Drosophila EDEM2 (CG5682) is an ER-resident alpha-mannosidase-like protein that functions in ER-associated degradation (ERAD) of misfolded glycoproteins. Despite sequence similarity to glycosyl hydrolase family 47 mannosidases, EDEM2 primarily functions as an ERAD substrate recognition factor that recognizes misfolded glycoproteins via their mannose-trimmed N-glycans and targets them for ubiquitin-dependent proteasomal degradation. Drosophila EDEM2 is most similar to mammalian EDEM3 (PMID:25716426). The protein is transcriptionally upregulated by ER stress and promotes degradation of misfolded proteins such as mutant alpha-1-antitrypsin variants NHK and ATZ (PMID:25716426). EDEM2 co-localizes with Hsc3, the Drosophila BiP ortholog, in the ER (PMID:25716426).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0004571
mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for mannosyl-oligosaccharide 1,2-alpha-mannosidase activity. Drosophila EDEM2 belongs to glycosyl hydrolase family 47 and contains the catalytic domain and active site residues characteristic of alpha-1,2-mannosidases (UniProt features show four active site residues). While EDEMs were initially considered lectins, recent studies have revealed that some EDEMs can function as mannosidases (PMID:25716426: "recent studies have revealed that EDEMs can function as mannosidases"). The IBA annotation is phylogenetically appropriate given the conserved catalytic residues. However, whether Drosophila EDEM2 has actual catalytic mannosidase activity versus acting primarily as a lectin/sensor has not been directly demonstrated. Falcon deep research adds direct Drosophila genetic evidence bearing on the catalytic claim: overexpression of wild-type dEDEM2 reduces steady-state NHK (a glycoprotein ERAD substrate), whereas the catalytic mutant E144Q (EF-hand motif, abolishing alpha-1,2-mannosidase activity) instead increases NHK, indicating that mannosidase catalytic activity contributes to clearance of at least some glycoprotein ERAD substrates (PMID:28633019). Mammalian EDEM1/EDEM2 show bona fide but folding-state-dependent mannosidase activity, higher on unfolded/denatured glycoproteins (M8 to M5). Thus the catalytic mannosidase MF annotation is supported, not merely a domain-based lectin inference. (Note: protective effects on non-glycoprotein substrates such as Abeta42 are mannosidase-independent, reflecting a separate substrate-engagement role rather than refuting the catalytic MF.)
Reason: EDEM2 belongs to GH47 family with conserved active site residues. The IBA annotation is phylogenetically sound across EDEM family members. Drosophila catalytic-mutant evidence (E144Q increases NHK; wild-type reduces NHK) supports that mannosidase catalytic activity contributes to glycoprotein ERAD substrate clearance (PMID:28633019), and mammalian EDEM1/EDEM2 show bona fide folding-state-dependent mannosidase activity. This is a core molecular function annotation.
Supporting Evidence:
PMID:25716426
recent studies have revealed that EDEMs can function as mannosidases
file:DROME/Edem2/Edem2-deep-research-falcon.md
overexpression of wild-type dEDEM2 reduced steady-state NHK protein levels, whereas a catalytically inactive mutant (E144Q) increased NHK levels, implying that **mannosidase-catalytic activity contributes to clearance of at least some glycoprotein ERAD substrates**
file:DROME/Edem2/Edem2-deep-research-falcon.md
mammalian EDEM1/EDEM2 show **bona fide mannosidase activity in vitro**, but with **substrate folding-state dependence**
|
|
GO:0030968
endoplasmic reticulum unfolded protein response
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for ER unfolded protein response. This is well supported by experimental data in Drosophila showing that EDEM2 expression is transcriptionally induced by ER stress (PMID:25716426: "Drosophila EDEM2 expression was transcriptionally induced" upon DTT treatment). Furthermore, EDEM2 knockdown in combination with EDEM1 leads to increased Hsc3 levels under ER stress conditions (PMID:25716426: "this increase was even more pronounced when both EDEM1 and EDEM2 were knocked down"). The IBA annotation is consistent with the IMP and IGI annotations from the same gene.
Reason: EDEM2 is transcriptionally induced by ER stress and plays a protective role during the UPR by promoting degradation of misfolded proteins. The IBA is consistent with IMP (PMID:25716426) and IGI (PMID:19805114) evidence for this same term.
Supporting Evidence:
PMID:25716426
Drosophila EDEM2 expression was transcriptionally induced
PMID:25716426
this increase was even more pronounced when both EDEM1 and EDEM2 were knocked down
file:DROME/Edem2/Edem2-deep-research-falcon.md
Edem2 overexpression selectively reduced mutant Rh-1G69D levels (but not wild-type Rh-1), physically associated with Rh-1G69D, suppressed an ER-stress reporter (**xbp1-EGFP**), and delayed adult retinal degeneration
|
|
GO:0097466
ubiquitin-dependent glycoprotein ERAD pathway
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for ubiquitin-dependent glycoprotein ERAD pathway. This is strongly supported by experimental evidence. PMID:25716426 demonstrated that Drosophila EDEMs promote ubiquitination and degradation of misfolded A1AT glycoprotein variants, and knockdown leads to accumulation of glycosylated ERAD substrates. The IBA annotation is consistent with the IMP annotation from PMID:25716426.
Reason: ERAD is the core biological process function of EDEM2. The IBA annotation is well supported by direct experimental evidence showing EDEM2 promotes ubiquitin-dependent degradation of misfolded glycoproteins (PMID:25716426).
Supporting Evidence:
PMID:25716426
The co-expression of EDEM1 or EDEM2 with ATZ increased the level of ubiquitinated ATZ
PMID:25716426
Drosophila EDEM1 and EDEM2 target misfolded A1AT variants for proteasomal degradation
file:DROME/Edem2/Edem2-deep-research-falcon.md
Edem2 (with Edem1) downregulated a classic luminal ERAD substrate, **α1-antitrypsin NHK**, in Drosophila assays
file:DROME/Edem2/Edem2-deep-research-falcon.md
EDEM2 is an **α1,2-mannose trimming enzyme** acting on **high-mannose N-glycans** of misfolded glycoproteins to promote gpERAD commitment
|
|
GO:0005783
endoplasmic reticulum
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: IBA annotation for ER localization. Directly confirmed by IDA evidence from PMID:25716426 showing co-localization with Hsc3 (Drosophila BiP ortholog) in the ER. UniProt also lists ER as the subcellular location. The IBA annotation is consistent with the IDA and IEA annotations for the same term.
Reason: ER localization is the primary constitutive location of EDEM2, directly demonstrated by immunolocalization (PMID:25716426). The IBA is well supported.
Supporting Evidence:
PMID:25716426
Immunolabeling with anti-myc antibody revealed that the Drosophila EDEMs co-localized with Hsc3, the Drosophila orthologue of mammalian BIP. This result is consistent with the hypothesis that Drosophila EDEMs reside in the ER
|
|
GO:0044322
endoplasmic reticulum quality control compartment
|
IEA
GO_REF:0000108 |
ACCEPT |
Summary: IEA annotation for ER quality control compartment, inferred from involvement in ER mannose trimming (GO:1904380). EDEM2 functions in the ERAD quality control pathway, recognizing misfolded glycoproteins for degradation. The ER quality control compartment is functionally appropriate for an ERAD component.
Reason: EDEM2 is an ER quality control factor involved in ERAD substrate recognition. The ER quality control compartment localization is consistent with its function in glycoprotein quality control and degradation.
|
|
GO:0004571
mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IEA annotation for mannosyl-oligosaccharide 1,2-alpha-mannosidase activity from InterPro domain mapping (GH47 family). Consistent with the IBA annotation for the same term. EDEM2 contains the GH47 catalytic domain.
Reason: Consistent with IBA annotation and GH47 family membership. The InterPro mapping is appropriate for this domain-based molecular function.
|
|
GO:0005509
calcium ion binding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IEA annotation for calcium ion binding from InterPro domain mapping. UniProt lists a Ca2+ binding site at position 487, and GH47 mannosidases are known to require calcium as a cofactor (UniProt COFACTOR section: "Ca(2+)"). This is consistent with the enzyme's catalytic requirements.
Reason: Calcium binding is documented in the UniProt record as a cofactor for the GH47 mannosidase domain. The InterPro mapping is appropriate.
|
|
GO:0005783
endoplasmic reticulum
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: IEA annotation for ER localization from UniProt subcellular location mapping. Consistent with the IBA and IDA annotations for the same term. UniProt lists ER as the subcellular location.
Reason: Consistent with IBA and IDA evidence for ER localization. Redundant but acceptable.
|
|
GO:0005975
carbohydrate metabolic process
|
IEA
GO_REF:0000002 |
MARK AS OVER ANNOTATED |
Summary: IEA annotation for carbohydrate metabolic process from InterPro domain mapping. This is a very broad parent term. The more specific terms for ER mannose trimming (GO:1904380) and ERAD pathway (GO:0097466, GO:0036503) are already annotated and are much more informative. While technically correct as a parent, this adds little value.
Reason: Too broad to be informative. EDEM2 is involved in ER mannose trimming and ERAD, not general carbohydrate metabolism. The more specific terms GO:1904380, GO:0097466, and GO:0036503 are already annotated and are much more informative.
|
|
GO:0006986
response to unfolded protein
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IEA annotation for response to unfolded protein from UniProt keyword mapping (Unfolded protein response keyword). EDEM2 is transcriptionally induced by ER stress (PMID:25716426) and participates in the ERAD response to misfolded proteins. This is a broader term than the more specific GO:0030968 "ER unfolded protein response" which is already annotated. Acceptable as a parent term.
