id: Q9BZQ6 gene_symbol: EDEM3 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: EDEM3 (ER degradation-enhancing alpha-mannosidase-like protein 3) is a soluble endoplasmic reticulum lumenal protein of glycoside hydrolase family 47 (GH47, EC 3.2.1.113), one of three mammalian Htm1/Mns1 homologues (EDEM1, EDEM2, EDEM3) acting in ER-associated degradation of glycoproteins (gpERAD). EDEM3 is an active, calcium-dependent alpha-1,2-mannosidase that accelerates glycoprotein ERAD by catalyzing the downstream mannose-trimming step from Man8GlcNAc2 to Man7GlcNAc2 and further trimming toward Man5GlcNAc2 isomers, generating the demannosylated glycans recognized by the downstream lectin OS-9. It acts mainly at the second trimming step (with EDEM1 contributing to a lesser extent), downstream of the first-step enzyme EDEM2, and, like EDEM1 but unlike EDEM2, it associates with the HRD1 adaptor SEL1L. Beyond misfolded ERAD substrates, EDEM3 may also trim N-glycans on general glycoproteins. It is unique among the EDEMs in containing a protease-associated (PA) domain of unknown function, is induced by the unfolded protein response, and is broadly expressed. Biallelic loss-of-function variants cause an autosomal-recessive congenital disorder of glycosylation (EDEM3-CDG / CDG2V) with neurodevelopmental delay. alternative_products: - name: '1' id: Q9BZQ6-1 - name: '2' id: Q9BZQ6-2 sequence_note: VSP_056375, VSP_056376 existing_annotations: - term: id: GO:0004571 label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: The defining molecular function of EDEM3; phylogenetic assignment of GH47 alpha-1,2-mannosidase activity is well supported across the EDEM/Htm1 family. action: ACCEPT reason: Core molecular function; corroborated by EC 3.2.1.113, RHEA catalytic reactions, and the IMP endogenous-knockout evidence. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans - term: id: GO:0030968 label: endoplasmic reticulum unfolded protein response evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: EDEM3 is a UPR-induced effector that 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: EDEM3 is a UPR-induced ERAD effector rather than a UPR signaling/sensing component; the informative function is the ERAD/mannose-trimming role. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: Involved in endoplasmic reticulum-associated degradation (ERAD) - term: id: GO:0097466 label: ubiquitin-dependent glycoprotein ERAD pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: EDEM3 functions in N-glycan-dependent (glycoprotein) ERAD, trimming glycans to commit misfolded glycoproteins for proteasomal degradation; an accurate, specific process for EDEM3. action: ACCEPT reason: Correct, specific core biological process; redundant with the experimental ERAD/mannose-trimming evidence. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: Accelerates the glycoprotein ERAD by proteasomes - term: id: GO:0004571 label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: Electronic assignment of the core GH47 alpha-1,2-mannosidase activity (with EC 3.2.1.113 and RHEA reactions), consistent with experimental evidence. action: ACCEPT reason: Correct core molecular function; redundant with IMP/ISS evidence. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: EC=3.2.1.113 - term: id: GO:0005509 label: calcium ion binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: GH47 mannosidases require a Ca2+ ion for catalysis; EDEM3 binds calcium as a structural/catalytic cofactor of its mannosidase activity. action: KEEP_AS_NON_CORE reason: Accurate cofactor requirement of the GH47 fold but not a standalone core function; the catalytic mannosidase activity is the informative function. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: Name=Ca(2+) - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: EDEM3 is an ER-resident lumenal protein; electronic (ARBA) assignment of ER localization is correct. action: ACCEPT reason: Correct site of action; redundant with the ER lumen annotation and UniProt subcellular location. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen' - term: id: GO:0005788 label: endoplasmic reticulum lumen evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: EDEM3 is a soluble ER lumenal protein (signal peptide, ER retention); electronic transfer of ER lumen localization is correct. action: ACCEPT reason: Correct compartment; consistent with UniProt subcellular location. supported_by: - reference_id: file:human/EDEM3/EDEM3-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 glycoprotein ERAD processes EDEM3 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/EDEM3/EDEM3-uniprot.txt supporting_text: catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans - term: id: GO:0006516 label: glycoprotein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: EDEM3 contributes to catabolism of glycoproteins via gpERAD; this parent process is correct but less informative than the specific glycoprotein ERAD term. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific ubiquitin-dependent glycoprotein ERAD pathway (GO:0097466) better captures EDEM3's role. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: Accelerates the glycoprotein ERAD by proteasomes - 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. EDEM3 is in fact a soluble ER lumenal 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; EDEM3 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/EDEM3/EDEM3-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:0000120 qualifier: involved_in review: summary: EDEM3 performs ER mannose trimming (Man8 to Man7 and beyond); 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: Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1 - term: id: GO:0036503 label: ERAD pathway evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Electronic assignment of the ERAD pathway, consistent with experimental evidence that EDEM3 accelerates gpERAD. action: ACCEPT reason: Correct core biological process; redundant with IMP evidence. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: Involved in endoplasmic reticulum-associated degradation (ERAD) - term: id: GO:0004571 label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity evidence_type: TAS original_reference_id: Reactome:R-HSA-6782685 qualifier: enables review: summary: Reactome curation of EDEM3 (with EDEM1) hydrolysing Man8b to Man5 glycans, an accurate representation of EDEM3's downstream trimming activity. action: ACCEPT reason: Correct core molecular function; consistent with the catalytic activity and IMP evidence. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans - term: id: GO:0036503 label: ERAD pathway evidence_type: IMP original_reference_id: PMID:25092655 qualifier: involved_in review: summary: Endogenous EDEM3 knockout increased Man8B levels and impaired the second trimming step, consistent with delayed gpERAD; EDEM3 accelerates glycoprotein ERAD. action: ACCEPT reason: Core biological process with direct experimental (IMP) support from endogenous gene knockout. supported_by: - reference_id: PMID:25092655 supporting_text: M8B is trimmed by EDEM1 and EDEM3 to Man7-5GlcNAc2, which are recognized by lectin OS-9 - term: id: GO:1904380 label: endoplasmic reticulum mannose trimming evidence_type: IMP original_reference_id: PMID:25092655 qualifier: involved_in review: summary: Endogenous EDEM3 knockout in human and chicken cells increased Man8B levels, demonstrating EDEM3 performs the second ER mannose-trimming step from Man8GlcNAc2 to Man7GlcNAc2. action: ACCEPT reason: Core biological process with direct experimental (IMP) support. supported_by: - reference_id: PMID:25092655 supporting_text: Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1 - term: id: GO:0004571 label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: Sequence-similarity transfer (from yeast Mns1, UniProtKB:P32906) of the alpha-1,2-mannosidase activity; consistent with the experimental and EC/RHEA evidence. action: ACCEPT reason: Correct core molecular function; consistent with IMP/IEA evidence. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: EC=3.2.1.113 - term: id: GO:1904382 label: mannose trimming involved in glycoprotein ERAD pathway evidence_type: TAS original_reference_id: Reactome:R-HSA-6782685 qualifier: involved_in review: summary: Reactome curation of EDEM3 mannose trimming within the glycoprotein ERAD pathway; an accurate, specific refinement of EDEM3's trimming contribution to ERAD. action: ACCEPT reason: Correct specific biological process linking the trimming activity to ERAD. supported_by: - reference_id: PMID:25092655 supporting_text: M8B is trimmed by EDEM1 and EDEM3 to Man7-5GlcNAc2, which are recognized by lectin OS-9 - 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 demonstrated that EDEM3 possesses alpha-1,2-mannosidase activity, performing the second trimming step Man8B to Man7; EDEM3 has the clearest catalytic activity of the three EDEMs. action: ACCEPT reason: Core molecular function with direct experimental (IMP) support. supported_by: - reference_id: PMID:25092655 supporting_text: Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1 - term: id: GO:0044322 label: endoplasmic reticulum quality control compartment evidence_type: TAS original_reference_id: Reactome:R-HSA-6782685 qualifier: located_in review: summary: Reactome curation of EDEM3 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs. action: ACCEPT reason: Correct compartment; consistent with EDEM3's ER residence and role in ERAD substrate trimming. supported_by: - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen' references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees 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:25092655 title: EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step. findings: - statement: Endogenous EDEM3 (mainly) and EDEM1 (to a lesser extent) catalyze the second trimming step Man8B to Man7, and EDEM1/EDEM3 trim M8B to Man7-5GlcNAc2 recognized by OS-9; 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 EDEM3 as the main second-step mannosidase of mammalian gpERAD and its SEL1L association. - id: PMID:16431915 title: EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. findings: - statement: EDEM3 is a 931-aa soluble Class I GH47 alpha-mannosidase homolog with a C-terminal protease-associated motif; overexpression accelerates gpERAD of misfolded alpha-1-antitrypsin NHK and TCRalpha and stimulates mannose trimming from misfolded and total glycoproteins, while the catalytic-site E147Q mutant abolishes trimming and greatly decreases ERAD enhancement, showing EDEM3 has alpha-1,2-mannosidase activity in vivo. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (PMID:16431915, doi:10.1074/jbc.M512191200). Original EDEM3 characterization establishing its in vivo alpha-1,2-mannosidase activity, the E147Q catalytic requirement, the PA motif, and ERAD acceleration. Not cached; reference added without verbatim supporting_text. - id: PMID:29784879 title: ER-resident protein 46 (ERp46) triggers the mannose-trimming activity of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3). findings: - statement: EDEM3 stably associates with the ER oxidoreductase ERp46 (TXNDC5) via a disulfide bond between ERp46 redox-active cysteines and the EDEM3 alpha-mannosidase domain; this redox-dependent covalent interaction is required to reconstitute EDEM3 mannose-trimming activity toward the misfolded substrate TCRalpha in vitro, coupling demannosylation to ER redox state. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (PMID:29784879, doi:10.1074/jbc.RA118.003129). Establishes ERp46/TXNDC5 as the disulfide-linked oxidoreductase partner gating EDEM3 activity, paralleling the EDEM2-TXNDC11 redox pair. Not cached; reference added without verbatim supporting_text. - id: PMID:33671632 title: EDEM3 Domains Cooperate to Perform Its Overall Cell Functioning. findings: - statement: EDEM3 comprises four modules - GH47 mannosidase-like, intermediate (IMD), protease-associated (PA), and intrinsically disordered (IDD) domains; the GH47 domain provides substrate binding even without mannose trimming and requires the IMD for folding, while PA and IDD domains do not affect trimming per se but modulate the ERAD turnover timing of specific misfolded clients (NHK, soluble tyrosinase mutant). EDEM3 has few stable ER interactors, consistent with transient substrate engagement. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (PMID:33671632, doi:10.3390/ijms22042172). Domain-dissection study defining the GH47/IMD/PA/IDD architecture and the PA/IDD roles in tuning ERAD timing and client selectivity. Not cached; reference added without verbatim supporting_text. - id: PMID:39838427 title: The endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 3 attenuates the unfolded protein response and has pro-survival and pro-viral roles in hepatoma cells and hepatocellular carcinoma patients. findings: - statement: EDEM3 is significantly upregulated in hepatocellular carcinoma tissues, with the highest levels in HBV-infected patients, and its expression associates with tumor progression and poor prognosis; EDEM3 overexpression attenuates the UPR and activates secretory autophagy to promote HBV production, whereas EDEM3 depletion induces ER stress and pro-apoptotic cell death. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (PMID:39838427, doi:10.1186/s12929-024-01103-9). Disease-context study showing pro-survival/pro-viral roles of EDEM3 in HCC/HBV via UPR attenuation and secretory autophagy. Not cached; reference added without verbatim supporting_text. - id: Reactome:R-HSA-6782685 title: EDEM1,3 hydrolyse (GlcNAc)2 (Man)8b to (GlcNAc)2 (Man)5 findings: [] - id: file:human/EDEM3/EDEM3-uniprot.txt title: UniProt entry Q9BZQ6 (EDEM3_HUMAN), ER degradation-enhancing alpha-mannosidase-like protein 3 findings: - statement: Calcium-dependent ER lumenal GH47 alpha-1,2-mannosidase (EC 3.2.1.113) that accelerates glycoprotein ERAD by trimming Man8GlcNAc2 to Man7GlcNAc2 and further to Man5 isomers; contains a protease-associated (PA) domain; biallelic variants cause CDG2V/EDEM3-CDG. reference_section_type: OTHER core_functions: - description: Calcium-dependent alpha-1,2-mannosidase that catalyzes the downstream ER mannose-trimming step from Man8GlcNAc2 to Man7GlcNAc2 (and further toward Man5GlcNAc2 isomers), accelerating glycoprotein ERAD by generating the demannosylated glycan recognized by the downstream lectin OS-9. 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: Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1 - reference_id: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans - reference_id: PMID:16431915 - reference_id: PMID:29784879 directly_involved_in: - id: GO:1904380 label: endoplasmic reticulum mannose trimming - id: GO:0036503 label: ERAD pathway - description: Accelerates ubiquitin-dependent ER-associated degradation of misfolded glycoproteins by trimming their N-glycans within the gpERAD pathway, acting downstream of EDEM2 and in association with the HRD1 adaptor SEL1L. 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: file:human/EDEM3/EDEM3-uniprot.txt supporting_text: Accelerates the glycoprotein ERAD by proteasomes - reference_id: PMID:16431915 directly_involved_in: - id: GO:0097466 label: ubiquitin-dependent glycoprotein ERAD pathway proposed_new_terms: [] suggested_questions: - question: What is the function of the EDEM3-specific protease-associated (PA) domain in substrate recognition or regulation of its mannosidase activity? - question: To what extent does EDEM3 trim N-glycans on correctly folded/general glycoproteins versus only misfolded ERAD substrates, and how does this relate to the EDEM3-CDG glycosylation phenotype? suggested_experiments: - description: Reconstitute purified EDEM3 (wild-type, catalytic-dead, and PA-domain-deleted) on defined Man8GlcNAc2 glycoprotein substrates to quantify the second-step trimming activity and the PA domain's contribution to substrate selection. - description: Glycomic and substrate-degradation profiling of EDEM3-CDG patient-variant knock-in cells to determine how loss of EDEM3 mannosidase activity alters N-glycan trimming on general versus misfolded glycoproteins.