id: Q96DZ1
gene_symbol: ERLEC1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ERLEC1 (also known as XTP3-B or Erlectin) is an ER-resident lectin containing
  two mannose 6-phosphate receptor homology (MRH) domains. It functions as a
  context-dependent triage factor in the endoplasmic reticulum-associated
  degradation (ERAD) pathway, recognizing misfolded glycoproteins via their
  trimmed N-glycan sugar moieties and delivering them to the HRD1-SEL1L ubiquitin
  ligase complex for retrotranslocation and proteasomal degradation. The
  C-terminal MRH domain (MRH2) mediates glycan binding with specificity for
  Man9GlcNAc2 (M9) and Man5-type high-mannose N-glycans exposing a terminal
  alpha-1,6-linked mannose motif (DOI:10.1093/glycob/cwp182,
  DOI:10.1111/febs.12157). ERLEC1 forms a large ER quality control scaffold
  complex together with OS-9, BiP (HSPA5), and the HRD1-SEL1L ubiquitin ligase.
  The long isoform (hXTP3-B-long) associates with this scaffold and can retard
  ERAD of both glycosylated and non-glycosylated substrates, while the short
  isoform is excluded from scaffold formation. SEL1L stabilizes ERLEC1 protein;
  SEL1L depletion causes accelerated ERLEC1 degradation (~40% loss over 10 hours
  in cycloheximide chase) without change in mRNA levels (DOI:10.1111/febs.12157).
  Genetic studies reveal that ERLEC1 and OS9 play redundant and antagonistic roles
  in ERAD: both redundantly promote glycoprotein degradation and stabilize
  SEL1L-HRD1, but ERLEC1 strongly inhibits degradation of non-glycosylated
  substrates, with OS9 antagonizing this inhibition, thereby tuning ERAD substrate
  selectivity (DOI:10.1016/j.molcel.2018.03.026). Mannose trimming by ER
  mannosidase I is required for substrate delivery from EDEM1 to XTP3-B,
  consistent with its role as a lectin-based ERAD cargo receptor rather than a
  chaperone.
alternative_products:
- name: 1 (hXTP3B-long)
  id: Q96DZ1-1
- name: 2 (hXTP3B-short)
  id: Q96DZ1-2
  sequence_note: VSP_015790
- name: '3'
  id: Q96DZ1-3
  sequence_note: VSP_047155
existing_annotations:
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation placing ERLEC1 in the ER lumen, inferred from phylogenetic
      analysis. This is strongly supported by multiple independent experimental
      studies. Cruciat et al. (PMID:16531414) showed that Erlectin is a luminal
      resident protein of the endoplasmic reticulum. Hosokawa et al.
      (PMID:18502753) confirmed ER lumen localization. Christianson et al.
      (PMID:18264092) also demonstrated ER lumen localization. UniProt annotates
      subcellular location as ER lumen with experimental evidence. ERLEC1 has a
      signal peptide (aa 1-33) and lacks a transmembrane domain, consistent with
      a soluble ER lumen protein retained by the quality control machinery.
    action: ACCEPT
    reason: >-
      ER lumen localization is a core feature of ERLEC1 function as an ERAD
      cargo receptor. The IBA annotation is fully consistent with multiple
      experimental (IDA) demonstrations of ER lumen localization.
    supported_by:
    - reference_id: PMID:16531414
      supporting_text: >-
        Like other members of the MRH family, Erlectin is a luminal resident
        protein of the endoplasmic reticulum
    - reference_id: PMID:18502753
      supporting_text: >-
        hXTP3-B long isoform associates with the HRD1-SEL1L membrane-anchored
        ubiquitin ligase complex and BiP, forming a 27 S ER quality control
        scaffold complex
- term:
    id: GO:0030970
    label: retrograde protein transport, ER to cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for involvement in retrograde protein transport, ER to
      cytosol, inferred from phylogenetic analysis including yeast Yos9p.
      ERLEC1/XTP3-B is a key component of the ERAD pathway that delivers
      misfolded glycoproteins to the HRD1-SEL1L ubiquitin ligase complex for
      retrotranslocation and proteasomal degradation (PMID:18264092,
      PMID:18502753). Hosokawa et al. (PMID:18502753) showed that ERLEC1 forms
      a scaffold complex that provides a platform for recognition and sorting
      of misfolded proteins prior to retrotranslocation into the cytoplasm.
      Groisman et al. (PMID:21062743) demonstrated that mannose trimming is
      required for substrate delivery from EDEM1 to XTP3-B and to late ERAD
      steps. This term is appropriate as ERLEC1 participates in the process
      that moves ER proteins to the cytosol for degradation.
    action: ACCEPT
    reason: >-
      Retrograde protein transport ER to cytosol is a core process that ERLEC1
      participates in as an ERAD cargo receptor. The IBA annotation is well
      supported by experimental evidence from multiple groups showing ERLEC1
      functions in delivering misfolded substrates to the retrotranslocation
      machinery.
