stablydisulfidebonded pages 2-4).

2.2 Preference for misfolded/unfolded glycoprotein substrates

In vitro work measuring EDEM activities reported that EDEM2 has modest mannosidase activity on free glycans and native glycoproteins, but substantially higher activity on denatured/unfolded glycoproteins, consistent with preferential action on ERAD clients rather than properly folded secretory proteins (shenkman2018mannosidaseactivityof pages 4-5, shenkman2018mannosidaseactivityof pages 4-4).

2.3 Requirement for oxidoreductase partners to enable activity

A central resolution to earlier β€œno activity” results is that EDEM2 requires an ER oxidoreductase partner. In human HCT116 cells, EDEM2 forms a stable disulfide-bonded complex with TXNDC11, and this covalent partnership is essential for mannose trimming and downstream ERAD (george2020edem2stablydisulfidebonded pages 9-10, george2020edem2stablydisulfidebonded pages 1-2, george2020edem2stablydisulfidebonded pages 4-5).

3) Localization and topology (where EDEM2 acts)

EDEM2 is described as an ER-resident factor functioning in the ER lumenal quality-control environment, where it participates in the earliest demannosylation step that commits glycoproteins to ERAD (murase2023regulationofthe pages 1-2, george2020edem2stablydisulfidebonded pages 2-4). Consistent with its role, reviews place EDEM proteins upstream of lectin-mediated delivery to SEL1L–HRD1 and downstream retrotranslocation (sΕ‚ominskawojewodzka2015theroleof pages 10-12, adams2019proteinqualitycontrol pages 6-7).

4) Pathway placement and interacting partners

4.1 TXNDC11 is a required functional partner (disulfide-linked complex)

George et al. showed EDEM2 is stably disulfide-bonded to TXNDC11, specifically EDEM2 Cys558 linked to TXNDC11 Cys692 (in TXNDC11’s Trx5 domain). Disrupting this bond (EDEM2 C558A or TXNDC11 C692S) prevents mannose trimming and impairs ERAD in cells (george2020edem2stablydisulfidebonded pages 9-10, george2020edem2stablydisulfidebonded pages 1-2, george2020edem2stablydisulfidebonded pages 4-5). The purified EDEM2–TXNDC11 complex displayed in vitro activity converting M9 to M8B, directly supporting enzymatic function of the complex (george2020edem2stablydisulfidebonded pages 1-2, george2020edem2stablydisulfidebonded pages 4-5).

4.2 Association with PDI-family oxidoreductases

EDEM2 was also reported to associate with PDI, and oxidoreductases (including TXNDC11 and PDI) enhanced EDEM2 activity in vitro in the unfolded-substrate assays (shenkman2018mannosidaseactivityof pages 4-5, george2020edem2stablydisulfidebonded pages 4-5, shenkman2018mannosidaseactivityof pages 4-4). Reviews place mammalian EDEM proteins within a broader paradigm of mannosidase–PDI-like complexes in ERAD initiation (suzuki2021foldingandquality pages 11-12).

4.3 Downstream lectins and ERAD machinery (OS9/XTP3B; SEL1L–HRD1)

Expert reviews describe that mannose trimming by EDEMs ultimately generates glycans exposing an Ξ±1,6-linked mannose recognized by MRH-domain lectins OS9 and XTP3B, which target substrates to the SEL1L–HRD1 dislocation/ubiquitination complex (sΕ‚ominskawojewodzka2015theroleof pages 10-12, adams2019proteinqualitycontrol pages 6-7). In updated pathway framing, EDEM2 provides the initiating M9β†’M8B step before further trimming by EDEM3/EDEM1, leading to OS9/XTP3B recruitment and delivery to SEL1L–HRD1 (ninagawa2024uggt1mediatedreglucosylationof pages 5-9).

5) Recent developments (prioritizing 2023–2024)

5.1 2023: Endogenous regulation of EDEM2 in HEK293 cells

Murase et al. (Jan 2023; BPB Reports; https://doi.org/10.1248/bpbreports.6.6_193) reported that ER stress increased EDEM2 mRNA in HEK293 cells, consistent with linkage to the IRE1–sXBP1 arm of the UPR, but EDEM2 protein abundance was strongly shaped by post-transcriptional mechanisms (murase2023regulationofthe pages 1-2). TXNDC11 deficiency decreased EDEM2 protein, consistent with TXNDC11 supporting EDEM2 stability/function (murase2023regulationofthe pages 1-2). They also provide evidence that EDEM2 itself is at least partly subject to SEL1L-mediated ERAD, since DTT-driven loss of EDEM2 was partly rescued by MG132 or SEL1L deficiency (murase2023regulationofthe pages 1-2).

5.2 2024: β€œTug-of-war” modelβ€”UGGT1 reglucosylation competes with EDEM-driven ERAD commitment

Ninagawa et al. (Sep 2024; eLife; https://doi.org/10.1101/2023.10.18.562958) provides a modern model of ERQC decision-making: UGGT1-mediated reglucosylation supports continued calnexin/calreticulin folding cycles, while EDEM-mediated mannose trimming commits substrates to gpERAD (ninagawa2024uggt1mediatedreglucosylationof pages 5-9, ninagawa2024uggt1mediatedreglucosylationof pages 1-5). Their gene-disruption experiments show that UGGT1 loss accelerates degradation of unstable/misfolded glycoproteins (e.g., ATF6Ξ±, NHK), and that this accelerated degradation depends on the mannose-trimming ERAD route (blocked in SEL1L-KO and EDEM-family knockout backgrounds, and stabilized by the mannosidase inhibitor kifunensine) (ninagawa2024uggt1mediatedreglucosylationof pages 5-9, ninagawa2024uggt1mediatedreglucosylationof pages 9-12).

6) Current applications and real-world implementations

6.1 Chemical and experimental modulation of the EDEM2 pathway

Class I Ξ±-mannosidase inhibitors are used to experimentally suppress mannose trimming and thereby alter ERAD commitment. In the 2024 pathway study, kifunensine stabilized an ERAD substrate (ATF6Ξ±) under conditions that otherwise accelerate degradation, supporting its use as a functional probe of the EDEM-dependent mannose trimming route (ninagawa2024uggt1mediatedreglucosylationof pages 5-9).

6.2 Translational/clinical-bioinformatics applications: EDEM2 as a biomarker candidate

Wu et al. (Jan 2023; Frontiers in Oncology; https://doi.org/10.3389/fonc.2022.1054012) reported EDEM2 overexpression in glioma datasets and validated expression by qPCR/IHC; EDEM2 knockdown reduced glioma cell migration/invasion in vitro (wu2023edem2isa pages 9-11). They also reported biomarker-like statistics: a prognostic nomogram including EDEM2 had C-index = 0.847, and EDEM2 expression predicted immunotherapy response with ROC AUC = 0.857 and 0.839 in two datasets; additional ROC AUCs included 0.988 for pathological grade and 0.673 for IDH status (wu2023edem2isa pages 9-11). EDEM2 expression correlated with tumor mutation burden (r = 0.473, p < 0.001) (wu2023edem2isa pages 9-11).

7) Expert synthesis: consensus, competing models, and open questions

7.1 Consensus model for EDEM2’s role

Across primary and review sources, the convergent model is: EDEM2 (with TXNDC11) performs the initial demannosylation step (M9β†’M8B), which enables subsequent EDEM-mediated processing and creation of glycan signals recognized by OS9/XTP3B for delivery to SEL1L–HRD1 ERAD (george2020edem2stablydisulfidebonded pages 1-2, ninagawa2024uggt1mediatedreglucosylationof pages 5-9, suzuki2021foldingandquality pages 11-12, sΕ‚ominskawojewodzka2015theroleof pages 10-12, adams2019proteinqualitycontrol pages 6-7).

7.2 Open mechanistic questions

Reviews emphasize that EDEMs can contribute via both enzymatic trimming and chaperone-like substrate binding (including glycan-independent binding to hydrophobic regions), and discuss alternative models in which EDEMs primarily (i) trigger demannosylation based on hydrophobic exposure, (ii) recognize misfolded proteins independently of trimming, or (iii) serve as delivery factors to the retrotranslocon (sΕ‚ominskawojewodzka2015theroleof pages 16-19, sΕ‚ominskawojewodzka2015theroleof pages 10-12). Recent regulation work also highlights incomplete understanding of how ER redox conditions and reducing agents affect the stability and association of EDEM2–TXNDC11 and unbound EDEM2 in vivo (murase2023regulationofthe pages 7-7).

