id: Q92611
gene_symbol: EDEM1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EDEM1 (ER degradation-enhancing alpha-mannosidase-like protein 1) is a single-pass type II endoplasmic reticulum membrane protein of glycoside hydrolase family 47 (GH47), one of three mammalian Htm1/Mns1 homologues (EDEM1, EDEM2, EDEM3) acting in the ER-associated degradation of glycoproteins (gpERAD). EDEM1 extracts terminally misfolded glycoproteins, but not proteins undergoing productive folding, from the calnexin/calreticulin folding cycle and accelerates their clearance, delivering aberrant substrates to the SEL1L/HRD1 dislocation and ubiquitination machinery and, via Derlin-2/-3, to the p97/VCP retrotranslocation system. It recognizes non-native protein structure in a glycan-independent manner (acting in part as a lectin/holdase-like factor), binding both glycosylated and nonglycosylated misfolded substrates, and it requires its mannosidase-like domain for association with SEL1L. EDEM1 possesses low alpha-1,2-mannosidase activity, contributing to the second mannose-trimming step (Man8GlcNAc2 to Man7GlcNAc2) that exposes the alpha-1,6-mannose recognized by downstream lectins (OS-9/XTP3-B); its catalytic activity is weak relative to its recognition/delivery role and was historically debated. EDEM1 is induced by the IRE1-XBP1 branch of the unfolded protein response, resides in the ER membrane and concentrates in the ER-derived quality control compartment (ERQC), and promotes ER-to-cytosol retrotranslocation of substrates including the ricin A chain.
alternative_products:
- name: '1'
  id: Q92611-1
- name: '2'
  id: Q92611-2
  sequence_note: VSP_056703, VSP_056704
existing_annotations:
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: GH47-family mannosidases use a calcium ion in the active site; EDEM1 retains this fold and binds calcium as a structural/catalytic cofactor. This is subsidiary to its recognition and ERAD functions, especially given its weak mannosidase activity.
    action: KEEP_AS_NON_CORE
    reason: Accurate structural cofactor attribute of the GH47 mannosidase-like domain, but not a standalone core function; the informative functions are misfolded protein recognition and ERAD.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: Belongs to the glycosyl hydrolase 47 family
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: EDEM1 is an ER-resident protein; electronic (ARBA) assignment of ER localization is consistent with experimental evidence.
    action: ACCEPT
    reason: Correct site of action; redundant with IDA ER and ERQC annotations.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: EDEM1 is a single-pass type II ER membrane protein; electronic transfer of ER membrane localization is correct.
    action: ACCEPT
    reason: Correct compartment; redundant with the ISS ER membrane annotation and UniProt subcellular location.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: Single-pass type II membrane protein
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Generic carbohydrate metabolic process from InterPro; far less informative than the specific ER mannose trimming and ERAD processes EDEM1 participates in.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-general parent; the specific ER mannose trimming (GO:1904380) and ERAD (GO:0036503) terms better capture the biology.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: Belongs to the glycosyl hydrolase 47 family
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic membrane localization from InterPro, superseded by the specific ER membrane annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative parent; EDEM1 is specifically an ER membrane protein.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic (ARBA) assignment of the ERAD pathway, consistent with extensive experimental evidence that EDEM1 accelerates ERAD of misfolded glycoproteins.
    action: ACCEPT
    reason: Correct core biological process; redundant with IMP/ISS evidence.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: It is directly involved in endoplasmic reticulum-associated degradation (ERAD)
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: EDEM1 contributes to ER mannose trimming (the Man8 to Man7 step); electronic assignment is consistent with the IMP evidence.
    action: ACCEPT
    reason: Correct biological process; redundant with the IMP annotation from endogenous knockout analysis.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1
- term:
    id: GO:1904154
    label: positive regulation of retrograde protein transport, ER to cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: EDEM1 promotes retrotranslocation of ERAD substrates from the ER to the cytosol; electronic assignment is consistent with the experimental ricin retrotranslocation data.
    action: KEEP_AS_NON_CORE
    reason: Real, specific aspect of EDEM1 function (substrate dislocation) but subordinate to the core recognition/ERAD role; redundant with the IMP/IGI annotations.
