Edem2

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 (lectin/sensor) 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 plays a protective role by promoting degradation of misfolded proteins
  such as mutant alpha-1-antitrypsin variants NHK and ATZ (PMID:25716426). EDEM2 co-localizes
  with Hsc3 (Drosophila BiP ortholog) in the ER (PMID:25716426). The GO:0051082 unfolded
  protein binding annotation reflects its recognition of misfolded glycoprotein substrates
  for ERAD, but this is a quality control sensor function, not chaperone activity.
  Per UPB project guidelines, ER quality control sensors should have GO:0051082 removed
  or marked as over-annotated.
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
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.'
    action: ACCEPT
    reason: EDEM2 belongs to GH47 family with conserved active site residues. The
      IBA annotation is phylogenetically sound across EDEM family members. Recent
      literature supports that EDEMs can have mannosidase activity (PMID:25716426).
      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
- 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
- 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
- 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.
- 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.
    supported_by:
    - reference_id: PMID:25716426
      supporting_text: Drosophila EDEM2 expression was transcriptionally induced
- 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
- 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
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: []