8) Summary tables (evidence at a glance)

Source Year Journal Experimental system / assays Enzymatic reaction Substrate specificity / preferences Required binding partners Main mechanistic conclusion URL Evidence
George et al. 2020 eLife Human HCT116 cells; EDEM2 knockout/rescue; cycloheximide chase; co-immunoprecipitation; non-reducing SDS-PAGE; purified complex in vitro glycan-trimming assays Converts Man9GlcNAc2 (M9) to Man8GlcNAc2 isomer B (M8B), the first demannosylation step in mammalian glycoprotein ERAD B-branch-specific removal of the outermost Ξ±1,2-linked mannose from M9; acts on ERAD glycoprotein substrates TXNDC11 required via stable intermolecular disulfide bond (EDEM2 C558–TXNDC11 C692); PDI associates with EDEM2 but TXNDC11 is essential for full activity Established human EDEM2 as the initiator mannosidase of gpERAD; EDEM2 alone is insufficient, but the EDEM2–TXNDC11 complex is catalytically active in vitro and required in cells for substrate trimming and degradation https://doi.org/10.7554/elife.53455 (george2020edem2stablydisulfidebonded pages 1-2, george2020edem2stablydisulfidebonded pages 4-5, george2020edem2stablydisulfidebonded pages 2-4)
Shenkman et al. 2018 Communications Biology Human cell-derived immunoprecipitated EDEM2; in vitro glycan trimming; HPLC analysis of free glycans, native glycoproteins, and denatured glycoproteins; co-IP Demonstrated bona fide Ξ±-mannosidase activity of EDEM2 on glycoprotein N-glycans; trimming observed from higher-mannose forms toward M7–M5 in vitro Activity is modest on free oligosaccharides and native glycoproteins but markedly enhanced on denatured/unfolded glycoproteins; supports preference for misfolded ERAD clients TXNDC11 and PDI interact with EDEM2; oxidoreductases enhance activity on glycoproteins EDEM2 is a functional ERAD mannosidase whose activity is folding-state sensitive, providing a mechanism for preferential targeting of unfolded/misfolded glycoproteins https://doi.org/10.1038/s42003-018-0174-8 (shenkman2018mannosidaseactivityof pages 4-5, shenkman2018mannosidaseactivityof pages 4-4)
Murase et al. 2023 BPB Reports HEK293 cells; ER stress induction (thapsigargin, tunicamycin, brefeldin A); MG132, DTT, cycloheximide; SEL1L- and TXNDC11-deficient cells; immunoblotting/qPCR Supports EDEM2 as the earliest ER-resident ERAD mannosidase in the pathway rather than redefining the catalytic chemistry Substrates are misfolded N-glycosylated ER proteins entering SEL1L-HRD1-dependent ERAD TXNDC11 stabilizes EDEM2 and supports its activity; EDEM2 also physically/functionally links to SEL1L-mediated ERAD Recent evidence indicates EDEM2 is post-transcriptionally regulated, depends on TXNDC11 for protein stability, and is itself at least partly turned over by SEL1L-mediated ERAD https://doi.org/10.1248/bpbreports.6.6_193 (murase2023regulationofthe pages 1-2, murase2023regulationofthe pages 2-4)
Ninagawa et al. 2024 eLife Gene-disrupted cells for UGGT1/2, SEL1L, and EDEM family components; degradation assays of ATF6Ξ±, NHK, and other ERAD substrates; inhibitor studies (kifunensine, DNJ) Places EDEM2 at the first mannose-trimming step (M9β†’M8B) within the broader sequential ERAD pathway that competes with UGGT1-mediated reglucosylation EDEM-dependent pathway acts on unstable/misfolded glycoproteins destined for OS9/XTP3B recognition and HRD1-SEL1L delivery EDEM2 functions as part of the EDEM2–TXNDC11 initiating step; downstream EDEM1/3 perform further trimming Current pathway model: glycoprotein fate is a tug-of-war between UGGT1-mediated refolding cycles and EDEM-driven mannose trimming; EDEM2 is the entry-point enzyme for degradation-directed trimming https://doi.org/10.1101/2023.10.18.562958 (ninagawa2024uggt1mediatedreglucosylationof pages 5-9, ninagawa2024uggt1mediatedreglucosylationof pages 12-16, ninagawa2024uggt1mediatedreglucosylationof pages 9-12, ninagawa2024uggt1mediatedreglucosylationof pages 1-5)

Table: This table summarizes primary mechanistic evidence for human EDEM2, including its catalytic reaction, substrate preferences, dependence on TXNDC11 and association with PDI, and the experimental systems used to define its role in glycoprotein ERAD. It is useful for functional annotation because it distinguishes direct biochemical evidence from broader pathway and regulatory studies.

Paper Publication date Topic Key findings Key quantitative results URL Citation
Murase et al., Regulation of the ER-Resident Mannosidase EDEM2 in HEK293 Cells Jan 2023 Regulation EDEM2 is an ER-resident initiator mannosidase whose expression is modestly induced by ER stress but regulated strongly post-transcriptionally; TXNDC11 supports EDEM2 stability, and EDEM2 is at least partly turned over by SEL1L-mediated ERAD EDEM2 mRNA decreased ~30% after 6 h MG132/CMA/CHX; EDEM2 protein decreased ~50% after 24 h CHX; TXNDC11 deficiency reduced EDEM2 protein; DTT-induced loss was partly rescued by MG132 or SEL1L deficiency https://doi.org/10.1248/bpbreports.6.6_193 (murase2023regulationofthe pages 2-4, murase2023regulationofthe pages 1-2)
Wu et al., EDEM2 is a diagnostic and prognostic biomarker and associated with immune infiltration in glioma: A comprehensive analysis Jan 2023 Disease biomarker EDEM2 is overexpressed in glioma, associated with poor prognosis, immune infiltration, and greater invasiveness; knockdown reduced U251 migration/invasion; high EDEM2 associated with ICI response and higher TMB Nomogram C-index = 0.847; ICI-response AUCs = 0.857 and 0.839; diagnostic AUC = 0.988 for pathological grade and 0.673 for IDH status; TMB correlation r = 0.473, p < 0.001; mutation frequency 0.4% in LGG and 0.7% in GBM https://doi.org/10.3389/fonc.2022.1054012 (wu2023edem2isa pages 1-2, wu2023edem2isa pages 9-11)
Ninagawa et al., UGGT1-mediated reglucosylation of N-glycan competes with ER-associated degradation of unstable and misfolded glycoproteins Sep 2024 Mechanism / pathway update Updated ERQC model in which UGGT1-driven reglucosylation competes with EDEM-mediated mannose trimming; EDEM2 is the initiating M9β†’M8B step, upstream of EDEM3/EDEM1 and OS9/XTP3B delivery to SEL1L-HRD1 UGGT1-KO and UGGT-DKO accelerated degradation of ATF6Ξ± and NHK; UGGT2-KO had little effect; degradation was blocked in SEL1L-KO and EDEM-TKO cells; kifunensine stabilized ATF6Ξ± in UGGT-DKO; no EDEM2-specific numeric AUC/correlation metrics reported https://doi.org/10.1101/2023.10.18.562958 (ninagawa2024uggt1mediatedreglucosylationof pages 5-9, ninagawa2024uggt1mediatedreglucosylationof pages 12-16, ninagawa2024uggt1mediatedreglucosylationof pages 9-12, ninagawa2024uggt1mediatedreglucosylationof pages 1-5)

Table: This table lists the 2023-2024 EDEM2-related papers identified in the current evidence set, organized by topic and publication date. It highlights the most useful quantitative results and pathway-level takeaways for mechanism, regulation, and biomarker interpretation.