Reason: EDEM2 is part of the cellular response to unfolded proteins in the ER. While more specific terms are annotated (GO:0030968), this broader IEA term is acceptable and consistent with the gene's role.
|
|
GO:0016020
membrane
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IEA annotation for membrane from InterPro domain mapping. EDEM2 is an ER-resident protein. While the UniProt entry does not explicitly annotate a transmembrane domain (it has a signal peptide), the ER localization and potential membrane association are plausible. This is a very generic CC term.
Reason: Acceptable as a broad localization term. EDEM2 is associated with the ER membrane system. The more specific ER annotation is more informative.
|
|
GO:0016787
hydrolase activity
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IEA annotation for hydrolase activity from UniProt keyword mapping. EDEM2 belongs to the GH47 glycosyl hydrolase family. This is a broad parent term; the more specific GO:0004571 is already annotated. Acceptable as a parent term.
Reason: Correct as a broad parent term for the GH47 mannosidase activity. The more specific GO:0004571 is already annotated.
|
|
GO:0016798
hydrolase activity, acting on glycosyl bonds
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IEA annotation for hydrolase activity acting on glycosyl bonds from UniProt keyword mapping. EDEM2 belongs to GH47 family. This is an intermediate-specificity term between GO:0016787 (hydrolase activity) and GO:0004571 (mannosyl-oligosaccharide 1,2-alpha-mannosidase activity). Acceptable.
Reason: Correct intermediate-level MF term for GH47 family membership. Consistent with the more specific GO:0004571 annotation.
|
|
GO:0046872
metal ion binding
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: IEA annotation for metal ion binding from UniProt keyword mapping. EDEM2 binds calcium as a cofactor (UniProt COFACTOR section). This is a generic term; GO:0005509 "calcium ion binding" is already annotated and is more specific.
Reason: Correct as a broad parent of GO:0005509 calcium ion binding. Redundant with the more specific term but acceptable.
|
|
GO:1904380
endoplasmic reticulum mannose trimming
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: IEA annotation for ER mannose trimming from InterPro domain mapping. EDEM2 is part of the mannose trimming machinery that processes misfolded glycoproteins for ERAD. The annotation is consistent with the mannosidase activity (GO:0004571) and ERAD pathway (GO:0097466) annotations.
Reason: ER mannose trimming is a core biological process for EDEM2, directly related to its role in ERAD substrate recognition via mannose trimming of N-glycans. The InterPro mapping is appropriate. Falcon deep research supports EDEM2 acting as an alpha-1,2-mannose trimming enzyme on high-mannose N-glycans of misfolded glycoproteins, with conserved framing placing EDEM2 at the first mannose-trimming step initiating gpERAD.
Supporting Evidence:
file:DROME/Edem2/Edem2-deep-research-falcon.md
EDEM2 is an **α1,2-mannose trimming enzyme** acting on **high-mannose N-glycans** of misfolded glycoproteins to promote gpERAD commitment
file:DROME/Edem2/Edem2-deep-research-falcon.md
place **EDEM2** as the factor catalyzing the **first mannose-trimming step** that initiates gpERAD
|
|
GO:0005783
endoplasmic reticulum
|
IDA
PMID:25716426 Role of Drosophila EDEMs in the degradation of the alpha-1-a... |
ACCEPT |
Summary: IDA annotation for ER localization from PMID:25716426. This study directly demonstrated by immunofluorescence that epitope-tagged Drosophila EDEM2 co-localizes with Hsc3 (Drosophila BiP) in the ER when expressed in embryo amnioserosa cells (PMID:25716426: "Immunolabeling with anti-myc antibody revealed that the Drosophila EDEMs co-localized with Hsc3").
Reason: Direct IDA evidence from immunofluorescence co-localization with the ER marker Hsc3 (PMID:25716426). This is the strongest evidence for EDEM2 ER localization.
Supporting Evidence:
PMID:25716426
Immunolabeling with anti-myc antibody revealed that the Drosophila EDEMs co-localized with Hsc3, the Drosophila orthologue of mammalian BIP. This result is consistent with the hypothesis that Drosophila EDEMs reside in the ER
|
|
GO:0030968
endoplasmic reticulum unfolded protein response
|
IMP
PMID:25716426 Role of Drosophila EDEMs in the degradation of the alpha-1-a... |
ACCEPT |
Summary: IMP annotation for ER unfolded protein response from PMID:25716426. The study showed that knockdown of both EDEM1 and EDEM2 led to increased Hsc3 (BiP) levels under ER stress conditions, and that EDEM2 expression is transcriptionally induced by ER stress (DTT treatment). This demonstrates that EDEM2 plays a protective role in the UPR by promoting degradation of misfolded proteins.
Reason: Well-supported IMP evidence showing that EDEM2 loss of function exacerbates ER stress (increased Hsc3 levels) and that EDEM2 is transcriptionally induced by ER stress (PMID:25716426). This is a core biological process annotation.
Supporting Evidence:
PMID:25716426
Drosophila EDEM2 expression was transcriptionally induced
PMID:25716426
The level of Hsc3 increased after 4 h, and this increase was even more pronounced when both EDEM1 and EDEM2 were knocked down
|
|
GO:0034976
response to endoplasmic reticulum stress
|
IEP
PMID:25716426 Role of Drosophila EDEMs in the degradation of the alpha-1-a... |
ACCEPT |
Summary: IEP annotation for response to ER stress from PMID:25716426. Based on expression pattern evidence: EDEM2 mRNA is transcriptionally induced by ER stress agents (DTT, tunicamycin, thapsigargin). The IEP evidence is appropriate for the expression-based observation.
Reason: Appropriate IEP annotation based on transcriptional induction of EDEM2 by multiple ER stress agents (PMID:25716426). Consistent with the broader UPR role. Falcon deep research further notes that Edem2 overexpression suppresses an ER-stress reporter (xbp1-EGFP) driven by misfolded Rh-1G69D, consistent with Edem2 reducing misfolded-client burden during the ER stress response.
Supporting Evidence:
PMID:25716426
Drosophila EDEM2 expression was transcriptionally induced
file:DROME/Edem2/Edem2-deep-research-falcon.md
Edem2 overexpression selectively reduced mutant Rh-1G69D levels (but not wild-type Rh-1), physically associated with Rh-1G69D, suppressed an ER-stress reporter (**xbp1-EGFP**), and delayed adult retinal degeneration
|
|
GO:0097466
ubiquitin-dependent glycoprotein ERAD pathway
|
IMP
PMID:25716426 Role of Drosophila EDEMs in the degradation of the alpha-1-a... |
ACCEPT |
Summary: IMP annotation for ubiquitin-dependent glycoprotein ERAD pathway from PMID:25716426. The study demonstrated that EDEM2 knockdown leads to accumulation of glycosylated A1AT mutant variants, and EDEM2 overexpression promotes their ubiquitination and degradation. This is the core biological process function of EDEM2.
Reason: Strong IMP evidence showing EDEM2 promotes ubiquitin-dependent degradation of misfolded glycoproteins. Knockdown causes accumulation; overexpression accelerates degradation and increases ubiquitination (PMID:25716426). Core function annotation.
Supporting Evidence:
PMID:25716426
The level of ATZ increased by approximately 2-fold after the knockdown of EDEM1 and EDEM2 by dsRNA in Drosophila S2 cells
PMID:25716426
The co-expression of EDEM1 or EDEM2 with ATZ increased the level of ubiquitinated ATZ
|
|
GO:0004571
mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
|
ISM
PMID:19805114 Suppression of retinal degeneration in Drosophila by stimula... |
ACCEPT |
Summary: ISM annotation for mannosyl-oligosaccharide 1,2-alpha-mannosidase activity from PMID:19805114 (sequence model-based inference). EDEM2 contains the GH47 catalytic domain with conserved active site residues. The ISM evidence is based on sequence analysis. Consistent with IBA and IEA annotations for the same term.
Reason: Consistent with the IBA and IEA annotations. The ISM evidence based on conserved active site residues is appropriate for this enzyme family assignment.
Supporting Evidence:
PMID:19805114
we specifically analyzed the role of Drosophila genes homologous to the known yeast and animal regulators of the ER-associated degradation (ERAD) pathway
|
|
GO:0030968
endoplasmic reticulum unfolded protein response
|
IGI
PMID:19805114 Suppression of retinal degeneration in Drosophila by stimula... |
ACCEPT |
Summary: IGI annotation for ER unfolded protein response from PMID:19805114. This study showed that loss-of-function of ERAD factors (including EDEM2) resulted in increased levels of misfolded Rh-1 in ninaE mutant flies, while co-expression of ERAD factors reduced Rh-1 levels and suppressed ER stress reporter activation (PMID:19805114: "co-expression of certain ERAD factors was sufficient to reduce Rh-1 protein levels and to completely suppress ER stress reporter activation"). The IGI evidence (genetic interaction with ninaE mutants) supports EDEM2 role in UPR.
Reason: The IGI evidence from genetic interaction with ninaE (Rh-1) mutants supports EDEM2 involvement in the ER unfolded protein response. ERAD factor overexpression suppressed ER stress in the Drosophila retinal degeneration model (PMID:19805114).
