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.
| 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 |
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Download this section (compressed HTML)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?
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.
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