9) Key takeaways for functional annotation

  • Primary molecular function: EDEM2 is an ER-resident GH47 Ξ±-mannosidase-like enzyme that, when complexed with TXNDC11, catalyzes the first N-glycan mannose trimming step in gpERAD: Man9GlcNAc2 β†’ Man8GlcNAc2 (isomer B) (george2020edem2stablydisulfidebonded pages 1-2, george2020edem2stablydisulfidebonded pages 4-5).
  • Substrate preference: EDEM2 activity is higher on unfolded/denatured glycoprotein substrates, consistent with preferential processing of misfolded ER clients (shenkman2018mannosidaseactivityof pages 4-5, shenkman2018mannosidaseactivityof pages 4-4).
  • Cellular compartment: ER (ERQC/ERAD pathway) (murase2023regulationofthe pages 1-2, george2020edem2stablydisulfidebonded pages 2-4).
  • Core partners: TXNDC11 (obligate disulfide-linked partner for activity), and association with PDI-family oxidoreductases (george2020edem2stablydisulfidebonded pages 9-10, shenkman2018mannosidaseactivityof pages 4-5, george2020edem2stablydisulfidebonded pages 4-5).
  • Pathway context: Mannose trimming by EDEM2/EDEMs enables recognition by OS9/XTP3B and delivery to SEL1L–HRD1, balanced against UGGT1-driven reglucosylation that favors folding (ninagawa2024uggt1mediatedreglucosylationof pages 5-9, sΕ‚ominskawojewodzka2015theroleof pages 10-12, adams2019proteinqualitycontrol pages 6-7).

References

  1. (george2020edem2stablydisulfidebonded pages 1-2): Ginto George, Satoshi Ninagawa, Hirokazu Yagi, Taiki Saito, Tokiro Ishikawa, Tetsushi Sakuma, Takashi Yamamoto, Koshi Imami, Yasushi Ishihama, Koichi Kato, Tetsuya Okada, and Kazutoshi Mori. Edem2 stably disulfide-bonded to txndc11 catalyzes the first mannose trimming step in mammalian glycoprotein erad. eLife, Feb 2020. URL: https://doi.org/10.7554/elife.53455, doi:10.7554/elife.53455. This article has 58 citations and is from a domain leading peer-reviewed journal.

  2. (george2020edem2stablydisulfidebonded pages 2-4): Ginto George, Satoshi Ninagawa, Hirokazu Yagi, Taiki Saito, Tokiro Ishikawa, Tetsushi Sakuma, Takashi Yamamoto, Koshi Imami, Yasushi Ishihama, Koichi Kato, Tetsuya Okada, and Kazutoshi Mori. Edem2 stably disulfide-bonded to txndc11 catalyzes the first mannose trimming step in mammalian glycoprotein erad. eLife, Feb 2020. URL: https://doi.org/10.7554/elife.53455, doi:10.7554/elife.53455. This article has 58 citations and is from a domain leading peer-reviewed journal.

  3. (sΕ‚ominskawojewodzka2015theroleof pages 1-4): Monika SΕ‚omiΕ„ska-WojewΓ³dzka and Kirsten Sandvig. The role of lectin-carbohydrate interactions in the regulation of er-associated protein degradation. Molecules, 20:9816-9846, May 2015. URL: https://doi.org/10.3390/molecules20069816, doi:10.3390/molecules20069816. This article has 63 citations.

  4. (sΕ‚ominskawojewodzka2015theroleof pages 10-12): Monika SΕ‚omiΕ„ska-WojewΓ³dzka and Kirsten Sandvig. The role of lectin-carbohydrate interactions in the regulation of er-associated protein degradation. Molecules, 20:9816-9846, May 2015. URL: https://doi.org/10.3390/molecules20069816, doi:10.3390/molecules20069816. This article has 63 citations.

  5. (adams2019proteinqualitycontrol pages 6-7): Benjamin M. Adams, Michela E. Oster, and Daniel N. Hebert. Protein quality control in the endoplasmic reticulum. The Protein Journal, 38:317-329, Apr 2019. URL: https://doi.org/10.1007/s10930-019-09831-w, doi:10.1007/s10930-019-09831-w. This article has 147 citations.

  6. (sΕ‚ominskawojewodzka2015theroleof pages 16-19): Monika SΕ‚omiΕ„ska-WojewΓ³dzka and Kirsten Sandvig. The role of lectin-carbohydrate interactions in the regulation of er-associated protein degradation. Molecules, 20:9816-9846, May 2015. URL: https://doi.org/10.3390/molecules20069816, doi:10.3390/molecules20069816. This article has 63 citations.

  7. (george2020edem2stablydisulfidebonded pages 4-5): Ginto George, Satoshi Ninagawa, Hirokazu Yagi, Taiki Saito, Tokiro Ishikawa, Tetsushi Sakuma, Takashi Yamamoto, Koshi Imami, Yasushi Ishihama, Koichi Kato, Tetsuya Okada, and Kazutoshi Mori. Edem2 stably disulfide-bonded to txndc11 catalyzes the first mannose trimming step in mammalian glycoprotein erad. eLife, Feb 2020. URL: https://doi.org/10.7554/elife.53455, doi:10.7554/elife.53455. This article has 58 citations and is from a domain leading peer-reviewed journal.

  8. (shenkman2018mannosidaseactivityof pages 4-5): Marina Shenkman, Efrat Ron, Rivka Yehuda, Ron Benyair, Isam Khalaila, and Gerardo Z. Lederkremer. Mannosidase activity of edem1 and edem2 depends on an unfolded state of their glycoprotein substrates. Communications Biology, Oct 2018. URL: https://doi.org/10.1038/s42003-018-0174-8, doi:10.1038/s42003-018-0174-8. This article has 71 citations and is from a peer-reviewed journal.

  9. (shenkman2018mannosidaseactivityof pages 4-4): Marina Shenkman, Efrat Ron, Rivka Yehuda, Ron Benyair, Isam Khalaila, and Gerardo Z. Lederkremer. Mannosidase activity of edem1 and edem2 depends on an unfolded state of their glycoprotein substrates. Communications Biology, Oct 2018. URL: https://doi.org/10.1038/s42003-018-0174-8, doi:10.1038/s42003-018-0174-8. This article has 71 citations and is from a peer-reviewed journal.

  10. (george2020edem2stablydisulfidebonded pages 9-10): Ginto George, Satoshi Ninagawa, Hirokazu Yagi, Taiki Saito, Tokiro Ishikawa, Tetsushi Sakuma, Takashi Yamamoto, Koshi Imami, Yasushi Ishihama, Koichi Kato, Tetsuya Okada, and Kazutoshi Mori. Edem2 stably disulfide-bonded to txndc11 catalyzes the first mannose trimming step in mammalian glycoprotein erad. eLife, Feb 2020. URL: https://doi.org/10.7554/elife.53455, doi:10.7554/elife.53455. This article has 58 citations and is from a domain leading peer-reviewed journal.

  11. (murase2023regulationofthe pages 1-2): Ryoichi Murase, Genki Kato, and Kentaro Oh-hashi. Regulation of the er-resident mannosidase edem2 in hek293 cells. BPB Reports, 6:193-199, Jan 2023. URL: https://doi.org/10.1248/bpbreports.6.6_193, doi:10.1248/bpbreports.6.6_193. This article has 3 citations.

  12. (suzuki2021foldingandquality pages 11-12): Tadashi Suzuki and Haruhiko Fujihira. Folding and quality control of glycoproteins. Comprehensive Glycoscience, pages 1-28, Dec 2021. URL: https://doi.org/10.1016/b978-0-12-409547-2.14947-9, doi:10.1016/b978-0-12-409547-2.14947-9. This article has 12 citations.

  13. (ninagawa2024uggt1mediatedreglucosylationof pages 5-9): Satoshi Ninagawa, Masaki Matsuo, Deng Ying, Shuichiro Oshita, Shinya Aso, Kazutoshi Matsushita, Mai Taniguchi, Akane Fueki, Moe Yamashiro, Kaoru Sugasawa, Shunsuke Saito, Koshi Imami, Yasuhiko Kizuka, Tetsushi Sakuma, Takashi Yamamoto, Hirokazu Yagi, Koichi Kato, and Kazutoshi Mori. Uggt1-mediated reglucosylation of n-glycan competes with er-associated degradation of unstable and misfolded glycoproteins. eLife, Sep 2024. URL: https://doi.org/10.1101/2023.10.18.562958, doi:10.1101/2023.10.18.562958. This article has 7 citations and is from a domain leading peer-reviewed journal.