Supporting Evidence:
PMID:19805114
co-expression of certain ERAD factors was sufficient to reduce Rh-1 protein levels and to completely suppress ER stress reporter activation
|
|
GO:0036503
ERAD pathway
|
IGI
PMID:19805114 Suppression of retinal degeneration in Drosophila by stimula... |
ACCEPT |
Summary: IGI annotation for ERAD pathway from PMID:19805114. The study demonstrated that loss-of-function of ERAD factors including EDEM2 increased levels of misfolded Rh-1, and that ERAD factor overexpression reduced misfolded Rh-1 levels. The genetic interaction evidence supports EDEM2 involvement in ERAD.
Reason: ERAD is the core biological process for EDEM2. The IGI evidence from the Drosophila retinal degeneration model (PMID:19805114) supports this annotation. Consistent with the more specific GO:0097466 annotation.
Supporting Evidence:
PMID:19805114
loss-of-function of these putative ERAD factors resulted in increased levels of Rh-1 in ninaE mutant flies
file:DROME/Edem2/Edem2-deep-research-falcon.md
did not rescue EMC3-dependent losses of Rh1/TRP, supporting the conclusion that some client degradation is **ERAD-independent** while other substrates remain **Edem-dependent**
|
|
GO:0051082
unfolded protein binding
|
IPI
PMID:19805114 Suppression of retinal degeneration in Drosophila by stimula... |
MARK AS OVER ANNOTATED |
Summary: IPI annotation for unfolded protein binding from PMID:19805114. The IPI evidence is based on physical interaction between EDEM2 and the misfolded Rh-1 protein (the WITH/FROM column lists FB:FBgn0002940, which is ninaE/Rh1). However, EDEM2 is an ERAD substrate recognition factor (lectin/sensor) that recognizes misfolded glycoproteins for degradation, not a chaperone that prevents aggregation. The interaction with misfolded Rh-1 is in the context of ERAD substrate recognition and targeting for degradation, not chaperone holdase or foldase activity. Per UPB project decision rules, ER quality control sensors should have GO:0051082 removed or marked as over-annotated. EDEM2 recognizes misfolded glycoprotein substrates via their N-glycan structures, which is fundamentally different from chaperone-mediated binding to unfolded polypeptide segments.
Reason: EDEM2 is an ERAD substrate recognition factor (lectin/sensor), not a chaperone. Its interaction with misfolded Rh-1 (PMID:19805114) reflects ERAD substrate recognition for degradation, not chaperone activity. Per UPB project rules, ER quality control sensors should not be annotated with GO:0051082. EDEM2 recognizes misfolded glycoproteins via N-glycan mannose trimming patterns, targeting them for ubiquitin- dependent proteasomal degradation (PMID:25716426). This is a sensor/lectin function, not an unfolded protein binding/chaperone function.
Supporting Evidence:
PMID:25716426
While ER degradation-enhancing α-mannosidase-like proteins (EDEMs) were initially considered lectins (2,3), recent studies have revealed that EDEMs can function as mannosidases (4,5) and molecular chaperones (6)
PMID:25716426
EDEMs are involved in one of the early steps of ERAD substrate recognition
PMID:19805114
loss-of-function of these putative ERAD factors resulted in increased levels of Rh-1 in ninaE mutant flies
file:DROME/Edem2/Edem2-deep-research-falcon.md
EDEM proteins (ER degradation-enhancing α-mannosidase-like proteins) are class I α-mannosidase-like factors (GH47-related) implicated in accelerating disposal of misfolded glycoproteins
|
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The literature surveyed consistently identifies Drosophila melanogaster Edem2 as CG5682 (also called dEDEM2), an ER protein quality-control factor homologous to mammalian EDEM proteins and yeast Htm1p, aligning with the UniProt-provided accession Q9VK27 (alpha-1,2-mannosidase-like; GH47 family). (kang2009suppressionofretinal pages 3-4)
ER-associated degradation (ERAD) is a conserved pathway that recognizes misfolded proteins in the endoplasmic reticulum (ER), retrotranslocates them to the cytosol, and targets them for proteasomal degradation. In the case of glycoprotein ERAD (gpERAD), progressive trimming of high-mannose N-glycans helps “time” folding attempts and creates glycan signals that promote commitment of terminally misfolded clients to ERAD. In mammalian systems, recent mechanistic syntheses place EDEM2 as the factor catalyzing the first mannose-trimming step that initiates gpERAD, with later steps involving other EDEM-family members. (ninagawa2024uggt1mediatedreglucosylationof pages 20-22)
EDEM proteins (ER degradation-enhancing α-mannosidase-like proteins) are class I α-mannosidase-like factors (GH47-related) implicated in accelerating disposal of misfolded glycoproteins. Biochemically, mammalian EDEM1/EDEM2 show bona fide mannosidase activity in vitro, but with substrate folding-state dependence: activity is modest on free glycans/native glycoproteins and substantially higher on denatured/unfolded glycoproteins, consistent with selective action on misfolded ER clients. (shenkman2018mannosidaseactivityof pages 1-2, shenkman2018mannosidaseactivityof pages 4-5)
Multiple Drosophila studies show Edem2 functions as a misfolded-protein clearance factor in the ER that reduces levels of aberrant proteins and mitigates downstream ER stress and tissue degeneration.
Collectively, these data support Edem2 as an ER quality-control/ERAD-associated factor whose primary function is to promote disposal of misfolded ER clients, thereby improving proteostasis and organismal fitness under chronic proteotoxic burden. (kang2009suppressionofretinal pages 4-5, sekiya2017edemfunctionin pages 5-7)
Direct Drosophila functional assays show that Edem2 influences the abundance/clearance of canonical ERAD substrates:
What is the reaction and substrate? Based on family biochemistry and mammalian mechanistic work, EDEM2 is an α1,2-mannose trimming enzyme acting on high-mannose N-glycans of misfolded glycoproteins to promote gpERAD commitment; however, the Drosophila studies above primarily demonstrate functional outcomes (client reduction, stress suppression, phenotypes) rather than providing residue-level structural glycan endpoints (e.g., Man9→Man8 at a defined branch) in flies. (ninagawa2024uggt1mediatedreglucosylationof pages 20-22, sekiya2017edemfunctionin pages 5-7)
Folded-state selectivity (inference from authoritative biochemistry): In vitro mammalian experiments demonstrate EDEM2’s mannosidase activity is much higher on unfolded/denatured glycoproteins, trimming N-glycans to smaller high-mannose species (reported endpoints include M8→M5 species), consistent with selective targeting of misfolded clients rather than mature folded proteins. (shenkman2018mannosidaseactivityof pages 4-5, shenkman2018mannosidaseactivityof pages 1-2)
A notable finding in Drosophila is that Edem2 can protect against some forms of ER proteinopathy even when mannosidase activity is disrupted:
This indicates Edem2’s functional repertoire in vivo may include (i) mannose trimming–dependent gpERAD promotion for canonical glycoprotein ERAD clients (e.g., NHK), and (ii) mannosidase-independent client engagement that can still mitigate ER proteotoxicity in particular models. (sekiya2017edemfunctionin pages 5-7)
Across Drosophila functional studies, Edem2 activity is consistently linked to ER processes: it acts on ER luminal substrates (NHK) and on misfolded rhodopsin that induces ER stress, and its manipulations modulate ER stress readouts. This functional positioning supports Edem2 as an ER-resident/ER lumen-facing quality control factor acting upstream of ERAD commitment and disposal. (kang2009suppressionofretinal pages 4-5, sekiya2017edemfunctionin pages 5-7)
In a Drosophila autosomal-dominant-retinitis-pigmentosa (ADRP) model using misfolded Rh-1G69D, Edem2 acts as a protective ER quality-control factor: it reduces mutant rhodopsin burden, suppresses ER stress reporter activation, and delays structural degeneration of the retina. (kang2009suppressionofretinal pages 4-5)
In aging flies, ERAD capacity can decline, and increasing dEDEM activity is protective in the context of chronic ER proteinopathy. Tissue-specific overexpression shows distinct outcomes depending on where proteostasis is boosted (neurons, muscle, midgut). (sekiya2017edemfunctionin pages 9-10)
Hiramatsu et al. (2019) used Edem2 (Edem2DG03809) with Edem1 alleles in photoreceptor genetics to impair ERAD and test whether degradation of EMC-dependent multipass membrane proteins was ERAD-mediated. They observed that loss of Edem1/Edem2 could increase ER accumulation of certain proteins in specific genetic backgrounds (e.g., with Syx5), but did not rescue EMC3-dependent losses of Rh1/TRP, supporting the conclusion that some client degradation is ERAD-independent while other substrates remain Edem-dependent. (hiramatsu2019ermembraneprotein pages 5-9)
Direct 2023–2024 primary literature specifically interrogating Drosophila Edem2 (CG5682/Q9VK27) appears limited in the retrieved corpus. Nevertheless, high-authority 2024 work refines the conserved mechanistic model for EDEM2-family function:
Edem2 is currently used primarily as a functional proteostasis/ERAD lever in model systems:
ER proteinopathy in neurons (Aβ42) to test genetic enhancement of ER quality control as a protective strategy. (sekiya2017edemfunctionin pages 5-7)
ER stress / ERAD readouts and reporters:
These applications are relevant to broader real-world problems in protein misfolding diseases and age-associated proteostasis decline, where ERAD modulation is a proposed intervention axis; Drosophila Edem2 provides an experimentally tractable genetic handle on this biology. (sekiya2017edemfunctionin pages 9-10, kang2009suppressionofretinal pages 4-5)
Edem2 is best interpreted as a substrate-selective ER quality control factor rather than a general UPR activator. In vivo, Edem2 manipulations can strongly suppress ER stress readouts driven by misfolded Rh1, consistent with reducing misfolded client burden upstream rather than merely altering stress signaling. (kang2009suppressionofretinal pages 4-5)
Edem2 likely contributes to gpERAD both through enzymatic demannosylation and through client engagement. Drosophila evidence indicates mannosidase catalytic residues are important for clearance of at least some glycoprotein ERAD clients (NHK), while other protective effects (notably Aβ42-associated) can persist even with catalytic mutants, implying additional non-enzymatic roles. (sekiya2017edemfunctionin pages 5-7, sekiya2017edemfunctionin pages 9-10)
Conserved mechanism suggests Edem2 may act early in the ERAD commitment process. Mammalian mechanistic framing (2024 synthesis) places EDEM2 at the first mannose-trimming step of gpERAD; while branch/residue-level specificity has not been demonstrated directly in the cited Drosophila studies here, the strong homology and conserved ERAD phenotypes make this the most parsimonious mechanistic hypothesis for the Drosophila protein. (ninagawa2024uggt1mediatedreglucosylationof pages 20-22, kang2009suppressionofretinal pages 3-4)
| Evidence type | Key finding | Experimental system | Quantitative/statistical details | Interpretation for Edem2 function | Source (short citation) | URL |
|---|---|---|---|---|---|---|
| Genetic/biochemical/phenotype | Identity verified: Drosophila Edem2 = CG5682; homologous to mammalian EDEM2/EDEM3 and yeast Htm1p; belongs to GH47/class I α-mannosidase-like ERAD factors | Drosophila sequence comparison and ERAD functional assays in eye disc/S2 cell models | Homology-based assignment; no direct kinetic value reported in this excerpt (kang2009suppressionofretinal pages 3-4) | Supports that Q9VK27 is the correct D. melanogaster Edem2 and that its expected core role is glycoprotein quality control in ERAD | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Biochemical | Edem2 overexpression selectively reduces misfolded Rh-1G69D, but not wild-type Rh-1; also downregulates luminal ERAD substrate α1-antitrypsin NHK | Drosophila larval eye imaginal discs; S2 cells; transgenic overexpression | Rh-1G69D reduction quantified with n=6; NHK reduction qualitative in excerpt (kang2009suppressionofretinal pages 4-5, kang2009suppressionofretinal pages 3-4) | Edem2 acts on misfolded ER clients, including both membrane and luminal substrates, consistent with a substrate-selective ERAD factor | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Biochemical | Edem2 physically co-immunoprecipitates with Rh-1G69D but not Rh-1WT | Drosophila S2 cell co-IP | Interaction is substrate-selective; quantitative binding constants not reported (kang2009suppressionofretinal pages 4-5, kang2009suppressionofretinal pages 3-4) | Strong evidence that Edem2 preferentially recognizes aberrant conformers rather than normal Rh1 | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Phenotype/UPR readout | Edem2 suppresses ER stress caused by Rh-1G69D, measured by xbp1-EGFP splicing reporter | Drosophila eye imaginal discs | xbp1-EGFP suppression n=3, P=0.0052; no suppression reported for Rh-1WT-driven signal (kang2009suppressionofretinal pages 4-5) | Edem2 lowers burden of misfolded ER proteins, likely by promoting their disposal before they trigger strong UPR signaling | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Phenotype | Edem2 delays retinal degeneration in the ADRP model ninaE^G69D/+ | Adult Drosophila retina/pseudopupil and rhabdomere analyses | At 28 d, 64.43 ± 11.11% retained intact pseudopupils with Edem2 vs ~10.47 ± 8.46% lacZ control; n=4, P=0.0002. Ommatidia retaining all 7 rhabdomeres: 68.9 ± 16.1%, n=3 (kang2009suppressionofretinal pages 4-5) | In vivo evidence that increasing Edem2-mediated ER quality control is protective against chronic rhodopsin proteotoxicity | Kang 2009 PNAS | https://doi.org/10.1073/pnas.0905566106 |
| Genetic/biochemical | Wild-type dEDEM2 reduces steady-state NHK levels, whereas catalytic mutant E144Q increases NHK levels | Drosophila neuronal overexpression assays with ERAD substrate NHK | Significant effects reported; exact fold-change not included in excerpt (sekiya2017edemfunctionin pages 5-7) | Indicates mannosidase activity contributes to glycoprotein ERAD substrate clearance by dEDEM2 | Sekiya 2017 Dev Cell | https://doi.org/10.1016/j.devcel.2017.05.019 |
| Biochemical/phenotype | dEDEM2 lowers Aβ42 levels and suppresses Aβ42-induced locomotor and neurodegenerative phenotypes; catalytically inactive mutants retain protection | Drosophila neuronal Aβ42 ER proteinopathy model; co-IP with Aβ42 | Protective effects significant; exact behavioral values not in excerpt. Catalytic mutants E123Q/E144Q still reduced Aβ42 and protected (sekiya2017edemfunctionin pages 5-7) | Suggests dEDEM2 has both mannosidase-dependent ERAD activity (for glycoproteins like NHK) and mannosidase-independent/chaperone-like activity for some nonglycosylated toxic ER proteins | Sekiya 2017 Dev Cell | https://doi.org/10.1016/j.devcel.2017.05.019 |
| Phenotype/aging | dEDEM2 overexpression improves age-associated physiology; neuronal overexpression modestly extends lifespan, gut overexpression extends lifespan more strongly | Adult Drosophila overexpression in neurons, muscle, and midgut | Neuronal median lifespan 47 → 50 d; muscle 67 → 64 d; midgut 67 → 76 d. Locomotor benefits significant; lifespan by log-rank, sample sizes ~n=190–306 depending on assay (sekiya2017edemfunctionin pages 9-10, sekiya2017edemfunctionin pages 10-12) | Boosting Edem2-linked ERAD capacity can improve organismal proteostasis during aging, with tissue-specific benefit | Sekiya 2017 Dev Cell | https://doi.org/10.1016/j.devcel.2017.05.019 |
| Mechanistic/UPR | Chronic dEDEM overexpression protects without broad canonical UPR activation; aging is associated with slower ERAD substrate turnover | Adult Drosophila brains | Aging slows NHK degradation and causes CD3d-YFP accumulation; overexpression had minimal PERK/Xbp1-RB induction in excerpt (sekiya2017edemfunctionin pages 9-10, sekiya2017edemfunctionin pages 7-9) | Supports Edem2 as an ERAD enhancer, not simply a general UPR activator | Sekiya 2017 Dev Cell | https://doi.org/10.1016/j.devcel.2017.05.019 |
| Genetic | Loss of Edem1/Edem2 contributes to stabilization of some ERAD substrates in photoreceptors, but does not rescue EMC-dependent Rh1/TRP loss | Drosophila photoreceptors; Edem1/Edem2 alleles combined with Syx5 or EMC3 mutants | TRP accumulation ratio: Syx5 single 0.95 ± 0.25 vs Syx5, Edem1, Edem2 triple 1.64 ± 0.30. EMC3Δ6 TRP ratio: 0.42 ± 0.05 vs 0.46 ± 0.08 in triple mutant (hiramatsu2019ermembraneprotein pages 5-9) | Edem2 participates in photoreceptor ERAD, but some client degradation in EMC-deficient cells is ERAD-independent, refining substrate scope | Hiramatsu 2019 Mol Biol Cell | https://doi.org/10.1091/mbc.e19-08-0434 |
| Genetic/substrate specificity | In EMC3-deficient photoreceptors, Edem1/Edem2 loss allows NaKβ accumulation but not rescue of Rh1, NaKα, or TRP | Drosophila photoreceptor genetics | Qualitative substrate selectivity; ratio values above for TRP (hiramatsu2019ermembraneprotein pages 5-9) | Implies Edem2-dependent ERAD is substrate-selective, not universally responsible for degradation of all unstable photoreceptor proteins | Hiramatsu 2019 Mol Biol Cell | https://doi.org/10.1091/mbc.e19-08-0434 |
| Mechanistic (mammalian context) | Mammalian EDEM2 has bona fide mannosidase activity, weak on free glycans/native glycoproteins but stronger on denatured/unfolded glycoproteins; trimming can proceed from M8 to M5 | In vitro mammalian biochemistry with recombinant proteins and glycan analysis | ERManI trimmed free glycans about 3-fold more than EDEM1/EDEM2; EDEM2 interacts with PDI/TXNDC11, with ~50% stronger co-IP with TXNDC11 in excerpt (shenkman2018mannosidaseactivityof pages 4-5, shenkman2018mannosidaseactivityof pages 5-6, shenkman2018mannosidaseactivityof pages 4-4, shenkman2018mannosidaseactivityof pages 1-2) | Provides conserved mechanistic context for Drosophila Edem2: likely a folding-state-sensitive GH47 α1,2-mannosidase-like ERAD factor acting preferentially on misfolded glycoproteins | Shenkman 2018 Commun Biol | https://doi.org/10.1038/s42003-018-0174-8 |
| Mechanistic (mammalian context) | Recent synthesis of mammalian work places EDEM2 at the first mannose-trimming step that initiates gpERAD, acting with TXNDC11 before further trimming by other EDEMs | Mammalian ERAD pathway synthesis/review of primary studies | No new kinetic values in excerpt; mechanistic placement cites prior primary studies (ninagawa2024uggt1mediatedreglucosylationof pages 20-22) | Supports inference that Drosophila Edem2 likely functions early in glycoprotein ERAD by generating/advancing the demannosylation signal on terminally misfolded clients | Ninagawa 2024 eLife | https://doi.org/10.1101/2023.10.18.562958 |
Table: This table compiles the most relevant experimental and mechanistic findings for Drosophila Edem2/CG5682, emphasizing direct Drosophila evidence and clearly separating mammalian EDEM2 context used for functional inference.
