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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The defining molecular function of EDEM3; phylogenetic assignment of GH47 alpha-1,2-mannosidase activity is well supported across the EDEM/Htm1 family. Reason: Core molecular function; corroborated by EC 3.2.1.113, RHEA catalytic reactions, and the IMP endogenous-knockout evidence. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans |
| GO:0030968 endoplasmic reticulum unfolded protein response | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: EDEM3 is a UPR-induced ERAD effector rather than a UPR signaling/sensing component; the informative function is the ERAD/mannose-trimming role. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt Involved in endoplasmic reticulum-associated degradation (ERAD) |
| GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway | IBA GO_REF:0000033 | ACCEPT | Summary: EDEM3 functions in N-glycan-dependent (glycoprotein) ERAD, trimming glycans to commit misfolded glycoproteins for proteasomal degradation; an accurate, specific process for EDEM3. Reason: Correct, specific core biological process; redundant with the experimental ERAD/mannose-trimming evidence. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt Accelerates the glycoprotein ERAD by proteasomes |
| GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Correct core molecular function; redundant with IMP/ISS evidence. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt EC=3.2.1.113 |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: GH47 mannosidases require a Ca2+ ion for catalysis; EDEM3 binds calcium as a structural/catalytic cofactor of its mannosidase activity. Reason: Accurate cofactor requirement of the GH47 fold but not a standalone core function; the catalytic mannosidase activity is the informative function. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt Name=Ca(2+) |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000117 | ACCEPT | Summary: EDEM3 is an ER-resident lumenal protein; electronic (ARBA) assignment of ER localization is correct. Reason: Correct site of action; redundant with the ER lumen annotation and UniProt subcellular location. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000120 | ACCEPT | Summary: EDEM3 is a soluble ER lumenal protein (signal peptide, ER retention); electronic transfer of ER lumen localization is correct. Reason: Correct compartment; consistent with UniProt subcellular location. Supporting Evidence: file:human/EDEM3/EDEM3-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 glycoprotein ERAD processes EDEM3 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/EDEM3/EDEM3-uniprot.txt catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans |
| GO:0006516 glycoprotein catabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: EDEM3 contributes to catabolism of glycoproteins via gpERAD; this parent process is correct but less informative than the specific glycoprotein ERAD term. Reason: Correct but generic; the specific ubiquitin-dependent glycoprotein ERAD pathway (GO:0097466) better captures EDEM3's role. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt Accelerates the glycoprotein ERAD by proteasomes |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | 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. Reason: Uninformative and inaccurate parent from a domain-based inference; EDEM3 is a soluble ER lumenal protein, better captured by ER lumen. Proposed replacements: endoplasmic reticulum lumen Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
| GO:1904380 endoplasmic reticulum mannose trimming | IEA GO_REF:0000120 | ACCEPT | Summary: EDEM3 performs ER mannose trimming (Man8 to Man7 and beyond); 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 Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1 |
| GO:0036503 ERAD pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of the ERAD pathway, consistent with experimental evidence that EDEM3 accelerates gpERAD. Reason: Correct core biological process; redundant with IMP evidence. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt Involved in endoplasmic reticulum-associated degradation (ERAD) |
| GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity | TAS Reactome:R-HSA-6782685 | ACCEPT | Summary: Reactome curation of EDEM3 (with EDEM1) hydrolysing Man8b to Man5 glycans, an accurate representation of EDEM3's downstream trimming activity. Reason: Correct core molecular function; consistent with the catalytic activity and IMP evidence. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans |
| GO:0036503 ERAD pathway | IMP PMID:25092655 EDEM2 initiates mammalian glycoprotein ERAD by catalyzing th... | ACCEPT | Summary: Endogenous EDEM3 knockout increased Man8B levels and impaired the second trimming step, consistent with delayed gpERAD; EDEM3 accelerates glycoprotein ERAD. Reason: Core biological process with direct experimental (IMP) support from endogenous gene knockout. Supporting Evidence: PMID:25092655 M8B is trimmed by EDEM1 and EDEM3 to Man7-5GlcNAc2, which are recognized by lectin OS-9 |
| GO:1904380 endoplasmic reticulum mannose trimming | IMP PMID:25092655 EDEM2 initiates mammalian glycoprotein ERAD by catalyzing th... | ACCEPT | 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. Reason: Core biological process with direct experimental (IMP) support. Supporting Evidence: PMID:25092655 Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1 |
| GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (from yeast Mns1, UniProtKB:P32906) of the alpha-1,2-mannosidase activity; consistent with the experimental and EC/RHEA evidence. Reason: Correct core molecular function; consistent with IMP/IEA evidence. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt EC=3.2.1.113 |
| GO:1904382 mannose trimming involved in glycoprotein ERAD pathway | TAS Reactome:R-HSA-6782685 | ACCEPT | Summary: Reactome curation of EDEM3 mannose trimming within the glycoprotein ERAD pathway; an accurate, specific refinement of EDEM3's trimming contribution to ERAD. Reason: Correct specific biological process linking the trimming activity to ERAD. Supporting Evidence: PMID:25092655 M8B is trimmed by EDEM1 and EDEM3 to Man7-5GlcNAc2, which are recognized by lectin OS-9 |
| 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 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. Reason: Core molecular function with direct experimental (IMP) support. Supporting Evidence: PMID:25092655 Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1 |
| GO:0044322 endoplasmic reticulum quality control compartment | TAS Reactome:R-HSA-6782685 | ACCEPT | Summary: Reactome curation of EDEM3 localization to the ER-derived quality control compartment (ERQC), where mannose trimming of ERAD substrates occurs. Reason: Correct compartment; consistent with EDEM3's ER residence and role in ERAD substrate trimming. Supporting Evidence: file:human/EDEM3/EDEM3-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen |
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Download this section (compressed HTML)Q: What is the function of the EDEM3-specific protease-associated (PA) domain in substrate recognition or regulation of its mannosidase activity?
Q: 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?
Experiment: 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.
Experiment: 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.
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