  14. (ninagawa2024uggt1mediatedreglucosylationof pages 1-5): Satoshi Ninagawa, Masaki Matsuo, Deng Ying, Shuichiro Oshita, Shinya Aso, Kazutoshi Matsushita, Mai Taniguchi, Akane Fueki, Moe Yamashiro, Kaoru Sugasawa, Shunsuke Saito, Koshi Imami, Yasuhiko Kizuka, Tetsushi Sakuma, Takashi Yamamoto, Hirokazu Yagi, Koichi Kato, and Kazutoshi Mori. Uggt1-mediated reglucosylation of n-glycan competes with er-associated degradation of unstable and misfolded glycoproteins. eLife, Sep 2024. URL: https://doi.org/10.1101/2023.10.18.562958, doi:10.1101/2023.10.18.562958. This article has 7 citations and is from a domain leading peer-reviewed journal.

  15. (ninagawa2024uggt1mediatedreglucosylationof pages 9-12): Satoshi Ninagawa, Masaki Matsuo, Deng Ying, Shuichiro Oshita, Shinya Aso, Kazutoshi Matsushita, Mai Taniguchi, Akane Fueki, Moe Yamashiro, Kaoru Sugasawa, Shunsuke Saito, Koshi Imami, Yasuhiko Kizuka, Tetsushi Sakuma, Takashi Yamamoto, Hirokazu Yagi, Koichi Kato, and Kazutoshi Mori. Uggt1-mediated reglucosylation of n-glycan competes with er-associated degradation of unstable and misfolded glycoproteins. eLife, Sep 2024. URL: https://doi.org/10.1101/2023.10.18.562958, doi:10.1101/2023.10.18.562958. This article has 7 citations and is from a domain leading peer-reviewed journal.

  16. (wu2023edem2isa pages 9-11): Yuxi Wu, Haofei Wang, Wei Xiang, and Dongye Yi. Edem2 is a diagnostic and prognostic biomarker and associated with immune infiltration in glioma: a comprehensive analysis. Frontiers in Oncology, Jan 2023. URL: https://doi.org/10.3389/fonc.2022.1054012, doi:10.3389/fonc.2022.1054012. This article has 8 citations.

  17. (murase2023regulationofthe pages 7-7): Ryoichi Murase, Genki Kato, and Kentaro Oh-hashi. Regulation of the er-resident mannosidase edem2 in hek293 cells. BPB Reports, 6:193-199, Jan 2023. URL: https://doi.org/10.1248/bpbreports.6.6_193, doi:10.1248/bpbreports.6.6_193. This article has 3 citations.

  18. (murase2023regulationofthe pages 2-4): Ryoichi Murase, Genki Kato, and Kentaro Oh-hashi. Regulation of the er-resident mannosidase edem2 in hek293 cells. BPB Reports, 6:193-199, Jan 2023. URL: https://doi.org/10.1248/bpbreports.6.6_193, doi:10.1248/bpbreports.6.6_193. This article has 3 citations.

  19. (ninagawa2024uggt1mediatedreglucosylationof pages 12-16): Satoshi Ninagawa, Masaki Matsuo, Deng Ying, Shuichiro Oshita, Shinya Aso, Kazutoshi Matsushita, Mai Taniguchi, Akane Fueki, Moe Yamashiro, Kaoru Sugasawa, Shunsuke Saito, Koshi Imami, Yasuhiko Kizuka, Tetsushi Sakuma, Takashi Yamamoto, Hirokazu Yagi, Koichi Kato, and Kazutoshi Mori. Uggt1-mediated reglucosylation of n-glycan competes with er-associated degradation of unstable and misfolded glycoproteins. eLife, Sep 2024. URL: https://doi.org/10.1101/2023.10.18.562958, doi:10.1101/2023.10.18.562958. This article has 7 citations and is from a domain leading peer-reviewed journal.

  20. (wu2023edem2isa pages 1-2): Yuxi Wu, Haofei Wang, Wei Xiang, and Dongye Yi. Edem2 is a diagnostic and prognostic biomarker and associated with immune infiltration in glioma: a comprehensive analysis. Frontiers in Oncology, Jan 2023. URL: https://doi.org/10.3389/fonc.2022.1054012, doi:10.3389/fonc.2022.1054012. This article has 8 citations.

Artifacts

Citations

  1. suzuki2021foldingandquality pages 11-12
  2. murase2023regulationofthe pages 1-2
  3. murase2023regulationofthe pages 7-7
  4. adams2019proteinqualitycontrol pages 6-7
  5. shenkman2018mannosidaseactivityof pages 4-5
  6. shenkman2018mannosidaseactivityof pages 4-4
  7. murase2023regulationofthe pages 2-4
  8. https://doi.org/10.1248/bpbreports.6.6_193
  9. https://doi.org/10.1101/2023.10.18.562958
  10. https://doi.org/10.3389/fonc.2022.1054012
  11. https://doi.org/10.7554/elife.53455
  12. https://doi.org/10.1038/s42003-018-0174-8
  13. https://doi.org/10.7554/elife.53455,
  14. https://doi.org/10.3390/molecules20069816,
  15. https://doi.org/10.1007/s10930-019-09831-w,
  16. https://doi.org/10.1038/s42003-018-0174-8,
  17. https://doi.org/10.1248/bpbreports.6.6_193,
  18. https://doi.org/10.1016/b978-0-12-409547-2.14947-9,
  19. https://doi.org/10.1101/2023.10.18.562958,
  20. https://doi.org/10.3389/fonc.2022.1054012,

πŸ“š Additional Documentation

Notes

(EDEM2-notes.md)

EDEM2 (Q9BV94) review notes

Identity

  • ER degradation-enhancing alpha-mannosidase-like protein 2 (C20orf31/C20orf49). 578 aa precursor; signal peptide 1-21; soluble ER lumenal protein (NOT a type II membrane protein, unlike EDEM1). GH47 family (Pfam PF01532; InterPro IPR044674 EDEM1/2/3). N-glycosylated.

Function (synthesis)

  • EDEM2 catalyzes the first mannose-trimming step of mammalian gpERAD, converting Man9GlcNAc2 (M9) to Man8GlcNAc2 isomer B (M8B). This was the surprising, defining finding from endogenous knockout analysis [PMID:25092655 "the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2, which was previously considered to lack enzymatic activity"; "EDEM2, a novel-type Htm1 homologue that catalyzes the first mannose trimming step from Man9GlcNAc2"].
  • The mannosidase activity requires the EF-hand glutamate E117; the E117Q mutant fails to rescue gpERAD [UniProt MUTAGEN 117 "E->Q: Loss of ERAD activity" ECO PubMed:25092655]; ["stable introduction of Flag-tagged hEDEM2, but not Flag-tagged hEDEM2-E117Q, into hEDEM2-KO cells restored degradation of endogenous hATF6"].
  • Catalytic activity historically controversial: the original characterization found NO mannosidase activity for recombinant EDEM2 PMID:15537790 and proposed a lectin role; the later endogenous-KO study established the activity. UniProt CAUTION records both. This is the source of a NOT GO:0004571 IDA (PMID:15537790) and a positive GO:0004571 IMP (PMID:25092655) β€” a genuine historical tension. Do NOT remove either experimental annotation.
  • EDEM2 is involved in ERAD of misfolded glycoproteins; overexpression accelerates degradation of misfolded alpha-1-antitrypsin (NHK) PMID:15537790; associates with misfolded A1AT PMID:15537790.
  • EDEM2 promotes ER-to-cytosol retrotranslocation (ricin A chain) [PMID:24200403 "EDEM2 is also involved in ricin retrotranslocation out of the ER"; "more ricin can interact with EDEM2 in comparison with EDEM1"]. IGI with EDEM1 (Q92611).
  • Unlike EDEM1/EDEM3, EDEM2 does NOT bind SEL1L PMID:25092655; EDEM2 acts upstream of EDEM1/3.
  • (Gene-set context: EDEM2's mannosidase activity is demonstrated in a disulfide-linked complex with TXNDC11; not directly in cached pubs but consistent with the "novel-type Htm1 homologue" framing.)