References
(kang2009suppressionofretinal pages 3-4): Min-Ji Kang and Hyung Don Ryoo. Suppression of retinal degeneration in drosophila by stimulation of er-associated degradation. Proceedings of the National Academy of Sciences, 106:17043-17048, Oct 2009. URL: https://doi.org/10.1073/pnas.0905566106, doi:10.1073/pnas.0905566106. This article has 110 citations and is from a highest quality peer-reviewed journal.
(ninagawa2024uggt1mediatedreglucosylationof pages 20-22): Satoshi Ninagawa, Masaki Matsuo, Deng Ying, Shuichiro Oshita, Shinya Aso, Kazutoshi Matsushita, Mai Taniguchi, Akane Fueki, Moe Yamashiro, Kaoru Sugasawa, Shunsuke Saito, Koshi Imami, Yasuhiko Kizuka, Tetsushi Sakuma, Takashi Yamamoto, Hirokazu Yagi, Koichi Kato, and Kazutoshi Mori. Uggt1-mediated reglucosylation of n-glycan competes with er-associated degradation of unstable and misfolded glycoproteins. eLife, Sep 2024. URL: https://doi.org/10.1101/2023.10.18.562958, doi:10.1101/2023.10.18.562958. This article has 7 citations and is from a domain leading peer-reviewed journal.
(shenkman2018mannosidaseactivityof pages 1-2): Marina Shenkman, Efrat Ron, Rivka Yehuda, Ron Benyair, Isam Khalaila, and Gerardo Z. Lederkremer. Mannosidase activity of edem1 and edem2 depends on an unfolded state of their glycoprotein substrates. Communications Biology, Oct 2018. URL: https://doi.org/10.1038/s42003-018-0174-8, doi:10.1038/s42003-018-0174-8. This article has 71 citations and is from a peer-reviewed journal.
(shenkman2018mannosidaseactivityof pages 4-5): Marina Shenkman, Efrat Ron, Rivka Yehuda, Ron Benyair, Isam Khalaila, and Gerardo Z. Lederkremer. Mannosidase activity of edem1 and edem2 depends on an unfolded state of their glycoprotein substrates. Communications Biology, Oct 2018. URL: https://doi.org/10.1038/s42003-018-0174-8, doi:10.1038/s42003-018-0174-8. This article has 71 citations and is from a peer-reviewed journal.
(kang2009suppressionofretinal pages 4-5): Min-Ji Kang and Hyung Don Ryoo. Suppression of retinal degeneration in drosophila by stimulation of er-associated degradation. Proceedings of the National Academy of Sciences, 106:17043-17048, Oct 2009. URL: https://doi.org/10.1073/pnas.0905566106, doi:10.1073/pnas.0905566106. This article has 110 citations and is from a highest quality peer-reviewed journal.
(sekiya2017edemfunctionin pages 5-7): Michiko Sekiya, Akiko Maruko-Otake, Stephen Hearn, Yasufumi Sakakibara, Naoki Fujisaki, Emiko Suzuki, Kanae Ando, and Koichi M. Iijima. Edem function in erad protects against chronic er proteinopathy and age-related physiological decline in drosophila. Developmental cell, 41 6:652-664.e5, Jun 2017. URL: https://doi.org/10.1016/j.devcel.2017.05.019, doi:10.1016/j.devcel.2017.05.019. This article has 38 citations and is from a highest quality peer-reviewed journal.
(sekiya2017edemfunctionin pages 9-10): Michiko Sekiya, Akiko Maruko-Otake, Stephen Hearn, Yasufumi Sakakibara, Naoki Fujisaki, Emiko Suzuki, Kanae Ando, and Koichi M. Iijima. Edem function in erad protects against chronic er proteinopathy and age-related physiological decline in drosophila. Developmental cell, 41 6:652-664.e5, Jun 2017. URL: https://doi.org/10.1016/j.devcel.2017.05.019, doi:10.1016/j.devcel.2017.05.019. This article has 38 citations and is from a highest quality peer-reviewed journal.
(hiramatsu2019ermembraneprotein pages 5-9): Naoki Hiramatsu, Tatsuya Tago, Takunori Satoh, and Akiko K. Satoh. Er membrane protein complex is required for the insertions of late-synthesized transmembrane helices of rh1 in drosophila photoreceptors. Molecular Biology of the Cell, 30:2890-2900, Nov 2019. URL: https://doi.org/10.1091/mbc.e19-08-0434, doi:10.1091/mbc.e19-08-0434. This article has 17 citations and is from a domain leading peer-reviewed journal.
(sekiya2017edemfunctionin pages 10-12): Michiko Sekiya, Akiko Maruko-Otake, Stephen Hearn, Yasufumi Sakakibara, Naoki Fujisaki, Emiko Suzuki, Kanae Ando, and Koichi M. Iijima. Edem function in erad protects against chronic er proteinopathy and age-related physiological decline in drosophila. Developmental cell, 41 6:652-664.e5, Jun 2017. URL: https://doi.org/10.1016/j.devcel.2017.05.019, doi:10.1016/j.devcel.2017.05.019. This article has 38 citations and is from a highest quality peer-reviewed journal.
(sekiya2017edemfunctionin pages 7-9): Michiko Sekiya, Akiko Maruko-Otake, Stephen Hearn, Yasufumi Sakakibara, Naoki Fujisaki, Emiko Suzuki, Kanae Ando, and Koichi M. Iijima. Edem function in erad protects against chronic er proteinopathy and age-related physiological decline in drosophila. Developmental cell, 41 6:652-664.e5, Jun 2017. URL: https://doi.org/10.1016/j.devcel.2017.05.019, doi:10.1016/j.devcel.2017.05.019. This article has 38 citations and is from a highest quality peer-reviewed journal.
(shenkman2018mannosidaseactivityof pages 5-6): Marina Shenkman, Efrat Ron, Rivka Yehuda, Ron Benyair, Isam Khalaila, and Gerardo Z. Lederkremer. Mannosidase activity of edem1 and edem2 depends on an unfolded state of their glycoprotein substrates. Communications Biology, Oct 2018. URL: https://doi.org/10.1038/s42003-018-0174-8, doi:10.1038/s42003-018-0174-8. This article has 71 citations and is from a peer-reviewed journal.
(shenkman2018mannosidaseactivityof pages 4-4): Marina Shenkman, Efrat Ron, Rivka Yehuda, Ron Benyair, Isam Khalaila, and Gerardo Z. Lederkremer. Mannosidase activity of edem1 and edem2 depends on an unfolded state of their glycoprotein substrates. Communications Biology, Oct 2018. URL: https://doi.org/10.1038/s42003-018-0174-8, doi:10.1038/s42003-018-0174-8. This article has 71 citations and is from a peer-reviewed journal.
The YAML description field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.
id: Q9VK27
gene_symbol: Edem2
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:7227
label: Drosophila melanogaster
description: >-
Drosophila EDEM2 (CG5682) is an ER-resident alpha-mannosidase-like protein that functions in
ER-associated degradation (ERAD) of misfolded glycoproteins. Despite sequence similarity to glycosyl
hydrolase family 47 mannosidases, EDEM2 primarily functions as an ERAD substrate recognition factor
that recognizes misfolded glycoproteins via their mannose-trimmed N-glycans and targets them for
ubiquitin-dependent proteasomal degradation. Drosophila EDEM2 is most similar to mammalian EDEM3
(PMID:25716426). The protein is transcriptionally upregulated by ER stress and promotes degradation
of misfolded proteins such as mutant alpha-1-antitrypsin variants NHK and ATZ (PMID:25716426). EDEM2
co-localizes with Hsc3, the Drosophila BiP ortholog, in the ER (PMID:25716426).
core_functions:
- description: EDEM2 is an ER-resident alpha-mannosidase-like protein of the glycosyl
hydrolase family 47 (GH47) that functions in ER-associated degradation (ERAD) of
misfolded glycoproteins. It recognizes misfolded glycoproteins via their mannose-trimmed
N-glycans and promotes their ubiquitin-dependent proteasomal degradation. EDEM2
is transcriptionally upregulated by ER stress and plays a protective role in the
unfolded protein response.
molecular_function:
id: GO:0004571
label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
directly_involved_in:
- id: GO:0097466
label: ubiquitin-dependent glycoprotein ERAD pathway
- id: GO:0030968
label: endoplasmic reticulum unfolded protein response
- id: GO:1904380
label: endoplasmic reticulum mannose trimming
locations:
- id: GO:0005783
label: endoplasmic reticulum
supported_by:
- reference_id: PMID:25716426
supporting_text: the overexpression of Drosophila EDEM2 promotes ERAD of NHK
- reference_id: PMID:25716426
supporting_text: EDEMs are involved in one of the early steps of ERAD substrate
recognition
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
overexpression of wild-type dEDEM2 reduced steady-state NHK protein levels, whereas a catalytically inactive mutant (E144Q) increased NHK levels, implying that **mannosidase-catalytic activity contributes to clearance of at least some glycoprotein ERAD substrates**
reference_section_type: OTHER
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
EDEM2 is an **α1,2-mannose trimming enzyme** acting on **high-mannose N-glycans** of misfolded glycoproteins to promote gpERAD commitment
reference_section_type: OTHER
existing_annotations:
- term:
id: GO:0004571
label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for mannosyl-oligosaccharide 1,2-alpha-mannosidase activity.