    supported_by:
    - reference_id: PMID:18502753
      supporting_text: >-
        this large ER quality control scaffold complex, containing ER lectins,
        a chaperone, and a ubiquitin ligase, provides a platform for the
        recognition and sorting of misfolded glycoproteins as well as
        nonglycosylated proteins prior to retrotranslocation into the cytoplasm
        for degradation
    - reference_id: PMID:18264092
      supporting_text: >-
        OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to
        ERAD substrates and, through the SEL1L adaptor, to the
        ER-membrane-embedded ubiquitin ligase Hrd1
    - reference_id: PMID:21062743
      supporting_text: >-
        Our results suggest that mannose trimming enables delivery of a
        substrate glycoprotein from EDEM1 to late ERAD steps through
        association with XTP3-B
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation from ARBA machine learning placing ERLEC1 in the
      endoplasmic reticulum. This is correct but less specific than
      GO:0005788 (endoplasmic reticulum lumen), which is supported by
      IDA evidence from multiple publications (PMID:16531414, PMID:18264092)
      and IBA evidence. ERLEC1 is a soluble ER lumen protein, not a
      membrane-associated protein, so the more specific ER lumen term is
      more appropriate. However, as an IEA annotation, it is acceptable to
      retain a broader term that is not incorrect.
    action: ACCEPT
    reason: >-
      While GO:0005783 (endoplasmic reticulum) is less specific than the
      experimentally supported GO:0005788 (ER lumen), it is not incorrect.
      The IEA annotation is a broader but valid computational inference.
      The more specific ER lumen localization is already captured by
      separate IDA and IBA annotations.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation mapping ERLEC1 to the ER lumen based on
      UniProtKB/Swiss-Prot subcellular location vocabulary. UniProt annotates
      ERLEC1 subcellular location as "Endoplasmic reticulum lumen" with
      experimental evidence from PMID:16531414 and PMID:18502753. This
      computational mapping is fully consistent with the experimental data.
    action: ACCEPT
    reason: >-
      The IEA mapping from UniProt subcellular location to GO:0005788 is
      correct and consistent with experimental evidence. ERLEC1 ER lumen
      localization is well established.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro (IPR045149, OS-9-like domain) mapping to the
      ER unfolded protein response. ERLEC1 is part of the ER quality control
      machinery but its primary role is in ERAD, not the canonical unfolded
      protein response (UPR) signaling pathway. The UPR is a transcriptional
      signaling response involving IRE1, PERK, and ATF6 pathways that activates
      gene expression to cope with ER stress. ERLEC1 does not participate in
      UPR signaling; rather, it functions downstream as a cargo receptor in
      ERAD, recognizing misfolded glycoproteins and delivering them to the
      HRD1-SEL1L complex for retrotranslocation (PMID:18264092, PMID:18502753).
      The ERAD pathway annotation (GO:0036503) is the more precise term.
    action: MODIFY
    reason: >-
      GO:0030968 (ER unfolded protein response) refers to the UPR signaling
      cascade, not to ERAD per se. ERLEC1 is not a UPR signaling component
      but rather an ERAD cargo receptor. The correct biological process term
      is GO:0036503 (ERAD pathway), which is already annotated separately.
      This IEA annotation likely arises from an overly broad InterPro-to-GO
      mapping for the OS-9-like domain family.
    proposed_replacement_terms:
    - id: GO:0036503
      label: ERAD pathway
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro (IPR045149, OS-9-like) mapping to the ERAD
      pathway. This is fully supported by extensive experimental evidence.
      ERLEC1/XTP3-B is a central component of the ERAD pathway, functioning
      as a lectin-based cargo receptor that recognizes misfolded glycoproteins
      and delivers them to the HRD1-SEL1L ubiquitin ligase complex
      (PMID:18264092, PMID:18502753, PMID:21062743). Groisman et al.
      (PMID:21062743) specifically demonstrated that mannose trimming is
      required for substrate delivery from EDEM1 to XTP3-B and to late ERAD
      steps. Christianson et al. (PMID:18264092) showed that XTP3-B binds to
      ERAD substrates and through SEL1L to HRD1, and is required for
      degradation of mutant alpha1-antitrypsin.
    action: ACCEPT
    reason: >-
      The ERAD pathway is the core biological process in which ERLEC1
      participates. The IEA annotation is correct and well supported by
      experimental evidence from multiple independent studies.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: TAS
  original_reference_id: PMID:21062743
  review:
    summary: >-
      TAS annotation for ERAD pathway involvement based on Groisman et al.
      (PMID:21062743). This paper directly demonstrates that XTP3-B functions
      in the ERAD pathway by showing that mannose trimming by ER mannosidase I
      is required for substrate delivery from EDEM1 to XTP3-B, and that
      inhibition of mannose trimming blocks substrate association with XTP3-B
      and with E3 ubiquitin ligases HRD1 and SCF(Fbs2). This establishes
      ERLEC1 as a lectin acting at a late step in the ERAD pathway, after
      mannose trimming and before ubiquitination and retrotranslocation.
    action: ACCEPT
    reason: >-
      ERAD pathway involvement is the core function of ERLEC1. The TAS
      annotation is well supported by the cited reference, which directly
      demonstrates ERLEC1 function in delivering substrates to late ERAD
      steps in a mannose-trimming-dependent manner.
    supported_by:
    - reference_id: PMID:21062743
      supporting_text: >-
        Our results suggest that mannose trimming enables delivery of a
        substrate glycoprotein from EDEM1 to late ERAD steps through
        association with XTP3-B
    - reference_id: PMID:21062743
      supporting_text: >-
        substrate association with XTP3-B and with the E3 ubiquitin ligases
        HRD1 and SCF(Fbs2) was inhibited
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:21062743
  review:
    summary: >-
      GO:0051082 (unfolded protein binding) is being obsoleted (go-ontology#30962).