Localization

  • ER lumen [PMID:15537790, EXP]. ER (IDA, PMID:24200403 MGI; PMID:15537790). ERQC (TAS Reactome).

Annotation review decisions

  • GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity: IMP (PMID:25092655) ACCEPT β€” CORE (first trimming step). TAS Reactome x5 ACCEPT. The NOT/IDA (PMID:15537790) KEEP_AS_NON_CORE (historical, superseded). Note: GOA TAS Reactome entries are mostly labeled "MAN1B1 hydrolyses..." but cross-annotated to EDEM2 because EDEM2 performs analogous trimming; accept as mannosidase activity.
  • GO:1904380 ER mannose trimming: IMP (PMID:25092655) ACCEPT core; TAS Reactome, IEA ACCEPT.
  • GO:0036503 ERAD pathway: IMP x2 (PMID:15537790, 25092655) ACCEPT core.
  • GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway (IBA): ACCEPT β€” specific and correct (N-glycan-dependent gpERAD).
  • GO:0030968 endoplasmic reticulum unfolded protein response (IBA): EDEM2 is UPR/IRE1-XBP1 induced and acts in ERAD; "involved_in UPR" is defensible but peripheral. KEEP_AS_NON_CORE (the protein is UPR-induced and functions in the ERAD arm; not a UPR signaling component).
  • GO:1904154 positive regulation of retrograde protein transport ER->cytosol (IMP/IGI PMID:24200403; IEA): ACCEPT/KEEP_AS_NON_CORE.
  • GO:0036510 trimming of terminal mannose on C branch (TAS Reactome): a specific trimming sub-step; ACCEPT (KEEP_AS_NON_CORE; specific Reactome substep). Note EDEM2 mainly does Man9->Man8B (B branch); C-branch trimming is borderline but TAS-curated, keep.
  • GO:0019082 viral protein processing (TAS Reactome, SARS-CoV-2 spike): real but peripheral; KEEP_AS_NON_CORE (mannosidase acting on viral substrate).
  • GO:0005509 calcium ion binding (IEA): GH47 cofactor; KEEP_AS_NON_CORE.
  • GO:0005788 ER lumen (IEA, EXP): ACCEPT.
  • GO:0005783 ER (IDA x2): ACCEPT.
  • GO:0044322 ERQC (TAS x5): ACCEPT.
  • GO:0005975 carbohydrate metabolic process / GO:0009100 glycoprotein metabolic process / GO:0016020 membrane (IEA): over-general -> MARK_AS_OVER_ANNOTATED. Note membrane is also arguably WRONG (EDEM2 is luminal/soluble), but InterPro-derived; mark over-annotated (uninformative; EDEM2 is luminal).

Falcon deep-research findings (incorporated 2026-06)

  • George et al. 2020 (eLife) is the central mechanistic paper: EDEM2 is stably disulfide-bonded to TXNDC11 (EDEM2 Cys558 to TXNDC11 Cys692, in TXNDC11 Trx5 CXXC motif), and this covalent bond is essential for the first mannose-trimming step and gpERAD in HCT116 cells PMID:32065582.
  • George 2020 provides the FIRST in vitro demonstration of EDEM-family mannosidase activity: the purified EDEM2-TXNDC11 complex converts Man9GlcNAc2 to Man8GlcNAc2 isomer B, reconciling the earlier "no activity" result for recombinant EDEM2 alone PMID:32065582. This is the disulfide-bonded-partner mechanism the notes previously flagged as "not in cached pubs."
  • Shenkman et al. 2018 (Commun Biol): EDEM2 mannosidase activity is folding-state dependent - modest on free glycans/native glycoproteins but markedly higher on denatured glycoproteins; EDEM2 associates with oxidoreductases including TXNDC11 and PDI, which enhance activity on glycoproteins but not free N-glycans PMID:30374462.
  • Ninagawa et al. 2024 (eLife, doi:10.7554/eLife.93117): glycoprotein fate is a tug-of-war between UGGT1-mediated reglucosylation (folding) and EDEM-mediated mannose trimming (degradation); EDEM2 provides the initiating M9->M8B step upstream of EDEM1/EDEM3 PMID:39654396.
  • Murase et al. 2023 (BPB Reports, doi:10.1248/bpbreports.6.6_193, NOT added as a formal reference - lower priority/3 citations): EDEM2 protein is strongly post-transcriptionally regulated; TXNDC11 deficiency decreases EDEM2 protein (TXNDC11 supports EDEM2 stability), and EDEM2 is itself partly a SEL1L-mediated ERAD substrate.
  • Wu et al. 2023 (Front Oncol) reports EDEM2 as a glioma biomarker (overexpression, prognosis, immune infiltration); not incorporated as it is correlative disease-association data not directly establishing molecular function.
  • References ADDED to review: PMID:32065582 (George 2020, HIGH), PMID:30374462 (Shenkman 2018, MEDIUM), PMID:39654396 (Ninagawa 2024, MEDIUM). PMID:32065582 also added (id only, no supporting_text - uncached) to the first core_function supported_by.

Pn Notes

(EDEM2-pn-notes.md)

EDEM2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9BV94
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-11
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: EDEM2 (ER degradation-enhancing alpha-mannosidase-like protein 2) is a soluble, N-glycosylated endoplasmic reticulum lumenal protein of glycoside hydrolase family 47 (GH47), one of three mammalian Htm1/Mns1 homologues (EDEM1, EDEM2, EDEM3) acting in ER-associated degradation of glycoproteins (gpERAD). EDEM2 catalyzes the initiating mannose-trimming step of mammalian gpERAD, converting Man9GlcNAc2 to Man8GlcNAc2 isomer B, an activity that requires the conserved EF-hand glutamate (E117) and is thought to operate within a disulfide-linked complex with the thioredoxin-domain protein TXNDC11. By generating Man8GlcNAc2, EDEM2 acts upstream of EDEM1 and EDEM3, which further trim the glycan to expose the alpha-1,6-mannose recognized by the downstream lectin OS-9. EDEM2 recognizes and binds misfolded glycoproteins (e.g. misfolded alpha-1-antitrypsin), accelerates their degradation, and promotes ER-to-cytosol retrotranslocation of substrates such as the ricin A chain; unlike EDEM1 and EDEM3 it does not bind the HRD1 adaptor SEL1L. It is induced by the IRE1-XBP1 branch of the unfolded protein response and is broadly expressed. Its catalytic mannosidase activity was historically controversial, with early recombinant assays detecting no activity before endogenous-knockout analysis established its role as the first-step mannosidase.
  • Existing/core annotation action counts: ACCEPT: 21; KEEP_AS_NON_CORE: 8; MARK_AS_OVER_ANNOTATED: 3

PN Consistency Summary

  • Consistency: Deep research ↔ review YAML ↔ PN annotation consistent. EDEM2 = soluble ER-lumenal GH47 protein that catalyzes the first trimming step Man9β†’Man8B (E117-dependent, in an obligate disulfide complex with TXNDC11), committing substrates to gpERAD upstream of EDEM1/EDEM3; does NOT bind SEL1L. The negated GO:0004571 IDA from PMID:15537790 (recombinant "no activity") is correctly retained as superseded by the positive GO:0004571 IMP (PMID:25092655) + E117Q mutant. Review and notes flag this explicitly. No contradictions.
  • PN story / NEW pressure: subtypeβ†’GO:1904382 marked more_specific_than_existing_goa. Note GOA already has GO:1904380 (ER mannose trimming, IMP+TAS+IEA) but NOT GO:1904382 (the ERAD-specific child) for EDEM2 β€” so the PN projection of GO:1904382 to EDEM2 is a defensible, more-specific real annotation (EDEM2 demonstrably trims in the gpERAD pathway, PMID:25092655). GO:1904382 verified real (OLS, non-obsolete). This is the one genuine ADD candidate among the EDEMs. [REF/MAP]
  • Evidence alignment: Strong overlap on PMID:25092655 (shared with EDEM1/3). Review adds the mechanistic TXNDC11 disulfide paper (PMID:32065582), folding-state dependence (PMID:30374462), and pathway model (PMID:39654396) beyond the PN row.
  • Verdict: Consistent and well-curated; catalytic (first-step) EDEM, NOT-mannosidase handled correctly. subtypeβ†’GO:1904382 is a defensible more-specific ADD; groupβ†’GO:0006487 is a loose/broad fit.