    supported_by:
    - reference_id: PMID:24200403
      supporting_text: This transport is promoted by EDEM1
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782685
  qualifier: enables
  review:
    summary: Reactome curation of EDEM1 (with EDEM3) hydrolysing Man8 to Man5 glycans. EDEM1 has genuine but low alpha-1,2-mannosidase activity contributing to the second trimming step.
    action: ACCEPT
    reason: Correct molecular function (weak but real, demonstrated by endogenous knockout); kept as supporting rather than the dominant function.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: all endogenous EDEMs possess mannosidase activity
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with EDEM1's site of action.
    action: ACCEPT
    reason: Correct compartment with direct experimental support.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: IMP
  original_reference_id: PMID:25092655
  qualifier: involved_in
  review:
    summary: Endogenous EDEM1 knockout in human and chicken cells increased Man8B levels, showing EDEM1 contributes (with EDEM3) to the second ER mannose-trimming step from Man8GlcNAc2 to Man7GlcNAc2.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support from endogenous gene knockout.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:25092655
  qualifier: involved_in
  review:
    summary: EDEM1 knockout delayed degradation of the gpERAD substrate ATF6alpha, which is degraded by the ubiquitin-proteasome system; supports a role in ubiquitin-dependent catabolism via ERAD.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic parent process; the more specific ERAD pathway (GO:0036503) better captures EDEM1's role.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: deletion of hEDEM1 significantly delayed the degradation of hATF6
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:21062743
  qualifier: involved_in
  review:
    summary: EDEM1 functions in ERAD by handing off substrate glycoproteins, after mannose trimming, to the late ERAD lectin XTP3-B and downstream E3 ligases.
    action: ACCEPT
    reason: Core biological process; experimentally links EDEM1 to the downstream ERAD machinery.
    supported_by:
    - reference_id: PMID:21062743
      supporting_text: mannose trimming enables delivery of a substrate glycoprotein from EDEM1 to late ERAD steps through association with XTP3-B
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:25092655
  qualifier: involved_in
  review:
    summary: Endogenous EDEM1 knockout delayed gpERAD of ATF6alpha, directly demonstrating EDEM1's role in the ERAD pathway.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: deletion of hEDEM1 significantly delayed the degradation of hATF6
- term:
    id: GO:1904382
    label: mannose trimming involved in glycoprotein ERAD pathway
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782685
  qualifier: involved_in
  review:
    summary: Reactome curation of EDEM1 mannose trimming within the glycoprotein ERAD pathway; an accurate, specific refinement of EDEM1's trimming contribution to ERAD.
    action: ACCEPT
    reason: Correct specific biological process linking the trimming activity to ERAD.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: M8B is trimmed by EDEM1 and EDEM3 to Man7-5GlcNAc2, which are recognized by lectin OS-9
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IDA
  original_reference_id: PMID:23233672
  qualifier: located_in
  review:
    summary: On proteasome inhibition, EDEM1 and other ERAD machinery accumulate with substrates in the ER-derived quality control compartment (ERQC), supporting an ERQC localization.
    action: ACCEPT
    reason: Genuine, functionally relevant localization with direct experimental support.
    supported_by:
    - reference_id: PMID:23233672
      supporting_text: accumulation of the nonglycosylated proteins and ERAD machinery in the endoplasmic reticulum-derived quality control compartment
- term:
    id: GO:0045047
    label: protein targeting to ER
  evidence_type: IMP
  original_reference_id: PMID:23233672
  qualifier: involved_in
  review:
    summary: This annotation derives from work showing EDEM1 targets misfolded substrates to the ER membrane dislocation/ERAD machinery, not co-translational targeting of nascent proteins to the ER. The GO term protein targeting to ER (import into the ER) poorly captures the demonstrated delivery-to-ERAD biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term denotes targeting of proteins into the ER (e.g. co-translational import), which is not what EDEM1 does; the experimental result is substrate delivery to the ER-membrane ERAD/dislocation complex. Retained (experimental basis) rather than removed, but the term is a poor fit.