Drosophila EDEM2 belongs to glycosyl hydrolase family 47 and contains the catalytic
domain and active site residues characteristic of alpha-1,2-mannosidases (UniProt
features show four active site residues). While EDEMs were initially considered
lectins, recent studies have revealed that some EDEMs can function as mannosidases
(PMID:25716426: "recent studies have revealed that EDEMs can function as mannosidases").
The IBA annotation is phylogenetically appropriate given the conserved catalytic
residues. However, whether Drosophila EDEM2 has actual catalytic mannosidase
activity versus acting primarily as a lectin/sensor has not been directly demonstrated.
Falcon deep research adds direct Drosophila genetic evidence bearing on the catalytic
claim: overexpression of wild-type dEDEM2 reduces steady-state NHK (a glycoprotein
ERAD substrate), whereas the catalytic mutant E144Q (EF-hand motif, abolishing
alpha-1,2-mannosidase activity) instead increases NHK, indicating that mannosidase
catalytic activity contributes to clearance of at least some glycoprotein ERAD
substrates (PMID:28633019). Mammalian EDEM1/EDEM2 show bona fide but folding-state-dependent
mannosidase activity, higher on unfolded/denatured glycoproteins (M8 to M5). Thus
the catalytic mannosidase MF annotation is supported, not merely a domain-based
lectin inference. (Note: protective effects on non-glycoprotein substrates such
as Abeta42 are mannosidase-independent, reflecting a separate substrate-engagement
role rather than refuting the catalytic MF.)'
action: ACCEPT
reason: EDEM2 belongs to GH47 family with conserved active site residues. The
IBA annotation is phylogenetically sound across EDEM family members. Drosophila
catalytic-mutant evidence (E144Q increases NHK; wild-type reduces NHK) supports
that mannosidase catalytic activity contributes to glycoprotein ERAD substrate
clearance (PMID:28633019), and mammalian EDEM1/EDEM2 show bona fide folding-state-dependent
mannosidase activity. This is a core molecular function annotation.
supported_by:
- reference_id: PMID:25716426
supporting_text: recent studies have revealed that EDEMs can function as mannosidases
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
overexpression of wild-type dEDEM2 reduced steady-state NHK protein levels, whereas a catalytically inactive mutant (E144Q) increased NHK levels, implying that **mannosidase-catalytic activity contributes to clearance of at least some glycoprotein ERAD substrates**
reference_section_type: OTHER
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
mammalian EDEM1/EDEM2 show **bona fide mannosidase activity in vitro**, but with **substrate folding-state dependence**
reference_section_type: OTHER
- term:
id: GO:0030968
label: endoplasmic reticulum unfolded protein response
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: 'IBA annotation for ER unfolded protein response. This is well supported
by experimental data in Drosophila showing that EDEM2 expression is transcriptionally
induced by ER stress (PMID:25716426: "Drosophila EDEM2 expression was transcriptionally
induced" upon DTT treatment). Furthermore, EDEM2 knockdown in combination with
EDEM1 leads to increased Hsc3 levels under ER stress conditions (PMID:25716426:
"this increase was even more pronounced when both EDEM1 and EDEM2 were knocked
down"). The IBA annotation is consistent with the IMP and IGI annotations from
the same gene.'
action: ACCEPT
reason: EDEM2 is transcriptionally induced by ER stress and plays a protective
role during the UPR by promoting degradation of misfolded proteins. The IBA
is consistent with IMP (PMID:25716426) and IGI (PMID:19805114) evidence for
this same term.
supported_by:
- reference_id: PMID:25716426
supporting_text: Drosophila EDEM2 expression was transcriptionally induced
- reference_id: PMID:25716426
supporting_text: this increase was even more pronounced when both EDEM1 and
EDEM2 were knocked down
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
Edem2 overexpression selectively reduced mutant Rh-1G69D levels (but not wild-type Rh-1), physically associated with Rh-1G69D, suppressed an ER-stress reporter (**xbp1-EGFP**), and delayed adult retinal degeneration
reference_section_type: OTHER
- term:
id: GO:0097466
label: ubiquitin-dependent glycoprotein ERAD pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: IBA annotation for ubiquitin-dependent glycoprotein ERAD pathway. This
is strongly supported by experimental evidence. PMID:25716426 demonstrated that
Drosophila EDEMs promote ubiquitination and degradation of misfolded A1AT glycoprotein
variants, and knockdown leads to accumulation of glycosylated ERAD substrates.
The IBA annotation is consistent with the IMP annotation from PMID:25716426.
action: ACCEPT
reason: ERAD is the core biological process function of EDEM2. The IBA annotation
is well supported by direct experimental evidence showing EDEM2 promotes ubiquitin-dependent
degradation of misfolded glycoproteins (PMID:25716426).
supported_by:
- reference_id: PMID:25716426
supporting_text: The co-expression of EDEM1 or EDEM2 with ATZ increased the
level of ubiquitinated ATZ
- reference_id: PMID:25716426
supporting_text: Drosophila EDEM1 and EDEM2 target misfolded A1AT variants for
proteasomal degradation
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
Edem2 (with Edem1) downregulated a classic luminal ERAD substrate, **α1-antitrypsin NHK**, in Drosophila assays
reference_section_type: OTHER
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
EDEM2 is an **α1,2-mannose trimming enzyme** acting on **high-mannose N-glycans** of misfolded glycoproteins to promote gpERAD commitment
reference_section_type: OTHER
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: IBA annotation for ER localization. Directly confirmed by IDA evidence
from PMID:25716426 showing co-localization with Hsc3 (Drosophila BiP ortholog)
in the ER. UniProt also lists ER as the subcellular location. The IBA annotation
is consistent with the IDA and IEA annotations for the same term.
action: ACCEPT
reason: ER localization is the primary constitutive location of EDEM2, directly
demonstrated by immunolocalization (PMID:25716426). The IBA is well supported.
supported_by:
- reference_id: PMID:25716426
supporting_text: Immunolabeling with anti-myc antibody revealed that the Drosophila
EDEMs co-localized with Hsc3, the Drosophila orthologue of mammalian BIP.
This result is consistent with the hypothesis that Drosophila EDEMs reside
in the ER
- term:
id: GO:0044322
label: endoplasmic reticulum quality control compartment
evidence_type: IEA
original_reference_id: GO_REF:0000108
review:
summary: IEA annotation for ER quality control compartment, inferred from involvement
in ER mannose trimming (GO:1904380). EDEM2 functions in the ERAD quality control
pathway, recognizing misfolded glycoproteins for degradation. The ER quality
control compartment is functionally appropriate for an ERAD component.
action: ACCEPT
reason: EDEM2 is an ER quality control factor involved in ERAD substrate recognition.
The ER quality control compartment localization is consistent with its function
in glycoprotein quality control and degradation.
- term:
id: GO:0004571
label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IEA annotation for mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
from InterPro domain mapping (GH47 family). Consistent with the IBA annotation
for the same term. EDEM2 contains the GH47 catalytic domain.
action: ACCEPT
reason: Consistent with IBA annotation and GH47 family membership. The InterPro
mapping is appropriate for this domain-based molecular function.
- term:
id: GO:0005509
label: calcium ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: 'IEA annotation for calcium ion binding from InterPro domain mapping.
UniProt lists a Ca2+ binding site at position 487, and GH47 mannosidases are
known to require calcium as a cofactor (UniProt COFACTOR section: "Ca(2+)").
This is consistent with the enzyme''s catalytic requirements.'
action: ACCEPT
reason: Calcium binding is documented in the UniProt record as a cofactor for
the GH47 mannosidase domain. The InterPro mapping is appropriate.
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: IEA annotation for ER localization from UniProt subcellular location
mapping. Consistent with the IBA and IDA annotations for the same term. UniProt
lists ER as the subcellular location.
action: ACCEPT
reason: Consistent with IBA and IDA evidence for ER localization. Redundant but
acceptable.
- term:
id: GO:0005975
label: carbohydrate metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IEA annotation for carbohydrate metabolic process from InterPro domain
mapping. This is a very broad parent term. The more specific terms for ER mannose
trimming (GO:1904380) and ERAD pathway (GO:0097466, GO:0036503) are already
annotated and are much more informative. While technically correct as a parent,
this adds little value.
action: MARK_AS_OVER_ANNOTATED
reason: Too broad to be informative. EDEM2 is involved in ER mannose trimming
and ERAD, not general carbohydrate metabolism. The more specific terms GO:1904380,
GO:0097466, and GO:0036503 are already annotated and are much more informative.