Full Consistency Review

  • UniProt: Q9BV94 Β· batch: proteostasis-batch-2026-06-11 Β· review status: COMPLETE
  • PN placement: ER proteostasis|Glycoproteostasis|N-glycosylation system|N-glycan processing|Mannose trimming ; PN-node mapping: subtype "Mannose trimming"=mapped/ok GO:1904382 (more_specific_than_existing_goa); group "N-glycosylation system"=mapped/ok GO:0006487 protein N-linked glycosylation (more_specific_than_existing_goa); intermediate type/class/branch=no_mapping.
  • Consistency: Deep research ↔ review YAML ↔ PN annotation consistent. EDEM2 = soluble ER-lumenal GH47 protein that catalyzes the first trimming step Man9β†’Man8B (E117-dependent, in an obligate disulfide complex with TXNDC11), committing substrates to gpERAD upstream of EDEM1/EDEM3; does NOT bind SEL1L. The negated GO:0004571 IDA from PMID:15537790 (recombinant "no activity") is correctly retained as superseded by the positive GO:0004571 IMP (PMID:25092655) + E117Q mutant. Review and notes flag this explicitly. No contradictions.
  • PN story / NEW pressure: subtypeβ†’GO:1904382 marked more_specific_than_existing_goa. Note GOA already has GO:1904380 (ER mannose trimming, IMP+TAS+IEA) but NOT GO:1904382 (the ERAD-specific child) for EDEM2 β€” so the PN projection of GO:1904382 to EDEM2 is a defensible, more-specific real annotation (EDEM2 demonstrably trims in the gpERAD pathway, PMID:25092655). GO:1904382 verified real (OLS, non-obsolete). This is the one genuine ADD candidate among the EDEMs. [REF/MAP]
  • Mapping strategy: This gene does sharpen the node: EDEM2 is the catalytic first-step mannosidase, the clearest "Mannose trimming" exemplar. subtypeβ†’GO:1904382 is appropriate and adds specificity over existing GO:1904380. groupβ†’GO:0006487 protein N-linked glycosylation (more_specific_than_existing_goa) is broader/upstream than EDEM2's degradative trimming and is a loose fit β€” borderline over-reach for a degradation-arm enzyme.
  • Evidence alignment: Strong overlap on PMID:25092655 (shared with EDEM1/3). Review adds the mechanistic TXNDC11 disulfide paper (PMID:32065582), folding-state dependence (PMID:30374462), and pathway model (PMID:39654396) beyond the PN row.
  • Verdict: Consistent and well-curated; catalytic (first-step) EDEM, NOT-mannosidase handled correctly. subtypeβ†’GO:1904382 is a defensible more-specific ADD; groupβ†’GO:0006487 is a loose/broad fit.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-11
  • review_yaml: genes/human/EDEM2/EDEM2-ai-review.yaml
  • PN workbook rows: 1

PN row 1: ER proteostasis | Glycoproteostasis | N-glycosylation system | N-glycan processing | Mannose trimming

  • UniProt: Q9BV94
  • In branches: ER
  • PN-node mapping records (path + ancestors):
    • [subtype] ER proteostasis|Glycoproteostasis|N-glycosylation system|N-glycan processing|Mannose trimming
      status=mapped scope=ok_for_propagation_to_go GO=[GO:1904382 mannose trimming involved in glycoprotein ERAD pathway]
      rationale: Within the ER proteostasis branch, this PN subtype denotes mannose trimming used in glycoprotein quality control and ERAD triage. That is close enough for propagation to the GO mannose-trimming-in-ERAD process, but the PN subtype is framed as a proteostasis step rather than a formal GO process class.
    • [type] ER proteostasis|Glycoproteostasis|N-glycosylation system|N-glycan processing
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [group] ER proteostasis|Glycoproteostasis|N-glycosylation system
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006487 protein N-linked glycosylation]
      rationale: This PN group captures the ER N-glycosylation machinery that installs and processes N-linked glycans during proteostasis. GO protein N-linked glycosylation is the best current propagation target in the local cache.
    • [class] ER proteostasis|Glycoproteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [branch] ER proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (2)

  • GO:0006487 protein N-linked glycosylation | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=ER proteostasis|Glycoproteostasis|N-glycosylation system
  • GO:1904382 mannose trimming involved in glycoprotein ERAD pathway | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=ER proteostasis|Glycoproteostasis|N-glycosylation system|N-glycan processing|Mannose trimming