    supported_by:
    - reference_id: PMID:19524542
      supporting_text: target aberrant proteins to the ER membrane dislocation and ubiquitination complex containing SEL1L
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IMP
  original_reference_id: PMID:23233672
  qualifier: enables
  review:
    summary: EDEM1 binds misfolded glycosylated and nonglycosylated substrates, associating with nonglycosylated proteins through a region outside its mannosidase-like domain; recognition of non-native protein structure is a core EDEM1 function.
    action: ACCEPT
    reason: Core molecular function; EDEM1's defining role is recognition of misfolded/non-native proteins for ERAD.
    supported_by:
    - reference_id: PMID:23233672
      supporting_text: EDEM1 associates through a region outside of its mannosidase-like domain with the nonglycosylated proteins
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IMP
  original_reference_id: PMID:25092655
  qualifier: enables
  review:
    summary: Endogenous gene knockout established that EDEM1 possesses (weak) alpha-1,2-mannosidase activity, contributing to the second trimming step Man8B to Man7. This resolved the long-standing mannosidase-versus-lectin controversy in favor of genuine but low catalytic activity.
    action: ACCEPT
    reason: Molecular function supported by endogenous knockout (IMP); EDEM1 has the weakest mannosidase activity of the three EDEMs, so this is retained as a supporting rather than dominant function.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: all endogenous EDEMs possess mannosidase activity
- term:
    id: GO:1904154
    label: positive regulation of retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:24200403
  qualifier: involved_in
  review:
    summary: EDEM1 promotes ER-to-cytosol retrotranslocation of the ricin A chain, a model retrotranslocation substrate handled like a misfolded ER protein.
    action: KEEP_AS_NON_CORE
    reason: Specific, experimentally supported aspect of EDEM1's ERAD/dislocation activity, but subordinate to the core recognition/ERAD role.
    supported_by:
    - reference_id: PMID:24200403
      supporting_text: This transport is promoted by EDEM1
- term:
    id: GO:1904154
    label: positive regulation of retrograde protein transport, ER to cytosol
  evidence_type: IGI
  original_reference_id: PMID:24200403
  qualifier: involved_in
  review:
    summary: Genetic-interaction evidence (with EDEM2, UniProtKB:Q9BV94) that EDEM1 promotes ricin A-chain retrotranslocation from the ER to the cytosol.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the IMP retrotranslocation annotation; a specific aspect of the dislocation function rather than the core role.
    supported_by:
    - reference_id: PMID:24200403
      supporting_text: more ricin can interact with EDEM2 in comparison with EDEM1
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1791155
  qualifier: located_in
  review:
    summary: Reactome curation of EDEM1 ERQC localization (EDEM expression context); consistent with direct IDA evidence.
    action: ACCEPT
    reason: Correct compartment; redundant with the IDA ERQC annotation.
    supported_by:
    - reference_id: PMID:23233672
      supporting_text: endoplasmic reticulum-derived quality control compartment
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782685
  qualifier: located_in
  review:
    summary: Reactome curation of EDEM1 ERQC localization in the mannose-trimming reaction context.
    action: ACCEPT
    reason: Correct compartment; redundant with the IDA ERQC annotation.
    supported_by:
    - reference_id: PMID:23233672
      supporting_text: endoplasmic reticulum-derived quality control compartment
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IMP
  original_reference_id: PMID:21062743
  qualifier: located_in
  review:
    summary: ER localization in the context of EDEM1-dependent ERAD substrate handoff.
    action: ACCEPT
    reason: Correct site of action; consistent with experimental ER/ERQC evidence.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:24200403
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization of EDEM1 in the ricin retrotranslocation study.
    action: ACCEPT
    reason: Correct compartment with direct experimental support.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  evidence_type: IDA
  original_reference_id: PMID:12610306
  qualifier: enables
  negated: true
  review:
    summary: A negated (NOT) experimental annotation reflecting the original proposal that EDEM1 lacks alpha-1,2-mannosidase activity, based on overexpression biochemistry. Later endogenous-knockout analysis (PMID:25092655) demonstrated that EDEM1 does possess weak mannosidase activity, so this negation is superseded but retained as the curated record of the early finding.
    action: KEEP_AS_NON_CORE
    reason: Genuine historical experimental (IDA) annotation that conflicts with later endogenous-KO evidence; per guidelines an experimental annotation is not removed on weak grounds. Flagged as superseded by PMID:25092655.
