EDEM1 (ER degradation-enhancing alpha-mannosidase-like protein 1) is a single-pass type II endoplasmic reticulum membrane protein of glycoside hydrolase family 47 (GH47), one of three mammalian Htm1/Mns1 homologues (EDEM1, EDEM2, EDEM3) acting in the ER-associated degradation of glycoproteins (gpERAD). EDEM1 extracts terminally misfolded glycoproteins, but not proteins undergoing productive folding, from the calnexin/calreticulin folding cycle and accelerates their clearance, delivering aberrant substrates to the SEL1L/HRD1 dislocation and ubiquitination machinery and, via Derlin-2/-3, to the p97/VCP retrotranslocation system. It recognizes non-native protein structure in a glycan-independent manner (acting in part as a lectin/holdase-like factor), binding both glycosylated and nonglycosylated misfolded substrates, and it requires its mannosidase-like domain for association with SEL1L. EDEM1 possesses low alpha-1,2-mannosidase activity, contributing to the second mannose-trimming step (Man8GlcNAc2 to Man7GlcNAc2) that exposes the alpha-1,6-mannose recognized by downstream lectins (OS-9/XTP3-B); its catalytic activity is weak relative to its recognition/delivery role and was historically debated. EDEM1 is induced by the IRE1-XBP1 branch of the unfolded protein response, resides in the ER membrane and concentrates in the ER-derived quality control compartment (ERQC), and promotes ER-to-cytosol retrotranslocation of substrates including the ricin A chain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| 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; EDEM1 retains this fold and binds calcium as a structural/catalytic cofactor. This is subsidiary to its recognition and ERAD functions, especially given its weak mannosidase activity. Reason: Accurate structural cofactor attribute of the GH47 mannosidase-like domain, but not a standalone core function; the informative functions are misfolded protein recognition and ERAD. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt Belongs to the glycosyl hydrolase 47 family |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000117 | ACCEPT | Summary: EDEM1 is an ER-resident protein; electronic (ARBA) assignment of ER localization is consistent with experimental evidence. Reason: Correct site of action; redundant with IDA ER and ERQC annotations. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: EDEM1 is a single-pass type II ER membrane protein; electronic transfer of ER membrane localization is correct. Reason: Correct compartment; redundant with the ISS ER membrane annotation and UniProt subcellular location. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt Single-pass type II membrane protein |
| 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 EDEM1 participates in. Reason: Over-general parent; the specific ER mannose trimming (GO:1904380) and ERAD (GO:0036503) terms better capture the biology. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt Belongs to the glycosyl hydrolase 47 family |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic membrane localization from InterPro, superseded by the specific ER membrane annotation. Reason: Uninformative parent; EDEM1 is specifically an ER membrane protein. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0036503 ERAD pathway | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) assignment of the ERAD pathway, consistent with extensive experimental evidence that EDEM1 accelerates ERAD of misfolded glycoproteins. Reason: Correct core biological process; redundant with IMP/ISS evidence. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt It is directly involved in endoplasmic reticulum-associated degradation (ERAD) |
| GO:1904380 endoplasmic reticulum mannose trimming | IEA GO_REF:0000120 | ACCEPT | Summary: EDEM1 contributes to ER mannose trimming (the Man8 to Man7 step); electronic assignment is consistent with the IMP evidence. Reason: Correct 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:1904154 positive regulation of retrograde protein transport, ER to cytosol | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: EDEM1 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 EDEM1 function (substrate dislocation) but subordinate to the core recognition/ERAD role; redundant with the IMP/IGI annotations. Supporting Evidence: PMID:24200403 This transport is promoted by EDEM1 |
| GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity | TAS Reactome:R-HSA-6782685 | ACCEPT | Summary: Reactome curation of EDEM1 (with EDEM3) hydrolysing Man8 to Man5 glycans. EDEM1 has genuine but low alpha-1,2-mannosidase activity contributing to the second trimming step. Reason: Correct molecular function (weak but real, demonstrated by endogenous knockout); kept as supporting rather than the dominant function. Supporting Evidence: PMID:25092655 all endogenous EDEMs possess mannosidase activity |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with EDEM1's site of action. Reason: Correct compartment with direct experimental support. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:1904380 endoplasmic reticulum mannose trimming | IMP PMID:25092655 EDEM2 initiates mammalian glycoprotein ERAD by catalyzing th... | ACCEPT | Summary: Endogenous EDEM1 knockout in human and chicken cells increased Man8B levels, showing EDEM1 contributes (with EDEM3) to the second ER mannose-trimming step from Man8GlcNAc2 to Man7GlcNAc2. Reason: Core biological process with direct experimental (IMP) support from endogenous gene knockout. Supporting Evidence: PMID:25092655 Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1 |