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

πŸ“„ View Raw YAML

 
id: Q9BV94
gene_symbol: EDEM2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EDEM2 (ER degradation-enhancing alpha-mannosidase-like protein 2) is a soluble, N-glycosylated endoplasmic reticulum lumenal protein of glycoside hydrolase family 47 (GH47), one of three mammalian Htm1/Mns1 homologues (EDEM1, EDEM2, EDEM3) acting in ER-associated degradation of glycoproteins (gpERAD). EDEM2 catalyzes the initiating mannose-trimming step of mammalian gpERAD, converting Man9GlcNAc2 to Man8GlcNAc2 isomer B, an activity that requires the conserved EF-hand glutamate (E117) and is thought to operate within a disulfide-linked complex with the thioredoxin-domain protein TXNDC11. By generating Man8GlcNAc2, EDEM2 acts upstream of EDEM1 and EDEM3, which further trim the glycan to expose the alpha-1,6-mannose recognized by the downstream lectin OS-9. EDEM2 recognizes and binds misfolded glycoproteins (e.g. misfolded alpha-1-antitrypsin), accelerates their degradation, and promotes ER-to-cytosol retrotranslocation of substrates such as the ricin A chain; unlike EDEM1 and EDEM3 it does not bind the HRD1 adaptor SEL1L. It is induced by the IRE1-XBP1 branch of the unfolded protein response and is broadly expressed. Its catalytic mannosidase activity was historically controversial, with early recombinant assays detecting no activity before endogenous-knockout analysis established its role as the first-step mannosidase.
alternative_products:
- name: '1'
  id: Q9BV94-1
- name: '2'
  id: Q9BV94-2
  sequence_note: VSP_013183
existing_annotations:
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: EDEM2 is induced by the IRE1-XBP1 branch of the unfolded protein response and functions in the ERAD arm of the ER stress response; phylogenetic assignment of involvement in the UPR is consistent with this.
    action: KEEP_AS_NON_CORE
    reason: EDEM2 is a UPR-induced effector acting in ERAD rather than a UPR signaling/sensing component; the informative function is the ERAD/mannose-trimming role.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: Belongs to the glycosyl hydrolase 47 family
- term:
    id: GO:0097466
    label: ubiquitin-dependent glycoprotein ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: EDEM2 functions in N-glycan-dependent (glycoprotein) ERAD, in which misfolded glycoproteins are ubiquitinated and degraded by the proteasome; this is an accurate, specific process for EDEM2.
    action: ACCEPT
    reason: Correct, specific core biological process; redundant with the experimental ERAD/mannose-trimming evidence.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: targets misfolded glycoproteins for degradation in an N-glycan-dependent manner
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: GH47-family mannosidases use a calcium ion in the active site; EDEM2 retains this fold and binds calcium as a structural/catalytic cofactor of its mannosidase activity.
    action: KEEP_AS_NON_CORE
    reason: Accurate structural cofactor attribute of the GH47 fold but not a standalone core function; the catalytic mannosidase activity is the informative function.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: Belongs to the glycosyl hydrolase 47 family
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: EDEM2 is a soluble ER lumenal protein (signal peptide, no transmembrane domain); electronic transfer of ER lumen localization is correct.
    action: ACCEPT
    reason: Correct compartment; redundant with the EXP ER lumen annotation and UniProt subcellular location.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Generic carbohydrate metabolic process from InterPro; far less informative than the specific ER mannose trimming and ERAD processes EDEM2 participates in.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general parent; the specific ER mannose trimming (GO:1904380) and glycoprotein ERAD terms better capture the biology.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: Belongs to the glycosyl hydrolase 47 family
- term:
    id: GO:0009100
    label: glycoprotein metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Generic glycoprotein metabolic process from ARBA; correct in essence but far less informative than the specific N-glycan trimming and ERAD annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general parent process; the specific glycan-trimming/ERAD terms are preferred.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: targets misfolded glycoproteins for degradation in an N-glycan-dependent manner
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic membrane localization from InterPro. EDEM2 is in fact a soluble ER lumenal protein, not a membrane protein, so this term is both uninformative and a poor fit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative and inaccurate parent from a domain-based inference; EDEM2 is a soluble ER lumenal protein, better captured by ER lumen.
    proposed_replacement_terms:
    - id: GO:0005788
      label: endoplasmic reticulum lumen
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: EDEM2 performs the first ER mannose-trimming step (Man9 to Man8B); electronic assignment is consistent with the IMP evidence.
    action: ACCEPT
    reason: Correct core biological process; redundant with the IMP annotation from endogenous knockout analysis.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:1904154
    label: positive regulation of retrograde protein transport, ER to cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: EDEM2 promotes retrotranslocation of ERAD substrates from the ER to the cytosol; electronic assignment is consistent with the experimental ricin retrotranslocation data.
    action: KEEP_AS_NON_CORE
    reason: Real, specific aspect of EDEM2 function (substrate dislocation) but subordinate to the core mannose-trimming/ERAD role; redundant with the IMP/IGI annotations.
    supported_by:
    - reference_id: PMID:24200403
      supporting_text: EDEM2 is also involved in ricin retrotranslocation out of the ER
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901024
  qualifier: enables
  review:
    summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
    action: ACCEPT
    reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901036
  qualifier: enables
  review:
    summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
    action: ACCEPT
    reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901039
  qualifier: enables
  review:
    summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
    action: ACCEPT
    reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901074
  qualifier: enables
  review:
    summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
    action: ACCEPT
    reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9696807
  qualifier: enables
  review:
    summary: Reactome curation of EDEM2 alpha-1,2-mannosidase activity in N-glycan mannose trimming. EDEM2 has demonstrated mannosidase activity catalyzing the first trimming step (Man9 to Man8B).
    action: ACCEPT
    reason: Core molecular function; EDEM2 catalyzes the initiating mannose-trimming step of gpERAD (endogenous-KO evidence).
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: IMP
  original_reference_id: PMID:25092655
  qualifier: involved_in
  review:
    summary: Endogenous EDEM2 knockout in human and chicken cells blocked conversion of Man9 to Man8B as effectively as the mannosidase inhibitor kifunensine, demonstrating EDEM2 performs the first ER mannose-trimming step.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support from endogenous gene knockout.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901032
  qualifier: involved_in
  review:
    summary: Reactome curation of EDEM2 ER mannose trimming in the ER Quality Control Compartment pathway.
    action: ACCEPT
    reason: Correct core biological process; redundant with the IMP evidence.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:15537790
  qualifier: involved_in
  review:
    summary: Overexpression of EDEM2 accelerated degradation of misfolded alpha-1-antitrypsin, directly implicating EDEM2 in the ERAD pathway.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support.
    supported_by:
    - reference_id: PMID:15537790
      supporting_text: Overexpression of EDEM2 accelerates the degradation of misfolded alpha1-antitrypsin, indicating that the protein is involved in ERAD
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:25092655
  qualifier: involved_in
  review:
    summary: Endogenous EDEM2 knockout most effectively blocked gpERAD of ATF6alpha, and the E117Q catalytic mutant failed to rescue, demonstrating EDEM2's central role in the ERAD pathway.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: stable introduction of Flag-tagged hEDEM2, but not Flag-tagged hEDEM2-E117Q, into hEDEM2-KO cells restored degradation of endogenous hATF6
- term:
    id: GO:0019082
    label: viral protein processing
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9694548
  qualifier: involved_in
  review:
    summary: Reactome annotation of EDEM2 in N-glycan mannose trimming of the SARS-CoV-2 spike glycoprotein. This is the generic mannosidase activity acting on a viral glycoprotein substrate, not a distinct viral function.
    action: KEEP_AS_NON_CORE
    reason: Real but peripheral; reflects the core mannosidase activity applied to a viral substrate rather than a dedicated viral-processing role.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:0036510
    label: trimming of terminal mannose on C branch
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901039
  qualifier: involved_in
  review:
    summary: Reactome curation of a specific terminal-mannose trimming sub-step. EDEM2 mainly initiates trimming on the B branch (Man9 to Man8B); this C-branch sub-step annotation is a Reactome-curated refinement.
    action: KEEP_AS_NON_CORE
    reason: Specific Reactome-curated trimming sub-step; retained as a non-core refinement of the mannosidase activity, whose principal demonstrated action is Man9 to Man8B.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: EXP
  original_reference_id: PMID:15537790
  qualifier: located_in
  review:
    summary: Recombinant EDEM2 is localized to the ER, consistent with its signal peptide and soluble lumenal topology.
    action: ACCEPT
    reason: Correct compartment with experimental support.
    supported_by:
    - reference_id: PMID:15537790
      supporting_text: recombinant EDEM2 is localized to the ER where it can associate with misfolded alpha1-antitrypsin
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:24200403
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization of EDEM2 in the ricin retrotranslocation study.
    action: ACCEPT
    reason: Correct site of action with direct experimental support.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:1904154
    label: positive regulation of retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:24200403
  qualifier: involved_in
  review:
    summary: EDEM2 promotes ER-to-cytosol retrotranslocation of the ricin A chain irrespective of translocon accessibility, supporting a role in substrate dislocation.
    action: KEEP_AS_NON_CORE
    reason: Specific, experimentally supported aspect of EDEM2's ERAD/dislocation activity, but subordinate to the core mannose-trimming/ERAD role.