      The suggested replacements are holdase chaperone activity or protein folding
      chaperone (GO:0044183), neither of which applies to ERLEC1. ERLEC1/XTP3-B is
      an ER lectin that recognizes misfolded glycoproteins via their trimmed N-glycan
      moieties as part of the ERAD pathway (PMID:21062743, PMID:18502753). It is not
      a chaperone. Groisman et al. (PMID:21062743) showed that mannose trimming by
      ER mannosidase I is required for substrate delivery from EDEM1 to XTP3-B,
      establishing ERLEC1 as a lectin-based cargo receptor rather than a protein that
      directly binds unfolded polypeptide chains. Christianson et al. (PMID:18264092)
      demonstrated that the MRH domains of XTP3-B are required for interaction with
      SEL1L but not with substrate, and that XTP3-B and OS-9 are components of
      quality control surveillance pathways that coordinate protein folding with
      membrane dislocation and ubiquitin conjugation. Hosokawa et al. (PMID:18502753)
      showed that hXTP3-B forms a scaffold with HRD1-SEL1L and BiP, and that the
      long isoform retarded ERAD of both glycosylated (NHK) and non-glycosylated
      (NHK-QQQ) substrates. While ERLEC1 does interact with misfolded proteins,
      this interaction is in the context of ERAD substrate recognition and delivery
      to the ubiquitin ligase complex, not chaperone-like unfolded protein binding.
      The ERAD pathway involvement is already captured by GO:0036503.
    action: REMOVE
    reason: >-
      GO:0051082 is being obsoleted. The replacement terms (holdase chaperone,
      foldase chaperone) do not apply to ERLEC1, which is a lectin-based ERAD cargo
      receptor, not a chaperone. ERLEC1 recognizes misfolded glycoproteins through
      their N-glycan sugar moieties (requiring mannose trimming) and delivers them
      to the HRD1-SEL1L ubiquitin ligase complex for degradation. This is substrate
      recognition for ERAD targeting, not chaperone-like binding to unfolded
      polypeptide chains. The relevant biological function is already captured by
      the ERAD pathway annotation (GO:0036503) and retrograde protein transport
      annotation (GO:0030970). Similar to SYVN1, ERLEC1 interacts with misfolded
      proteins as part of the ERAD machinery, which does not constitute unfolded
      protein binding in the chaperone sense.
    additional_reference_ids:
    - PMID:18502753
    - PMID:18264092
    - PMID:16531414
    supported_by:
    - reference_id: PMID:21062743
      supporting_text: >-
        Our results suggest that mannose trimming enables delivery of a
        substrate glycoprotein from EDEM1 to late ERAD steps through
        association with XTP3-B
    - reference_id: PMID:21062743
      supporting_text: >-
        substrate association with XTP3-B and with the E3 ubiquitin ligases
        HRD1 and SCF(Fbs2) was inhibited
    - reference_id: PMID:18264092
      supporting_text: >-
        OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to
        ERAD substrates and, through the SEL1L adaptor, to the
        ER-membrane-embedded ubiquitin ligase Hrd1
    - reference_id: PMID:18264092
      supporting_text: >-
        Both proteins contain conserved mannose 6-phosphate receptor homology
        (MRH) domains, which are required for interaction with SEL1L, but not
        with substrate
    - reference_id: PMID:18264092
      supporting_text: >-
        XTP3-B and OS-9 are components of distinct, partially redundant,
        quality control surveillance pathways that coordinate protein folding
        with membrane dislocation and ubiquitin conjugation in mammalian cells
    - reference_id: PMID:18502753
      supporting_text: >-
        hXTP3-B long isoform associates with the HRD1-SEL1L membrane-anchored
        ubiquitin ligase complex and BiP, forming a 27 S ER quality control
        scaffold complex
    - reference_id: PMID:18502753
      supporting_text: >-
        this large ER quality control scaffold complex, containing ER lectins,
        a chaperone, and a ubiquitin ligase, provides a platform for the
        recognition and sorting of misfolded glycoproteins as well as
        nonglycosylated proteins prior to retrotranslocation into the cytoplasm
        for degradation
    - reference_id: PMID:16531414
      supporting_text: >-
        Erlectin functions in N-glycan recognition in the endoplasmic
        reticulum, suggesting that it may regulate glycoprotein traffic
- term:
    id: GO:1904153
    label: negative regulation of retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:25660456
  review:
    summary: >-
      IMP annotation for negative regulation of retrograde protein transport
      (ER to cytosol) based on Zhong et al. (PMID:25660456). This paper used
      RNAi knockdown and a dislocation-reconstituted GFP (drGFP) assay to
      assess the requirement of ERAD components for dislocation of NHK (null
      Hong Kong variant of alpha1-antitrypsin). The study found that knockdown
      of 7 of 21 ERAD components enhanced NHK dislocation. If ERLEC1 knockdown
      enhanced dislocation, this would be consistent with a negative regulatory
      role. However, this seemingly contradicts the established role of ERLEC1
      as a facilitator of ERAD (delivering substrates to the ubiquitin ligase).