| GO:0006511 ubiquitin-dependent protein catabolic process | IMP PMID:25092655 EDEM2 initiates mammalian glycoprotein ERAD by catalyzing th... | KEEP AS NON CORE | Summary: EDEM1 knockout delayed degradation of the gpERAD substrate ATF6alpha, which is degraded by the ubiquitin-proteasome system; supports a role in ubiquitin-dependent catabolism via ERAD. Reason: Correct but generic parent process; the more specific ERAD pathway (GO:0036503) better captures EDEM1's role. Supporting Evidence: PMID:25092655 deletion of hEDEM1 significantly delayed the degradation of hATF6 |
| GO:0036503 ERAD pathway | IMP PMID:21062743 Mannose trimming is required for delivery of a glycoprotein ... | ACCEPT | Summary: EDEM1 functions in ERAD by handing off substrate glycoproteins, after mannose trimming, to the late ERAD lectin XTP3-B and downstream E3 ligases. Reason: Core biological process; experimentally links EDEM1 to the downstream ERAD machinery. Supporting Evidence: PMID:21062743 mannose trimming enables delivery of a substrate glycoprotein from EDEM1 to late ERAD steps through association with XTP3-B |
| GO:0036503 ERAD pathway | IMP PMID:25092655 EDEM2 initiates mammalian glycoprotein ERAD by catalyzing th... | ACCEPT | Summary: Endogenous EDEM1 knockout delayed gpERAD of ATF6alpha, directly demonstrating EDEM1's role in the ERAD pathway. Reason: Core biological process with direct experimental (IMP) support. Supporting Evidence: PMID:25092655 deletion of hEDEM1 significantly delayed the degradation of hATF6 |
| GO:1904382 mannose trimming involved in glycoprotein ERAD pathway | TAS Reactome:R-HSA-6782685 | ACCEPT | Summary: Reactome curation of EDEM1 mannose trimming within the glycoprotein ERAD pathway; an accurate, specific refinement of EDEM1'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:0044322 endoplasmic reticulum quality control compartment | IDA PMID:23233672 A shared endoplasmic reticulum-associated degradation pathwa... | ACCEPT | Summary: On proteasome inhibition, EDEM1 and other ERAD machinery accumulate with substrates in the ER-derived quality control compartment (ERQC), supporting an ERQC localization. Reason: Genuine, functionally relevant localization with direct experimental support. Supporting Evidence: PMID:23233672 accumulation of the nonglycosylated proteins and ERAD machinery in the endoplasmic reticulum-derived quality control compartment |
| GO:0045047 protein targeting to ER | IMP PMID:23233672 A shared endoplasmic reticulum-associated degradation pathwa... | MARK AS OVER ANNOTATED | Summary: This annotation derives from work showing EDEM1 targets misfolded substrates to the ER membrane dislocation/ERAD machinery, not co-translational targeting of nascent proteins to the ER. The GO term protein targeting to ER (import into the ER) poorly captures the demonstrated delivery-to-ERAD biology. Reason: The term denotes targeting of proteins into the ER (e.g. co-translational import), which is not what EDEM1 does; the experimental result is substrate delivery to the ER-membrane ERAD/dislocation complex. Retained (experimental basis) rather than removed, but the term is a poor fit. Supporting Evidence: PMID:19524542 target aberrant proteins to the ER membrane dislocation and ubiquitination complex containing SEL1L |
| GO:0051787 misfolded protein binding | IMP PMID:23233672 A shared endoplasmic reticulum-associated degradation pathwa... | ACCEPT | Summary: EDEM1 binds misfolded glycosylated and nonglycosylated substrates, associating with nonglycosylated proteins through a region outside its mannosidase-like domain; recognition of non-native protein structure is a core EDEM1 function. Reason: Core molecular function; EDEM1's defining role is recognition of misfolded/non-native proteins for ERAD. Supporting Evidence: PMID:23233672 EDEM1 associates through a region outside of its mannosidase-like domain with the nonglycosylated proteins |
| 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 established that EDEM1 possesses (weak) alpha-1,2-mannosidase activity, contributing to the second trimming step Man8B to Man7. This resolved the long-standing mannosidase-versus-lectin controversy in favor of genuine but low catalytic activity. Reason: Molecular function supported by endogenous knockout (IMP); EDEM1 has the weakest mannosidase activity of the three EDEMs, so this is retained as a supporting rather than dominant function. Supporting Evidence: PMID:25092655 all endogenous EDEMs possess mannosidase activity |
| 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: EDEM1 promotes ER-to-cytosol retrotranslocation of the ricin A chain, a model retrotranslocation substrate handled like a misfolded ER protein. Reason: Specific, experimentally supported aspect of EDEM1's ERAD/dislocation activity, but subordinate to the core recognition/ERAD role. Supporting Evidence: PMID:24200403 This transport is promoted by EDEM1 |
| 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 EDEM2, UniProtKB:Q9BV94) that EDEM1 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-1791155 | ACCEPT | Summary: Reactome curation of EDEM1 ERQC localization (EDEM expression context); consistent with direct IDA evidence. Reason: Correct compartment; redundant with the IDA ERQC annotation. Supporting Evidence: PMID:23233672 endoplasmic reticulum-derived quality control compartment |