    supported_by:
    - reference_id: PMID:25092655
      supporting_text: it had originally been proposed that EDEM1 has no α1,2-mannosidase
        activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19524542
  qualifier: enables
  review:
    summary: Physical interaction with SEL1L (UniProtKB:Q9UBV2), the HRD1-complex adaptor through which EDEM1 delivers substrates to the dislocation machinery. The bare protein binding term is uninformative; the SEL1L interaction is captured by the misfolded protein binding and ERAD annotations.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction (SEL1L) but bare protein binding is uninformative per curation guidelines; the functional consequence is reflected in the ERAD/recognition terms.
    supported_by:
    - reference_id: PMID:19524542
      supporting_text: its association with the ER membrane adaptor protein SEL1L
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19934218
  qualifier: enables
  review:
    summary: Physical interaction with rod opsin (UniProtKB:P08100), an EDEM1 client glycoprotein. The bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real client interaction (rod opsin) but bare protein binding is uninformative; EDEM1's recognition function is captured by misfolded protein binding.
    supported_by:
    - reference_id: PMID:19934218
      supporting_text: rod opsin co-immunoprecipitated with EDEM1
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:19524542
  qualifier: enables
  review:
    summary: EDEM1 directly and specifically binds non-native proteins in a glycan-independent manner, demonstrating recognition of misfolded protein structure independent of N-glycan trimming.
    action: ACCEPT
    reason: Core molecular function; direct demonstration of misfolded/non-native protein recognition.
    supported_by:
    - reference_id: PMID:19524542
      supporting_text: EDEM1 specifically binds nonnative proteins in a glycan-independent manner
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16449189
  qualifier: enables
  review:
    summary: Physical interactions with Derlin-2 (UniProtKB:Q9GZP9) and Derlin-3 (UniProtKB:Q96Q80), which link EDEM to p97/VCP for substrate extraction. The bare protein binding term is uninformative; the functional role is reflected in the ERAD annotations.
    action: KEEP_AS_NON_CORE
    reason: Records real Derlin-2/-3 interactions providing the EDEM-to-p97 link, but bare protein binding is uninformative per guidelines.
    supported_by:
    - reference_id: PMID:16449189
      supporting_text: Derlin-2 and -3 are associated with EDEM and p97
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer (from mouse Q925U4) of ER membrane localization; EDEM1 is a single-pass type II ER membrane protein.
    action: ACCEPT
    reason: Correct compartment; consistent with UniProt subcellular location and IDA evidence.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: Single-pass type II membrane protein
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity transfer of the ERAD pathway role from the mouse ortholog; consistent with extensive human experimental evidence.
    action: ACCEPT
    reason: Correct core biological process; redundant with IMP evidence.
    supported_by:
    - reference_id: file:human/EDEM1/EDEM1-uniprot.txt
      supporting_text: It is directly involved in endoplasmic reticulum-associated degradation (ERAD)
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12610306
  title: Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle.
  findings:
  - statement: EDEM extracts misfolded glycoproteins, but not glycoproteins undergoing productive folding, from the calnexin cycle; overexpression accelerates release and ERAD.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational demonstration of EDEM1's role in extracting misfolded glycoproteins from the calnexin cycle. Also the source of the NOT mannosidase IDA (early no-activity view, later superseded by PMID:25092655).
- id: PMID:16449189
  title: Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation.
  findings:
  - statement: Derlin-2 and -3 are associated with EDEM and p97 and provide the missing link between EDEM and p97 in degradation of misfolded glycoproteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the EDEM1-DERL2/DERL3 protein binding annotations; establishes the EDEM-to-p97 link.
- id: PMID:19524542
  title: EDEM1 recognition and delivery of misfolded proteins to the SEL1L-containing ERAD complex.
  findings:
  - statement: EDEM1 specifically binds non-native proteins in a glycan-independent manner; its mannosidase-like domain is required for SEL1L association but not for substrate binding.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key evidence for glycan-independent misfolded protein recognition and the SEL1L delivery model; supports the misfolded protein binding core function.
- id: PMID:19934218
  title: A dual role for EDEM1 in the processing of rod opsin.
  findings:
  - statement: EDEM1 is a chaperone of rod opsin; it promotes degradation of misfolded P23H rod opsin and reduces aggregation, with binding independent of mannose trimming.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the rod opsin (P08100) interaction; supports trimming-independent client recognition and ER membrane localization.