      Hosokawa et al. (PMID:18502753) showed that overexpression of the long
      isoform of hXTP3-B retarded ERAD of both NHK and NHK-QQQ, which is
      consistent with a negative regulatory effect when in excess. This
      paradoxical role may reflect that excess ERLEC1 sequesters substrates or
      blocks the retrotranslocation channel. The annotation captures the
      experimental observation but should be interpreted cautiously as possibly
      reflecting an overexpression/dosage artifact rather than a normal
      physiological function.
    action: KEEP_AS_NON_CORE
    reason: >-
      The annotation captures a real experimental observation (IMP evidence)
      but the negative regulation of retrotranslocation is likely not the
      primary physiological role of ERLEC1. Its core function is as a cargo
      receptor that facilitates ERAD. The negative regulatory effect may
      reflect dosage-dependent or context-dependent modulation. Hosokawa et al.
      (PMID:18502753) also observed that hXTP3-B overexpression retards ERAD,
      consistent with a scaffolding role where excess cargo receptor can
      sequester substrates away from the retrotranslocation machinery.
    additional_reference_ids:
    - PMID:18502753
    supported_by:
    - reference_id: PMID:25660456
      supporting_text: >-
        knockdown of 7 of the 21 components enhanced NHK dislocation
    - reference_id: PMID:18502753
      supporting_text: >-
        both isoforms retard ERAD of the human alpha(1)-antitrypsin variant
        null Hong Kong (NHK), a terminally misfolded glycoprotein
    - reference_id: PMID:18502753
      supporting_text: >-
        The hXTP3-B long isoform strongly inhibited ERAD of NHK-QQQ, which
        lacks all of the N-glycosylation sites of NHK
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362412
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-5362412: SYVN1 ubiquitinates Hh
      C-terminal fragments) placing ERLEC1 in the ER quality control
      compartment (ERQC). The ERQC is a pericentriolar ER-derived compartment
      where ERAD machinery concentrates along with misfolded substrates.
      Groisman et al. (PMID:21062743) showed that XTP3-B associates with ERAD
      substrates and E3 ligases in a mannose-trimming-dependent manner,
      consistent with localization to the ERQC. The Reactome entry describes
      ERLEC1 as a lectin in the ERAD machinery that helps target Hedgehog
      C-terminal fragments for degradation. This is a reasonable localization
      annotation for ERLEC1 given its role in ERAD substrate recognition.
    action: ACCEPT
    reason: >-
      ERQC localization is consistent with ERLEC1 function in ERAD. As a
      cargo receptor that concentrates with ERAD machinery and substrates,
      ERLEC1 localizes to this quality control compartment. Multiple
      Reactome entries reference the same biological role; this is one of
      many duplicate TAS annotations from different Reactome reactions.
    supported_by:
    - reference_id: PMID:21062743
      supporting_text: >-
        substrate association with XTP3-B and with the E3 ubiquitin ligases
        HRD1 and SCF(Fbs2) was inhibited
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362437
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-5362437: C-terminal Hh fragments
      are bound by lectins). This Reactome entry explicitly states that
      depletion of OS9 and ERLEC1 abrogates degradation of Hh-C fragments,
      and that they may target Hh-C to the retrotranslocation channel via
      interaction with SEL1. ERQC localization is appropriate for ERLEC1
      given its established role as an ERAD lectin cargo receptor.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a different Reactome
      reaction. Same rationale as for R-HSA-5362412: ERLEC1 localizes to
      the ERQC as part of its ERAD cargo receptor function.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362441
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-5362441: C-terminal Hh fragments
      are recruited to SEL1:SYVN1 at the ER membrane). ERLEC1 participates
      in recruiting substrates to the SEL1L-SYVN1 complex at the ER membrane,
      consistent with ERQC localization.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a different Reactome
      reaction describing the same ERAD process for Hh fragments.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362450
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-5362450: Hh processing variants
      bind lectins). This entry describes how OS9 and ERLEC1 lectins are
      required for degradation of Hh processing-defective variants via the
      ERAD pathway, consistent with ERQC localization.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a different Reactome
      reaction describing ERAD of Hedgehog processing variants.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362459
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-5362459: VCP-catalyzed ATP
      hydrolysis promotes the translocation of Hh-C into the cytosol).
      ERLEC1 is part of the ERAD machinery that operates within the ERQC.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      describing the VCP-dependent retrotranslocation step for Hh-C
      fragments in which ERLEC1 participates upstream.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5387386
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-5387386: Hh processing variants
      are recruited to SEL1:SYVN at the ER membrane). ERLEC1 participates
      in recruiting Hh processing variants to the ubiquitin ligase complex.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction.
