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.