| GO:0044322 endoplasmic reticulum quality control compartment | TAS Reactome:R-HSA-6782685 | ACCEPT | Summary: Reactome curation of EDEM1 ERQC localization in the mannose-trimming reaction context. Reason: Correct compartment; redundant with the IDA ERQC annotation. Supporting Evidence: PMID:23233672 endoplasmic reticulum-derived quality control compartment |
| GO:0005783 endoplasmic reticulum | IMP PMID:21062743 Mannose trimming is required for delivery of a glycoprotein ... | ACCEPT | Summary: ER localization in the context of EDEM1-dependent ERAD substrate handoff. Reason: Correct site of action; consistent with experimental ER/ERQC evidence. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| 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 EDEM1 in the ricin retrotranslocation study. Reason: Correct compartment with direct experimental support. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0004571 mannosyl-oligosaccharide 1,2-alpha-mannosidase activity | IDA NOT PMID:12610306 Role of EDEM in the release of misfolded glycoproteins from ... | KEEP AS NON CORE | Summary: A negated (NOT) experimental annotation reflecting the original proposal that EDEM1 lacks alpha-1,2-mannosidase activity, based on overexpression biochemistry. Later endogenous-knockout analysis (PMID:25092655) demonstrated that EDEM1 does possess weak 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. Supporting Evidence: PMID:25092655 it had originally been proposed that EDEM1 has no Ξ±1,2-mannosidase activity |
| GO:0005515 protein binding | IPI PMID:19524542 EDEM1 recognition and delivery of misfolded proteins to the ... | KEEP AS NON CORE | Summary: Physical interaction with SEL1L (UniProtKB:Q9UBV2), the HRD1-complex adaptor through which EDEM1 delivers substrates to the dislocation machinery. The bare protein binding term is uninformative; the SEL1L interaction is captured by the misfolded protein binding and ERAD annotations. Reason: Records a real interaction (SEL1L) but bare protein binding is uninformative per curation guidelines; the functional consequence is reflected in the ERAD/recognition terms. Supporting Evidence: PMID:19524542 its association with the ER membrane adaptor protein SEL1L |
| GO:0005515 protein binding | IPI PMID:19934218 A dual role for EDEM1 in the processing of rod opsin. | KEEP AS NON CORE | Summary: Physical interaction with rod opsin (UniProtKB:P08100), an EDEM1 client glycoprotein. The bare protein binding term is uninformative. Reason: Real client interaction (rod opsin) but bare protein binding is uninformative; EDEM1's recognition function is captured by misfolded protein binding. Supporting Evidence: PMID:19934218 rod opsin co-immunoprecipitated with EDEM1 |
| GO:0051787 misfolded protein binding | IDA PMID:19524542 EDEM1 recognition and delivery of misfolded proteins to the ... | ACCEPT | Summary: EDEM1 directly and specifically binds non-native proteins in a glycan-independent manner, demonstrating recognition of misfolded protein structure independent of N-glycan trimming. Reason: Core molecular function; direct demonstration of misfolded/non-native protein recognition. Supporting Evidence: PMID:19524542 EDEM1 specifically binds nonnative proteins in a glycan-independent manner |
| GO:0005515 protein binding | IPI PMID:16449189 Derlin-2 and Derlin-3 are regulated by the mammalian unfolde... | KEEP AS NON CORE | Summary: Physical interactions with Derlin-2 (UniProtKB:Q9GZP9) and Derlin-3 (UniProtKB:Q96Q80), which link EDEM to p97/VCP for substrate extraction. The bare protein binding term is uninformative; the functional role is reflected in the ERAD annotations. Reason: Records real Derlin-2/-3 interactions providing the EDEM-to-p97 link, but bare protein binding is uninformative per guidelines. Supporting Evidence: PMID:16449189 Derlin-2 and -3 are associated with EDEM and p97 |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (from mouse Q925U4) of ER membrane localization; EDEM1 is a single-pass type II ER membrane protein. Reason: Correct compartment; consistent with UniProt subcellular location and IDA evidence. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt Single-pass type II membrane protein |
| GO:0036503 ERAD pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the ERAD pathway role from the mouse ortholog; consistent with extensive human experimental evidence. Reason: Correct core biological process; redundant with IMP evidence. Supporting Evidence: file:human/EDEM1/EDEM1-uniprot.txt It is directly involved in endoplasmic reticulum-associated degradation (ERAD) |
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Download this section (compressed HTML)Q: To what extent does EDEM1 function in vivo as a catalytic mannosidase versus a lectin/holdase-like recognition factor, and how is the balance set by expression level and ER stress?
Q: What structural features outside the mannosidase-like domain mediate EDEM1's glycan-independent recognition of non-native protein structure?
Experiment: Reconstitute substrate handoff with purified EDEM1, ERManI, EDEM2/3 and SEL1L on defined misfolded glycoprotein substrates to quantify the relative contributions of EDEM1 catalysis versus recognition/holdase activity to ERAD commitment.
Experiment: Domain-swap and point-mutation analysis of the EDEM1 mannosidase-like domain in endogenous knock-in cells to separate catalytic, SEL1L-binding, and non-native-protein-binding activities and test their individual requirements for ERAD of glycosylated and nonglycosylated substrates.
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