      Same biological context as other Hh ERAD entries.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5387389
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-5387389: Hh processing variants
      are translocated to the cytosol in a VCP-dependent manner). Part of
      the Hh ERAD pathway in which ERLEC1 acts as cargo receptor.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      in the Hh ERAD pathway.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5483238
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-5483238: Hh processing variants
      are ubiquitinated). ERLEC1 functions upstream of the ubiquitination
      step in ERAD, within the ERQC.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      describing Hh variant ubiquitination in which ERLEC1 participates.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866542
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-8866542: VCP-catalyzed ATP
      hydrolysis promotes the translocation of misfolded CFTR into the
      cytosol). ERLEC1 is part of the ERAD machinery for misfolded CFTR,
      consistent with ERQC localization.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      describing CFTR ERAD in which ERLEC1 participates as cargo receptor.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866546
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-8866546: RNF5 and RNF185
      ubiquitinate misfolded CFTR). ERLEC1 operates within the ERQC
      as part of the CFTR ERAD pathway.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      in the CFTR ERAD pathway.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866551
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-8866551: CFTR binds components
      of the ERAD machinery for ubiquitination and degradation). ERLEC1
      is one of the ERAD components that binds misfolded CFTR in the ERQC.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      describing CFTR binding to ERAD components including ERLEC1.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866854
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-8866854: VCP-catalyzed ATP
      hydrolysis promotes the translocation of CFTR F508del into the
      cytosol). ERLEC1 participates in ERAD of the common CF-causing
      CFTR F508del mutation, within the ERQC.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      in the CFTR F508del ERAD pathway.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866856
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-8866856: RNF5 and RNF185
      ubiquitinate CFTR F508del). ERLEC1 is part of the ERAD machinery
      for CFTR F508del within the ERQC.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      in the CFTR F508del ERAD pathway.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866857
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-8866857: CFTR F508del binds
      components of the ERAD machinery for ubiquitination and degradation).
      ERLEC1 is an ERAD component that binds misfolded CFTR F508del.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      describing CFTR F508del ERAD.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931264
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-9931264: Active transport of
      ubiquitinated CD274 from ER to cytosol). ERLEC1 participates in
      ERAD of CD274 (PD-L1) within the ERQC.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      describing CD274 ERAD.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931298
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-9931298: Ubiquitination of CD274
      by ERAD complex). ERLEC1 is part of the ERAD complex that
      ubiquitinates CD274.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      describing CD274 ubiquitination by ERAD.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931313
  review:
    summary: >-
      TAS annotation from Reactome (R-HSA-9931313: p-S195-CD274 binds
      ERAD complex). ERLEC1 is part of the ERAD complex that binds
      phosphorylated CD274 for degradation.
    action: ACCEPT
    reason: >-
      Duplicate ERQC localization annotation from a Reactome reaction
      describing CD274 ERAD. Last of the 16 duplicate Reactome TAS
      annotations for ERQC localization, all consistent with ERLEC1
      role in ERAD.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18502753
  review:
    summary: >-
      IPI annotation for protein binding based on Hosokawa et al.
      (PMID:18502753), with UniProtKB:Q13438 (OS-9/OS9) as the interacting
      partner. This paper showed that hXTP3-B forms an ER quality control
      scaffold complex with OS-9, HRD1-SEL1L, and BiP. The interaction
      between ERLEC1 and OS-9 is in the context of the ERAD scaffold complex.
      While the interaction is real, GO:0005515 (protein binding) is
      uninformative. A more specific term such as GO:0051787 (misfolded
      protein binding) would capture the functional context, though the
      direct interaction with OS-9 is more of a scaffold co-complex
      interaction. The term could be modified to misfolded protein binding
      to reflect ERLEC1 function, but since the with/from is OS-9 (a
      co-complex partner, not a misfolded substrate), the annotation as
      stated is simply documenting a physical interaction.
    action: MODIFY
    reason: >-
      GO:0005515 (protein binding) is uninformative per curation guidelines.
      ERLEC1 binds misfolded glycoproteins as a cargo receptor. The more
      informative term is GO:0051787 (misfolded protein binding), which
      captures ERLEC1 core molecular function of recognizing misfolded
      glycoprotein substrates for ERAD.
    proposed_replacement_terms:
    - id: GO:0051787
      label: misfolded protein binding
    supported_by:
    - reference_id: PMID:18502753
      supporting_text: >-
        this large ER quality control scaffold complex, containing ER lectins,
        a chaperone, and a ubiquitin ligase, provides a platform for the
        recognition and sorting of misfolded glycoproteins as well as
        nonglycosylated proteins prior to retrotranslocation into the cytoplasm
        for degradation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IDA
  original_reference_id: PMID:16531414
  review:
    summary: >-
      IDA annotation for protein binding based on Cruciat et al.
      (PMID:16531414). This paper identified Erlectin as a protein that
      interacts with Kremen2 (KREMEN2), a coreceptor for Dickkopf1 in Wnt
      signaling. The interaction with Kremen2 is glycosylation-dependent
      (abolished by Kremen2 deglycosylation) and requires the second MRH
      domain of Erlectin (G379S mutation abolishes binding). Overexpression
      of Erlectin inhibited transport of Krm2 to the cell surface. This
      interaction reflects ERLEC1 lectin activity in glycoprotein quality
      control. GO:0005515 is uninformative; the functional activity is
      better captured by misfolded protein binding or N-glycan recognition.
    action: MODIFY
    reason: >-
      GO:0005515 (protein binding) is uninformative per curation guidelines.
      The interaction with Kremen2 via N-glycan recognition represents
      ERLEC1 lectin function in the ER. The more informative term is
      GO:0051787 (misfolded protein binding), reflecting ERLEC1 role in
      recognizing glycoproteins for ER quality control.
    proposed_replacement_terms:
    - id: GO:0051787
      label: misfolded protein binding
    supported_by:
    - reference_id: PMID:16531414
      supporting_text: >-
        Erlectin functions in N-glycan recognition in the endoplasmic
        reticulum, suggesting that it may regulate glycoprotein traffic
    - reference_id: PMID:16531414
      supporting_text: >-
        It contains two MRH domains, of which one is essential for Krm2
        binding, and this interaction is abolished by Krm2 deglycosylation
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18264092
  review:
    summary: >-
      IPI annotation for protein binding based on Christianson et al.