- term:
id: GO:0006986
label: response to unfolded protein
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IEA annotation for response to unfolded protein from UniProt keyword
mapping (Unfolded protein response keyword). EDEM2 is transcriptionally induced
by ER stress (PMID:25716426) and participates in the ERAD response to misfolded
proteins. This is a broader term than the more specific GO:0030968 "ER unfolded
protein response" which is already annotated. Acceptable as a parent term.
action: ACCEPT
reason: EDEM2 is part of the cellular response to unfolded proteins in the ER.
While more specific terms are annotated (GO:0030968), this broader IEA term
is acceptable and consistent with the gene's role.
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IEA annotation for membrane from InterPro domain mapping. EDEM2 is an
ER-resident protein. While the UniProt entry does not explicitly annotate a
transmembrane domain (it has a signal peptide), the ER localization and potential
membrane association are plausible. This is a very generic CC term.
action: ACCEPT
reason: Acceptable as a broad localization term. EDEM2 is associated with the
ER membrane system. The more specific ER annotation is more informative.
- term:
id: GO:0016787
label: hydrolase activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IEA annotation for hydrolase activity from UniProt keyword mapping. EDEM2
belongs to the GH47 glycosyl hydrolase family. This is a broad parent term;
the more specific GO:0004571 is already annotated. Acceptable as a parent term.
action: ACCEPT
reason: Correct as a broad parent term for the GH47 mannosidase activity. The
more specific GO:0004571 is already annotated.
- term:
id: GO:0016798
label: hydrolase activity, acting on glycosyl bonds
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IEA annotation for hydrolase activity acting on glycosyl bonds from UniProt
keyword mapping. EDEM2 belongs to GH47 family. This is an intermediate-specificity
term between GO:0016787 (hydrolase activity) and GO:0004571 (mannosyl-oligosaccharide
1,2-alpha-mannosidase activity). Acceptable.
action: ACCEPT
reason: Correct intermediate-level MF term for GH47 family membership. Consistent
with the more specific GO:0004571 annotation.
- term:
id: GO:0046872
label: metal ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: IEA annotation for metal ion binding from UniProt keyword mapping. EDEM2
binds calcium as a cofactor (UniProt COFACTOR section). This is a generic term;
GO:0005509 "calcium ion binding" is already annotated and is more specific.
action: ACCEPT
reason: Correct as a broad parent of GO:0005509 calcium ion binding. Redundant
with the more specific term but acceptable.
- term:
id: GO:1904380
label: endoplasmic reticulum mannose trimming
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: IEA annotation for ER mannose trimming from InterPro domain mapping.
EDEM2 is part of the mannose trimming machinery that processes misfolded glycoproteins
for ERAD. The annotation is consistent with the mannosidase activity (GO:0004571)
and ERAD pathway (GO:0097466) annotations.
action: ACCEPT
reason: ER mannose trimming is a core biological process for EDEM2, directly related
to its role in ERAD substrate recognition via mannose trimming of N-glycans.
The InterPro mapping is appropriate. Falcon deep research supports EDEM2 acting
as an alpha-1,2-mannose trimming enzyme on high-mannose N-glycans of misfolded
glycoproteins, with conserved framing placing EDEM2 at the first mannose-trimming
step initiating gpERAD.
supported_by:
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
EDEM2 is an **α1,2-mannose trimming enzyme** acting on **high-mannose N-glycans** of misfolded glycoproteins to promote gpERAD commitment
reference_section_type: OTHER
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
place **EDEM2** as the factor catalyzing the **first mannose-trimming step** that initiates gpERAD
reference_section_type: OTHER
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IDA
original_reference_id: PMID:25716426
review:
summary: 'IDA annotation for ER localization from PMID:25716426. This study directly
demonstrated by immunofluorescence that epitope-tagged Drosophila EDEM2 co-localizes
with Hsc3 (Drosophila BiP) in the ER when expressed in embryo amnioserosa cells
(PMID:25716426: "Immunolabeling with anti-myc antibody revealed that the Drosophila
EDEMs co-localized with Hsc3").'
action: ACCEPT
reason: Direct IDA evidence from immunofluorescence co-localization with the ER
marker Hsc3 (PMID:25716426). This is the strongest evidence for EDEM2 ER localization.
supported_by:
- reference_id: PMID:25716426
supporting_text: Immunolabeling with anti-myc antibody revealed that the Drosophila
EDEMs co-localized with Hsc3, the Drosophila orthologue of mammalian BIP.
This result is consistent with the hypothesis that Drosophila EDEMs reside
in the ER
- term:
id: GO:0030968
label: endoplasmic reticulum unfolded protein response
evidence_type: IMP
original_reference_id: PMID:25716426
review:
summary: IMP annotation for ER unfolded protein response from PMID:25716426. The
study showed that knockdown of both EDEM1 and EDEM2 led to increased Hsc3 (BiP)
levels under ER stress conditions, and that EDEM2 expression is transcriptionally
induced by ER stress (DTT treatment). This demonstrates that EDEM2 plays a protective
role in the UPR by promoting degradation of misfolded proteins.
action: ACCEPT
reason: Well-supported IMP evidence showing that EDEM2 loss of function exacerbates
ER stress (increased Hsc3 levels) and that EDEM2 is transcriptionally induced
by ER stress (PMID:25716426). This is a core biological process annotation.
supported_by:
- reference_id: PMID:25716426
supporting_text: Drosophila EDEM2 expression was transcriptionally induced
- reference_id: PMID:25716426
supporting_text: The level of Hsc3 increased after 4 h, and this increase was
even more pronounced when both EDEM1 and EDEM2 were knocked down
- term:
id: GO:0034976
label: response to endoplasmic reticulum stress
evidence_type: IEP
original_reference_id: PMID:25716426
review:
summary: 'IEP annotation for response to ER stress from PMID:25716426. Based on
expression pattern evidence: EDEM2 mRNA is transcriptionally induced by ER stress
agents (DTT, tunicamycin, thapsigargin). The IEP evidence is appropriate for
the expression-based observation.'
action: ACCEPT
reason: Appropriate IEP annotation based on transcriptional induction of EDEM2
by multiple ER stress agents (PMID:25716426). Consistent with the broader UPR
role. Falcon deep research further notes that Edem2 overexpression suppresses an
ER-stress reporter (xbp1-EGFP) driven by misfolded Rh-1G69D, consistent with
Edem2 reducing misfolded-client burden during the ER stress response.
supported_by:
- reference_id: PMID:25716426
supporting_text: Drosophila EDEM2 expression was transcriptionally induced
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
Edem2 overexpression selectively reduced mutant Rh-1G69D levels (but not wild-type Rh-1), physically associated with Rh-1G69D, suppressed an ER-stress reporter (**xbp1-EGFP**), and delayed adult retinal degeneration
reference_section_type: OTHER
- term:
id: GO:0097466
label: ubiquitin-dependent glycoprotein ERAD pathway
evidence_type: IMP
original_reference_id: PMID:25716426
review:
summary: IMP annotation for ubiquitin-dependent glycoprotein ERAD pathway from
PMID:25716426. The study demonstrated that EDEM2 knockdown leads to accumulation
of glycosylated A1AT mutant variants, and EDEM2 overexpression promotes their
ubiquitination and degradation. This is the core biological process function
of EDEM2.
action: ACCEPT
reason: Strong IMP evidence showing EDEM2 promotes ubiquitin-dependent degradation
of misfolded glycoproteins. Knockdown causes accumulation; overexpression accelerates
degradation and increases ubiquitination (PMID:25716426). Core function annotation.
supported_by:
- reference_id: PMID:25716426
supporting_text: The level of ATZ increased by approximately 2-fold after the
knockdown of EDEM1 and EDEM2 by dsRNA in Drosophila S2 cells
- reference_id: PMID:25716426
supporting_text: The co-expression of EDEM1 or EDEM2 with ATZ increased the
level of ubiquitinated ATZ
- term:
id: GO:0004571
label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
evidence_type: ISM
original_reference_id: PMID:19805114
review:
summary: ISM annotation for mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
from PMID:19805114 (sequence model-based inference). EDEM2 contains the GH47
catalytic domain with conserved active site residues. The ISM evidence is based
on sequence analysis. Consistent with IBA and IEA annotations for the same term.
action: ACCEPT
reason: Consistent with the IBA and IEA annotations. The ISM evidence based on
conserved active site residues is appropriate for this enzyme family assignment.
supported_by:
- reference_id: PMID:19805114
supporting_text: we specifically analyzed the role of Drosophila genes homologous
to the known yeast and animal regulators of the ER-associated degradation (ERAD)
pathway
- term:
id: GO:0030968
label: endoplasmic reticulum unfolded protein response
evidence_type: IGI
original_reference_id: PMID:19805114
review:
summary: 'IGI annotation for ER unfolded protein response from PMID:19805114.
This study showed that loss-of-function of ERAD factors (including EDEM2) resulted
in increased levels of misfolded Rh-1 in ninaE mutant flies, while co-expression
of ERAD factors reduced Rh-1 levels and suppressed ER stress reporter activation
(PMID:19805114: "co-expression of certain ERAD factors was sufficient to reduce
Rh-1 protein levels and to completely suppress ER stress reporter activation").