    supported_by:
    - reference_id: PMID:24200403
      supporting_text: EDEM2 promotes ricin retrotranslocation irrespectively of ER translocon accessibility
- term:
    id: GO:1904154
    label: positive regulation of retrograde protein transport, ER to cytosol
  evidence_type: IGI
  original_reference_id: PMID:24200403
  qualifier: involved_in
  review:
    summary: Genetic-interaction evidence (with EDEM1, UniProtKB:Q92611) that EDEM2 promotes ricin A-chain retrotranslocation from the ER to the cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the IMP retrotranslocation annotation; a specific aspect of the dislocation function rather than the core role.
    supported_by:
    - reference_id: PMID:24200403
      supporting_text: more ricin can interact with EDEM2 in comparison with EDEM1
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901024
  qualifier: located_in
  review:
    summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
    action: ACCEPT
    reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901036
  qualifier: located_in
  review:
    summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
    action: ACCEPT
    reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901039
  qualifier: located_in
  review:
    summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
    action: ACCEPT
    reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901074
  qualifier: located_in
  review:
    summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
    action: ACCEPT
    reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9696807
  qualifier: located_in
  review:
    summary: Reactome curation of EDEM2 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs.
    action: ACCEPT
    reason: Correct compartment; consistent with EDEM2's ER residence and role in ERAD substrate trimming.
    supported_by:
    - reference_id: file:human/EDEM2/EDEM2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IMP
  original_reference_id: PMID:25092655
  qualifier: enables
  review:
    summary: Endogenous gene knockout and the catalytically inactivating E117Q mutation established that EDEM2 possesses alpha-1,2-mannosidase activity catalyzing the first trimming step (Man9 to Man8B), resolving the long-standing controversy over its catalytic activity.
    action: ACCEPT
    reason: Core molecular function with direct experimental (IMP) support; EDEM2 is the first-step mannosidase of mammalian gpERAD.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: EDEM2, a novel-type Htm1 homologue that catalyzes the first mannose trimming step from Man9GlcNAc2
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:15537790
  qualifier: located_in
  review:
    summary: Direct evidence that recombinant EDEM2 localizes to the ER.
    action: ACCEPT
    reason: Correct compartment with direct experimental support.
    supported_by:
    - reference_id: PMID:15537790
      supporting_text: recombinant EDEM2 is localized to the ER where it can associate with misfolded alpha1-antitrypsin
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IDA
  original_reference_id: PMID:15537790
  qualifier: enables
  negated: true
  review:
    summary: A negated (NOT) experimental annotation reflecting the original characterization, in which recombinant EDEM2 showed no alpha-1,2-mannosidase activity, leading to a proposed lectin role. Endogenous-knockout analysis (PMID:25092655) and the E117Q mutant later established that EDEM2 does possess mannosidase activity, so this negation is superseded but retained as the curated record of the early finding.
    action: KEEP_AS_NON_CORE
    reason: Genuine historical experimental (IDA) annotation that conflicts with later endogenous-KO evidence; per guidelines an experimental annotation is not removed on weak grounds. Flagged as superseded by PMID:25092655 (UniProt CAUTION documents both views).
    supported_by:
    - reference_id: PMID:15537790
      supporting_text: Using recombinantly generated EDEM2, no alpha-1,2 mannosidase activity was observed
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15537790
  title: Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins.
  findings:
  - statement: Recombinant EDEM2 showed no alpha-1,2-mannosidase activity, localized to the ER, associated with misfolded alpha-1-antitrypsin, and its overexpression accelerated ERAD of misfolded alpha-1-antitrypsin.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original EDEM2 characterization; source of ER lumen localization and the ERAD involvement, and of the NOT mannosidase IDA (no-activity view, later superseded by PMID:25092655).
- id: PMID:24200403
  title: The role of EDEM2 compared with EDEM1 in ricin transport from the endoplasmic reticulum to the cytosol.
  findings:
  - statement: EDEM2 promotes ER-to-cytosol retrotranslocation of the ricin A chain irrespective of translocon accessibility, and binds ricin more efficiently than EDEM1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports the retrograde protein transport (ER to cytosol) annotations and ER localization for EDEM2.
- id: PMID:25092655
  title: EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step.
  findings:
  - statement: Endogenous EDEM2 catalyzes the first mannose-trimming step Man9 to Man8B; EDEM2 is a novel-type Htm1 homologue, resolving the controversy over its catalytic activity.
    reference_section_type: ABSTRACT
  - statement: The catalytically inactivating E117Q mutant failed to restore gpERAD of ATF6alpha in EDEM2-KO cells, tying EDEM2's mannosidase activity to ERAD; SEL1L binds EDEM1 and EDEM3 but not EDEM2.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive endogenous-knockout study; establishes EDEM2 as the first-step mannosidase of mammalian gpERAD and the E117 catalytic requirement.
- id: PMID:32065582
  title: EDEM2 stably disulfide-bonded to TXNDC11 catalyzes the first mannose trimming step in mammalian glycoprotein ERAD.
  findings:
  - statement: EDEM2 is stably disulfide-bonded to the thioredoxin-domain protein TXNDC11 (EDEM2 Cys558 to TXNDC11 Cys692 in the Trx5 CXXC motif); this covalent bond is essential for mannose trimming and gpERAD, and the purified EDEM2-TXNDC11 complex converts Man9GlcNAc2 to Man8GlcNAc2 isomer B in vitro - the first clear demonstration of in vitro mannosidase activity for an EDEM-family protein.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:32065582, doi:10.7554/eLife.53455). Mechanistic landmark establishing the obligate EDEM2-TXNDC11 disulfide-linked complex and the first reconstituted in vitro EDEM mannosidase activity (M9 to M8B). Not cached; reference added without verbatim supporting_text.
- id: PMID:30374462
  title: Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates.
  findings:
  - statement: Immunoprecipitated EDEM2 has bona fide alpha-mannosidase activity that is modest on free glycans and native glycoproteins but markedly higher on denatured/unfolded glycoproteins, providing a mechanism for preferential trimming of misfolded ERAD clients; oxidoreductases including TXNDC11 and PDI associate with EDEM2.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:30374462, doi:10.1038/s42003-018-0174-8). Shows EDEM2 mannosidase activity is folding-state dependent (preferential on unfolded glycoproteins). Not cached; reference added without verbatim supporting_text.
- id: PMID:39654396
  title: UGGT1-mediated reglucosylation of N-glycan competes with ER-associated degradation of unstable and misfolded glycoproteins.
  findings:
  - statement: Glycoprotein fate in the ER reflects a tug-of-war between UGGT1-mediated reglucosylation (favoring calnexin/calreticulin folding cycles) and EDEM-mediated mannose trimming (committing substrates to gpERAD); EDEM2 provides the initiating Man9-to-Man8B step upstream of EDEM1/EDEM3 and OS-9/XTP3-B delivery to SEL1L-HRD1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:39654396, doi:10.7554/eLife.93117). Updated pathway model placing EDEM2 as the entry-point mannosidase of the degradation arm. Not cached; reference added without verbatim supporting_text.
- id: Reactome:R-HSA-901024
  title: MAN1B1 hydrolyses 1,2-linked mannose (a branch)
  findings: []
- id: Reactome:R-HSA-901032
  title: ER Quality Control Compartment (ERQC)
  findings: []
- id: Reactome:R-HSA-901036
  title: MAN1B1 hydrolyses a second 1,2-linked mannose (a branch)
  findings: []
- id: Reactome:R-HSA-901039
  title: MAN1B1 hydrolyses 1,2-linked mannose (c branch)
  findings: []
- id: Reactome:R-HSA-901074
  title: MAN1B1,EDEM2 hydrolyse 1,2-linked mannose (b branch)
  findings: []
- id: Reactome:R-HSA-9694548
  title: Maturation of spike protein
  findings: []
- id: Reactome:R-HSA-9696807
  title: N-glycan mannose trimming of Spike
  findings: []
- id: file:human/EDEM2/EDEM2-uniprot.txt
  title: UniProt entry Q9BV94 (EDEM2_HUMAN), ER degradation-enhancing alpha-mannosidase-like protein 2
  findings:
  - statement: Soluble ER lumenal GH47 protein involved in N-glycan-dependent gpERAD; initiates ERAD by trimming Man9GlcNAc2 to Man8GlcNAc2 (E117-dependent); catalytic activity historically controversial; UPR-induced.
    reference_section_type: OTHER
core_functions:
- description: Catalyzes the initiating mannose-trimming step of mammalian glycoprotein ERAD, converting Man9GlcNAc2 to Man8GlcNAc2 isomer B (requiring the EF-hand glutamate E117), thereby committing misfolded glycoproteins to the gpERAD pathway upstream of EDEM1/EDEM3.
  molecular_function:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: PMID:25092655
    supporting_text: EDEM2, a novel-type Htm1 homologue that catalyzes the first mannose trimming step from Man9GlcNAc2
  - reference_id: PMID:25092655
    supporting_text: the upstream mannose trimming from Man9GlcNAc2 to Man8GlcNAc2 is conducted mainly by EDEM2
  - reference_id: PMID:32065582
  directly_involved_in:
  - id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  - id: GO:0036503
    label: ERAD pathway
- description: Recognizes and binds misfolded glycoproteins in the ER lumen and accelerates their ER-associated degradation, including promoting their retrotranslocation from the ER to the cytosol.
  molecular_function:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: PMID:15537790
    supporting_text: Overexpression of EDEM2 accelerates the degradation of misfolded alpha1-antitrypsin, indicating that the protein is involved in ERAD
  directly_involved_in:
  - id: GO:0097466
    label: ubiquitin-dependent glycoprotein ERAD pathway
proposed_new_terms: []
suggested_questions:
- question: How does the disulfide-linked partnership with TXNDC11 regulate EDEM2's first-step mannosidase activity and substrate selection in vivo?
- question: Why is the Man9-to-Man8B step inefficient in mammalian cells (M9 and M8B coexist) compared with the highly efficient yeast Mns1 step, and what sets this rate-limiting behavior?
suggested_experiments:
- description: Reconstitute purified EDEM2 (wild-type and E117Q) with and without TXNDC11 on defined Man9GlcNAc2 glycoprotein substrates to quantify the first-step trimming activity and the contribution of the disulfide complex.
- description: Endogenous knock-in of catalytic and substrate-binding EDEM2 mutants followed by glycomics and substrate-degradation assays to separate EDEM2's mannosidase activity from its misfolded-glycoprotein recognition during gpERAD commitment.