      (PMID:18264092), with multiple interacting partners (UniProtKB:P11021
      HSPA5/BiP, UniProtKB:Q86TM6 SYVN1/HRD1, UniProtKB:Q9UBV2 SEL1L).
      This paper showed that XTP3-B binds to ERAD substrates and through
      SEL1L to HRD1. The MRH domains are required for interaction with
      SEL1L but not with substrate. XTP3-B and OS-9 are components of
      distinct, partially redundant quality control surveillance pathways.
      GO:0005515 is uninformative; ERLEC1 interactions with SEL1L and
      HRD1 reflect its role as a substrate adaptor for the ERAD ubiquitin
      ligase complex.
    action: MODIFY
    reason: >-
      GO:0005515 (protein binding) is uninformative per curation guidelines.
      The interactions documented here are functionally significant: ERLEC1
      binding to SEL1L and HRD1 via its MRH domains reflects its role as
      a substrate adaptor that bridges misfolded glycoproteins to the E3
      ubiquitin ligase complex. The most informative molecular function
      term would be GO:0051787 (misfolded protein binding), capturing
      ERLEC1 core activity of recognizing misfolded substrates.
    proposed_replacement_terms:
    - id: GO:0051787
      label: misfolded protein binding
    supported_by:
    - reference_id: PMID:18264092
      supporting_text: >-
        OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to
        ERAD substrates and, through the SEL1L adaptor, to the
        ER-membrane-embedded ubiquitin ligase Hrd1
    - reference_id: PMID:18264092
      supporting_text: >-
        Both proteins contain conserved mannose 6-phosphate receptor homology
        (MRH) domains, which are required for interaction with SEL1L, but not
        with substrate
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IDA
  original_reference_id: PMID:16531414
  review:
    summary: >-
      IDA annotation for ER lumen localization based on Cruciat et al.
      (PMID:16531414). This paper demonstrated by immunofluorescence and
      mass spectrometry that Erlectin is a luminal resident protein of the
      endoplasmic reticulum. ERLEC1 has a signal peptide (aa 1-33) and
      lacks a transmembrane domain, consistent with a soluble ER lumen
      protein.
    action: ACCEPT
    reason: >-
      ER lumen localization is a well-established core feature of ERLEC1,
      directly demonstrated by Cruciat et al. The IDA evidence is strong
      and consistent with the protein sequence (signal peptide, no TM
      domain) and with other experimental studies.
    supported_by:
    - reference_id: PMID:16531414
      supporting_text: >-
        Like other members of the MRH family, Erlectin is a luminal resident
        protein of the endoplasmic reticulum
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IDA
  original_reference_id: PMID:18264092
  review:
    summary: >-
      IDA annotation for ER lumen localization based on Christianson et al.
      (PMID:18264092). This paper confirmed that XTP3-B/Erlectin is an
      ER-resident glycoprotein, consistent with ER lumen localization
      established by Cruciat et al. (PMID:16531414) and Hosokawa et al.
      (PMID:18502753).
    action: ACCEPT
    reason: >-
      Independent experimental confirmation of ER lumen localization by
      a second research group. Consistent with all other evidence.
    supported_by:
    - reference_id: PMID:18264092
      supporting_text: >-
        OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to
        ERAD substrates and, through the SEL1L adaptor, to the
        ER-membrane-embedded ubiquitin ligase Hrd1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16531414
  review:
    summary: >-
      IPI annotation for protein binding based on Cruciat et al.
      (PMID:16531414), with UniProtKB:Q8K1S7 (mouse Kremen2) as the
      interacting partner. This paper identified Erlectin in a proteomic
      approach as a protein that interacts with Kremen2. The interaction
      is glycosylation-dependent and requires the MRH domain of Erlectin.
      GO:0005515 is uninformative; this interaction reflects ERLEC1 lectin
      activity in N-glycan recognition and glycoprotein quality control.
    action: MODIFY
    reason: >-
      GO:0005515 (protein binding) is uninformative per curation guidelines.
      The interaction with glycosylated Kremen2 via the MRH domain reflects
      ERLEC1 lectin function. The more informative term is GO:0051787
      (misfolded protein binding), as ERLEC1 recognizes glycoproteins in
      the context of ER quality control.
    proposed_replacement_terms:
    - id: GO:0051787
      label: misfolded protein binding
    supported_by:
    - reference_id: PMID:16531414
      supporting_text: >-
        It contains two MRH domains, of which one is essential for Krm2
        binding, and this interaction is abolished by Krm2 deglycosylation
    - reference_id: PMID:16531414
      supporting_text: >-
        The overexpression of Erlectin inhibits transport of Krm2 to the
        cell surface
- term:
    id: GO:0051787
    label: misfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:18264092
  review:
    summary: >-
      NEW annotation proposed for GO:0051787 (misfolded protein binding).