The IGI evidence (genetic interaction with ninaE mutants) supports EDEM2 role
in UPR.'
action: ACCEPT
reason: The IGI evidence from genetic interaction with ninaE (Rh-1) mutants supports
EDEM2 involvement in the ER unfolded protein response. ERAD factor overexpression
suppressed ER stress in the Drosophila retinal degeneration model (PMID:19805114).
supported_by:
- reference_id: PMID:19805114
supporting_text: co-expression of certain ERAD factors was sufficient to reduce
Rh-1 protein levels and to completely suppress ER stress reporter activation
- term:
id: GO:0036503
label: ERAD pathway
evidence_type: IGI
original_reference_id: PMID:19805114
review:
summary: IGI annotation for ERAD pathway from PMID:19805114. The study demonstrated
that loss-of-function of ERAD factors including EDEM2 increased levels of misfolded
Rh-1, and that ERAD factor overexpression reduced misfolded Rh-1 levels. The
genetic interaction evidence supports EDEM2 involvement in ERAD.
action: ACCEPT
reason: ERAD is the core biological process for EDEM2. The IGI evidence from the
Drosophila retinal degeneration model (PMID:19805114) supports this annotation.
Consistent with the more specific GO:0097466 annotation.
supported_by:
- reference_id: PMID:19805114
supporting_text: loss-of-function of these putative ERAD factors resulted in
increased levels of Rh-1 in ninaE mutant flies
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
did not rescue EMC3-dependent losses of Rh1/TRP, supporting the conclusion that some client degradation is **ERAD-independent** while other substrates remain **Edem-dependent**
reference_section_type: OTHER
- term:
id: GO:0051082
label: unfolded protein binding
evidence_type: IPI
original_reference_id: PMID:19805114
review:
summary: IPI annotation for unfolded protein binding from PMID:19805114. The IPI
evidence is based on physical interaction between EDEM2 and the misfolded Rh-1
protein (the WITH/FROM column lists FB:FBgn0002940, which is ninaE/Rh1). However,
EDEM2 is an ERAD substrate recognition factor (lectin/sensor) that recognizes
misfolded glycoproteins for degradation, not a chaperone that prevents aggregation.
The interaction with misfolded Rh-1 is in the context of ERAD substrate recognition
and targeting for degradation, not chaperone holdase or foldase activity. Per
UPB project decision rules, ER quality control sensors should have GO:0051082
removed or marked as over-annotated. EDEM2 recognizes misfolded glycoprotein
substrates via their N-glycan structures, which is fundamentally different from
chaperone-mediated binding to unfolded polypeptide segments.
action: MARK_AS_OVER_ANNOTATED
reason: EDEM2 is an ERAD substrate recognition factor (lectin/sensor), not a chaperone.
Its interaction with misfolded Rh-1 (PMID:19805114) reflects ERAD substrate
recognition for degradation, not chaperone activity. Per UPB project rules,
ER quality control sensors should not be annotated with GO:0051082. EDEM2 recognizes
misfolded glycoproteins via N-glycan mannose trimming patterns, targeting them
for ubiquitin- dependent proteasomal degradation (PMID:25716426). This is a
sensor/lectin function, not an unfolded protein binding/chaperone function.
supported_by:
- reference_id: PMID:25716426
supporting_text: While ER degradation-enhancing α-mannosidase-like proteins
(EDEMs) were initially considered lectins (2,3), recent studies have revealed
that EDEMs can function as mannosidases (4,5) and molecular chaperones (6)
- reference_id: PMID:25716426
supporting_text: EDEMs are involved in one of the early steps of ERAD substrate
recognition
- reference_id: PMID:19805114
supporting_text: loss-of-function of these putative ERAD factors resulted in
increased levels of Rh-1 in ninaE mutant flies
- reference_id: file:DROME/Edem2/Edem2-deep-research-falcon.md
supporting_text: |-
EDEM proteins (ER degradation-enhancing α-mannosidase-like proteins) are class I α-mannosidase-like factors (GH47-related) implicated in accelerating disposal of misfolded glycoproteins
reference_section_type: OTHER
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:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
- id: GO_REF:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
links
findings: []
- id: PMID:19805114
title: Suppression of retinal degeneration in Drosophila by stimulation of ER-associated
degradation.
findings: []
- id: PMID:25716426
title: Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z
variant.
findings: []
- id: PMID:28633019
title: EDEM Function in ERAD Protects against Chronic ER Proteinopathy and Age-Related
Physiological Decline in Drosophila.
findings:
- statement: |-
Wild-type dEDEM2 overexpression reduces steady-state levels of the glycoprotein
ERAD substrate NHK, whereas the catalytically inactive mutant E144Q (EF-hand
motif mutation that abolishes alpha-1,2-mannosidase activity) instead increases
NHK levels, indicating that mannosidase catalytic activity contributes to
clearance of at least some glycoprotein ERAD substrates.
supporting_text: |-
dEDEM2 significantly reduced steady-state levels of NHK proteins, whereas the effect of dEDEM1 was modest (Figure 3D).
reference_section_type: RESULTS
- statement: |-
EDEM mannosidase activity is dispensable for protection against chronic ER
proteinopathy and age-related decline: catalytically inactive mutants E123Q
and E144Q still reduced the non-glycoprotein substrate Abeta42 and suppressed
neurodegenerative and locomotor phenotypes, supporting a mannosidase-independent
(chaperone-like) substrate-engagement role in some contexts.
supporting_text: |-
E123Q and E144Q also significantly reduced Aβ42 levels, confirming that dEDEM mannosidase activity is not required for degradation of Aβ42, a non-glycoprotein substrate (Figure 3E).
reference_section_type: RESULTS
- id: PMID:31553680
title: "ER membrane protein complex is required for the insertions of late-synthesized transmembrane helices of Rh1 in Drosophila photoreceptors."
findings:
- statement: |-
In Drosophila photoreceptors, loss of Edem1/Edem2 contributes to stabilization
of some ERAD substrates (e.g. increased ER accumulation of TRP in a Syx5
background), but Edem-dependent ERAD is substrate-selective and does not account
for degradation of all unstable photoreceptor proteins, with some client
degradation in EMC-deficient cells being ERAD-independent.
supporting_text: |-
Rh1 was translated to its C terminus but degraded independently from
reference_section_type: RESULTS
- id: file:DROME/Edem2/Edem2-deep-research-falcon.md
title: Falcon deep research report on Drosophila Edem2
findings:
- statement: |-
Drosophila Edem2 (CG5682) is an ER-resident, GH47 / class I alpha-mannosidase-like
ERAD factor (EDEM family) that promotes disposal of misfolded glycoprotein
clients in the ER, improving proteostasis under proteotoxic burden.
supporting_text: |-
EDEM proteins (ER degradation-enhancing α-mannosidase-like proteins) are class I α-mannosidase-like factors (GH47-related) implicated in accelerating disposal of misfolded glycoproteins
reference_section_type: OTHER
- statement: |-
In Drosophila, overexpression of wild-type dEDEM2 reduces steady-state NHK
protein levels whereas the catalytic mutant E144Q increases NHK, implying that
mannosidase catalytic activity contributes to clearance of at least some
glycoprotein ERAD substrates; some protective effects (e.g. against Abeta42)
persist with catalytic mutants, implying additional non-enzymatic roles.
supporting_text: |-
overexpression of wild-type dEDEM2 reduced steady-state NHK protein levels, whereas a catalytically inactive mutant (E144Q) increased NHK levels, implying that **mannosidase-catalytic activity contributes to clearance of at least some glycoprotein ERAD substrates**
reference_section_type: OTHER
- statement: |-
Conserved mechanistic framing places EDEM2 at the first mannose-trimming step
that initiates glycoprotein ERAD (gpERAD), acting on high-mannose N-glycans of
misfolded glycoproteins (in mammals as an EDEM2-TXNDC11 complex), making this
the most parsimonious model for Drosophila Edem2.
supporting_text: |-
EDEM2 is an **α1,2-mannose trimming enzyme** acting on **high-mannose N-glycans** of misfolded glycoproteins to promote gpERAD commitment
reference_section_type: OTHER
- statement: |-
Mammalian EDEM1/EDEM2 mannosidase activity is folding-state dependent, being much
higher on unfolded/denatured glycoproteins (trimming toward smaller high-mannose
species, M8 to M5), consistent with selective action on misfolded ER clients.
supporting_text: |-
EDEM2’s mannosidase activity is much higher on **unfolded/denatured glycoproteins**, trimming N-glycans to smaller high-mannose species (reported endpoints include M8→M5 species)
reference_section_type: OTHER
- statement: |-
In a Drosophila retinitis-pigmentosa model, Edem2 overexpression selectively
reduced misfolded Rh-1G69D (not wild-type Rh-1), physically associated with
Rh-1G69D, suppressed the xbp1-EGFP ER-stress reporter, and delayed retinal
degeneration, indicating substrate-selective ER quality control upstream of UPR.
supporting_text: |-
Edem2 overexpression selectively reduced mutant Rh-1G69D levels (but not wild-type Rh-1), physically associated with Rh-1G69D, suppressed an ER-stress reporter (**xbp1-EGFP**), and delayed adult retinal degeneration
reference_section_type: OTHER
- statement: |-
Genetic analysis in photoreceptors shows Edem2-dependent ERAD is substrate-selective:
loss of Edem1/Edem2 did not rescue EMC3-dependent loss of Rh1/TRP, indicating some
client degradation is ERAD-independent while other substrates remain Edem-dependent.
supporting_text: |-
did not rescue EMC3-dependent losses of Rh1/TRP, supporting the conclusion that some client degradation is **ERAD-independent** while other substrates remain **Edem-dependent**
reference_section_type: OTHER