- id: PMID:21062743
  title: Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B and to late endoplasmic reticulum-associated degradation steps.
  findings:
  - statement: Mannose trimming enables handoff of a substrate glycoprotein from EDEM1 to the late ERAD lectin XTP3-B and downstream E3 ligases; EDEM1 binding itself is trimming-independent.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Places EDEM1 upstream of XTP3-B/HRD1 in the ERAD pathway; supports the ERAD and ER localization annotations.
- id: PMID:23233672
  title: A shared endoplasmic reticulum-associated degradation pathway involving the EDEM1 protein for glycosylated and nonglycosylated proteins.
  findings:
  - statement: EDEM1 is used by both glycosylated and nonglycosylated misfolded substrates, binding nonglycosylated proteins through a region outside its mannosidase-like domain; ERAD machinery accumulates in the ERQC on proteasome inhibition.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports misfolded protein binding (glycan-independent), ERQC localization, and the shared ERAD pathway.
- id: PMID:24200403
  title: The role of EDEM2 compared with EDEM1 in ricin transport from the endoplasmic reticulum to the cytosol.
  findings:
  - statement: EDEM1 (and EDEM2) promote retrotranslocation of the ricin A chain from the ER to the cytosol, modeling ERAD-substrate dislocation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports the positive regulation of retrograde protein transport (ER to cytosol) annotations and ER localization.
- id: PMID:25092655
  title: EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step.
  findings:
  - statement: All endogenous EDEMs possess mannosidase activity; EDEM3 and to a lesser extent EDEM1 perform the second trimming step (Man8B to Man7), resolving the mannosidase-versus-lectin controversy.
    reference_section_type: ABSTRACT
  - statement: EDEM1 has the weakest mannosidase activity of the three EDEMs and can also enhance gpERAD independently of catalysis (lectin-like) when overexpressed.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive endogenous-knockout study; establishes EDEM1's weak mannosidase activity and its role in the second trimming step and gpERAD.
- id: PMID:30374462
  title: Mannosidase activity of EDEM1 and EDEM2 depends on an unfolded state of their glycoprotein substrates.
  findings:
  - statement: In vitro, EDEM1 (and EDEM2) mannosidase activity is modest on free oligosaccharides and native glycoproteins but significantly higher on a denatured glycoprotein, explaining how slow background trimming becomes selective for misfolded substrates; the EDEMs associate with oxidoreductases including PDI and TXNDC11.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:30374462, doi:10.1038/s42003-018-0174-8). Demonstrates EDEM1 has bona fide in vitro mannosidase activity that is folding-state dependent (preferential on unfolded/denatured glycoproteins), complementing the endogenous-KO evidence (PMID:25092655). Not cached; reference added without verbatim supporting_text.
- id: PMID:32423001
  title: EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired.
  findings:
  - statement: EDEM1 is found in auto-regulatory complexes with ERAD components; its N-terminal disordered region mediates interaction with misfolded proteins, and EDEM1 overexpression can drive client degradation via autophagy/ER-phagy when proteasomal degradation or dislocation is impaired.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:32423001, doi:10.3390/ijms21103468). Adds the N-terminal intrinsically disordered region as the misfolded-protein-interaction module and shows EDEM1 engages autophagy/ER-phagy as a backup ERAD route. Not cached; reference added without verbatim supporting_text.
- id: PMID:38682256
  title: Turnover of EDEM1, an ERAD-enhancing factor, is mediated by multiple degradation routes.
  findings:
  - statement: EDEM1 is itself turned over by both ERAD (SEL1L/Hrd1, YOD1, XTP3B, ERdj3, VIMP, BAG6, JB12) and autophagy in folded-state-dependent manner; OS9 binds EDEM1 but did not drive its turnover. EDEM1 has a fast half-life (~3 h) and exists in soluble and membrane-associated forms.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:38682256, doi:10.1111/gtc.13117). Establishes that EDEM1, an ERAD accelerator, is itself an ERAD/autophagy substrate (autoregulation). Not cached; reference added without verbatim supporting_text.