      Multiple studies demonstrate that ERLEC1/XTP3-B binds to misfolded
      glycoproteins in the ER. Christianson et al. (PMID:18264092) showed
      that XTP3-B binds to ERAD substrates (mutant alpha1-antitrypsin NHK).
      Hosokawa et al. (PMID:18502753) showed that hXTP3-B forms a scaffold
      complex for recognition and sorting of misfolded glycoproteins and
      nonglycosylated proteins. Groisman et al. (PMID:21062743) demonstrated
      that substrate association with XTP3-B depends on mannose trimming.
      This term is more informative than the generic GO:0005515 (protein
      binding) annotations currently present and accurately captures
      ERLEC1 core molecular function as a lectin that recognizes misfolded
      glycoprotein substrates for ERAD.
    action: NEW
    reason: >-
      GO:0051787 (misfolded protein binding) is the most informative
      molecular function term for ERLEC1. It replaces the uninformative
      GO:0005515 (protein binding) annotations and provides the correct
      replacement for the obsolescent GO:0051082 (unfolded protein binding).
      ERLEC1 specifically binds misfolded glycoproteins (not simply unfolded
      polypeptides) as a cargo receptor for ERAD.
    additional_reference_ids:
    - PMID:18502753
    - PMID:21062743
    supported_by:
    - reference_id: PMID:18264092
      supporting_text: >-
        OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to
        ERAD substrates and, through the SEL1L adaptor, to the
        ER-membrane-embedded ubiquitin ligase Hrd1
    - reference_id: PMID:18502753
      supporting_text: >-
        this large ER quality control scaffold complex, containing ER lectins,
        a chaperone, and a ubiquitin ligase, provides a platform for the
        recognition and sorting of misfolded glycoproteins as well as
        nonglycosylated proteins prior to retrotranslocation into the cytoplasm
        for degradation
    - reference_id: PMID:21062743
      supporting_text: >-
        substrate association with XTP3-B and with the E3 ubiquitin ligases
        HRD1 and SCF(Fbs2) was inhibited
- term:
    id: GO:0097466
    label: ubiquitin-dependent glycoprotein ERAD pathway
  evidence_type: TAS
  original_reference_id: PMID:21062743
  review:
    summary: >-
      NEW annotation proposed for GO:0097466 (ubiquitin-dependent glycoprotein
      ERAD pathway). This term is more specific than GO:0036503 (ERAD pathway)
      and captures the fact that ERLEC1 specifically functions in the
      glycoprotein-specific branch of ERAD. Groisman et al. (PMID:21062743)
      showed that mannose trimming of N-glycans is required for substrate
      delivery from EDEM1 to XTP3-B, establishing ERLEC1 as a lectin that
      acts specifically in glycoprotein ERAD. The broader GO:0036503 (ERAD
      pathway) annotation should be retained as well, since Hosokawa et al.
      (PMID:18502753) showed that the long isoform also affects ERAD of the
      non-glycosylated NHK-QQQ substrate.
    action: NEW
    reason: >-
      GO:0097466 is a more specific child term of GO:0036503 that precisely
      captures ERLEC1 role in the glycoprotein-specific branch of ERAD,
      where it recognizes trimmed N-glycans on misfolded substrates. This
      provides higher annotation specificity while the broader ERAD pathway
      term is retained for the non-glycoprotein ERAD role.
    additional_reference_ids:
    - PMID:18264092
    - PMID:18502753
    supported_by:
    - reference_id: PMID:21062743
      supporting_text: >-
        Our results suggest that mannose trimming enables delivery of a
        substrate glycoprotein from EDEM1 to late ERAD steps through
        association with XTP3-B
    - reference_id: PMID:21062743
      supporting_text: >-
        the mannosidase inhibitor kifunensine or ERManI knockdown do not
        affect binding of an ERAD substrate glycoprotein to EDEM1. In
        contrast, substrate association with XTP3-B and with the E3
        ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited
core_functions:
- description: >-
    ERLEC1 functions as a lectin-based cargo receptor and context-dependent triage
    factor in the ERAD pathway. Its C-terminal MRH domain (MRH2) binds
    Man9GlcNAc2 (M9) and Man5-type high-mannose N-glycans, specifically
    recognizing a terminal alpha-1,6-linked mannose motif that is exposed during
    progressive demannosylation of misfolded glycoproteins (DOI:10.1093/glycob/cwp182,
    DOI:10.1111/febs.12157). ERLEC1 delivers recognized substrates to the
    HRD1-SEL1L ubiquitin ligase complex for retrotranslocation and proteasomal
    degradation. Mannose trimming by ER mannosidase I is required for substrate
    delivery from EDEM1 to ERLEC1. SEL1L stabilizes ERLEC1 protein within the
    ERAD complex (DOI:10.1111/febs.12157). Genetic studies reveal that ERLEC1 and
    OS9 have redundant roles in promoting glycoprotein ERAD but antagonistic roles
    regarding non-glycosylated substrates: ERLEC1 inhibits degradation of
    non-glycosylated proteins, with OS9 counteracting this inhibition, thereby
    tuning ERAD substrate selectivity and fidelity (DOI:10.1016/j.molcel.2018.03.026).