- id: PMID:38773321
  title: ER-to-lysosome-associated degradation acts as failsafe mechanism upon ERAD dysfunction.
  findings:
  - statement: Pharmacologic or genetic inhibition of ERAD components, including silencing EDEM1, reroutes canonical ERAD clients (NHK, BACE457delta) to degradative endolysosomes via the ER-phagy receptor FAM134B and the LC3 lipidation machinery.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:38773321, doi:10.1038/s44319-024-00165-y). Shows EDEM1 loss/inhibition activates a compensatory FAM134B-dependent ERLAD route. Not cached; reference added without verbatim supporting_text.
- id: PMID:37528230
  title: Mechanisms of substrate processing during ER-associated protein degradation.
  findings:
  - statement: Authoritative review placing EDEM-family mannosidases among the luminal processing factors that cooperate with chaperones and lectins to deliver misfolded glycoproteins to HRD1-SEL1L-dependent ERAD.
    reference_section_type: OTHER
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:37528230, doi:10.1038/s41580-023-00633-8). Recent Nat Rev MCB review providing consensus ERAD pathway framing for EDEM1. Background/contextual.
- id: Reactome:R-HSA-1791155
  title: Expression of EDEM
  findings: []
- id: Reactome:R-HSA-6782685
  title: EDEM1,3 hydrolyse (GlcNAc)2 (Man)8b to (GlcNAc)2 (Man)5
  findings: []
- id: file:human/EDEM1/EDEM1-uniprot.txt
  title: UniProt entry Q92611 (EDEM1_HUMAN), ER degradation-enhancing alpha-mannosidase-like protein 1
  findings:
  - statement: Single-pass type II ER membrane GH47 protein that extracts misfolded glycoproteins from the calnexin cycle and targets them for ERAD (N-glycan-independent, via SEL1L); has low mannosidase activity (Man8GlcNAc2 to Man7GlcNAc2); interacts with SEL1L, DERL2, DERL3.
    reference_section_type: OTHER
core_functions:
- description: Recognizes terminally misfolded/non-native glycoproteins (and some nonglycosylated proteins) and extracts them from the calnexin/calreticulin folding cycle, delivering them to the SEL1L/HRD1 dislocation and ubiquitination machinery for ER-associated degradation.
  molecular_function:
    id: GO:0051787
    label: misfolded protein binding
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  - id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  supported_by:
  - reference_id: PMID:19524542
    supporting_text: EDEM1 specifically binds nonnative proteins in a glycan-independent manner
  - reference_id: PMID:12610306
    supporting_text: EDEM was shown to extract misfolded glycoproteins, but not glycoproteins undergoing productive folding, from the calnexin cycle
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: Possesses low alpha-1,2-mannosidase activity contributing to the second ER mannose-trimming step (Man8GlcNAc2 to Man7GlcNAc2), generating the alpha-1,6-mannose-exposed glycan recognized by downstream lectins (OS-9/XTP3-B) in glycoprotein ERAD.
  molecular_function:
    id: GO:0004571
    label: mannosyl-oligosaccharide 1,2-alpha-mannosidase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:25092655
    supporting_text: Mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 is performed mainly by EDEM3 and to a lesser extent by EDEM1
  - reference_id: PMID:30374462
  directly_involved_in:
  - id: GO:1904380
    label: endoplasmic reticulum mannose trimming
proposed_new_terms: []
suggested_questions:
- question: To what extent does EDEM1 function in vivo as a catalytic mannosidase versus a lectin/holdase-like recognition factor, and how is the balance set by expression level and ER stress?
- question: What structural features outside the mannosidase-like domain mediate EDEM1's glycan-independent recognition of non-native protein structure?
suggested_experiments:
- description: Reconstitute substrate handoff with purified EDEM1, ERManI, EDEM2/3 and SEL1L on defined misfolded glycoprotein substrates to quantify the relative contributions of EDEM1 catalysis versus recognition/holdase activity to ERAD commitment.
- description: Domain-swap and point-mutation analysis of the EDEM1 mannosidase-like domain in endogenous knock-in cells to separate catalytic, SEL1L-binding, and non-native-protein-binding activities and test their individual requirements for ERAD of glycosylated and nonglycosylated substrates.