  molecular_function:
    id: GO:0051787
    label: misfolded protein binding
  directly_involved_in:
    - id: GO:0036503
      label: ERAD pathway
    - id: GO:0097466
      label: ubiquitin-dependent glycoprotein ERAD pathway
    - id: GO:0030970
      label: retrograde protein transport, ER to cytosol
  locations:
    - id: GO:0005788
      label: endoplasmic reticulum lumen
    - id: GO:0044322
      label: endoplasmic reticulum quality control compartment
  supported_by:
    - reference_id: PMID:18264092
      supporting_text: >-
        OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to
        ERAD substrates and, through the SEL1L adaptor, to the
        ER-membrane-embedded ubiquitin ligase Hrd1
    - reference_id: PMID:21062743
      supporting_text: >-
        Our results suggest that mannose trimming enables delivery of a
        substrate glycoprotein from EDEM1 to late ERAD steps through
        association with XTP3-B
    - reference_id: PMID:18502753
      supporting_text: >-
        this large ER quality control scaffold complex, containing ER lectins,
        a chaperone, and a ubiquitin ligase, provides a platform for the
        recognition and sorting of misfolded glycoproteins as well as
        nonglycosylated proteins prior to retrotranslocation into the cytoplasm
        for degradation
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: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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:16531414
  title: The MRH protein Erlectin is a member of the endoplasmic reticulum synexpression
    group and functions in N-glycan recognition.
  findings: []
- id: PMID:18264092
  title: OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin
    ligase complex for ERAD.
  findings: []
- id: PMID:18502753
  title: Human XTP3-B forms an endoplasmic reticulum quality control scaffold with
    the HRD1-SEL1L ubiquitin ligase complex and BiP.
  findings: []
- 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: []
- id: PMID:25660456
  title: Identification of ERAD components essential for dislocation of the null Hong
    Kong variant of α-1-antitrypsin (NHK).
  findings: []
- id: DOI:10.1093/glycob/cwp182
  title: Human XTP3-B binds to alpha1-antitrypsin variant nullHong Kong via the C-terminal
    MRH domain in a glycan-dependent manner.
  findings:
  - statement: >-
      ERLEC1/XTP3-B C-terminal MRH domain mediates binding to Man9GlcNAc2 and
      Man5-type high-mannose N-glycans with specificity for a terminal
      Manα1,6Man motif
  - statement: >-
      Glycan-dependent binding to misfolded alpha1-antitrypsin NHK was abolished
      by Endo H treatment (p < 0.001)
- id: DOI:10.1111/febs.12157
  title: Endoplasmic reticulum lectin XTP3-B inhibits endoplasmic reticulum-associated
    degradation of a misfolded alpha1-antitrypsin variant.
  findings:
  - statement: >-
      ERLEC1/XTP3-B inhibits ERAD of misfolded alpha1-antitrypsin NHK carrying
      M9 glycans, acting as a negative regulator that may protect newly
      synthesized glycoproteins from premature degradation
  - statement: >-
      Lectin activity is required for substrate engagement but not for SEL1L
      association
  - statement: >-
      SEL1L depletion causes accelerated ERLEC1 degradation (~40% protein loss
      over 10 hours in cycloheximide chase, mRNA unchanged), indicating SEL1L
      stabilizes ERLEC1 protein
- id: DOI:10.1016/j.molcel.2018.03.026
  title: Redundant and antagonistic roles of XTP3B and OS9 in decoding glycan and non-glycan
    degrons in ER-associated degradation.
  findings:
  - statement: >-
      OS9 and XTP3B redundantly promote glycoprotein ERAD and stabilize the
      SEL1L-HRD1 complex
  - statement: >-
      XTP3B strongly inhibits degradation of non-glycosylated substrates, with
      OS9 antagonizing this inhibition
  - statement: >-
      Relative abundance of OS9 vs XTP3B and distribution of glycan vs
      non-glycan degrons within substrates shapes ERAD fidelity and
      processivity
- id: DOI:10.1093/glycob/cwq013
  title: The role of MRH domain-containing lectins in ERAD.
  findings:
  - statement: >-
      Review placing ERLEC1/XTP3-B and OS-9 as MRH-domain lectins that decode
      glycan-based degradation signals and associate with the SEL1L-HRD1 ERAD
      complex
- id: DOI:10.1038/s41467-024-45633-0
  title: SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex.
  findings:
  - statement: >-
      SEL1L hypomorphic variant SEL1L-S658P attenuates SEL1L-HRD1 interaction
      (~5-fold reduction) while preserving SEL1L-lectin interactions with
      OS9/ERLEC1
  - statement: >-
      ERLEC1 interaction with SEL1L is maintained even when the overall ERAD
      complex is compromised
- id: Reactome:R-HSA-5362412
  title: SYVN1 ubiquitinates Hh C-terminal fragments
  findings: []
- id: Reactome:R-HSA-5362437
  title: C-terminal Hh fragments are bound by lectins
  findings: []
- id: Reactome:R-HSA-5362441
  title: C-terminal Hh fragments are recruited to SEL1:SYVN1 at the ER membrane
  findings: []
- id: Reactome:R-HSA-5362450
  title: Hh processing variants bind lectins
  findings: []
- id: Reactome:R-HSA-5362459
  title: VCP-catalyzed ATP hydrolysis promotes the translocation of Hh-C into the
    cytosol
  findings: []
- id: Reactome:R-HSA-5387386
  title: Hh processing variants are recruited to SEL1:SYVN at the ER membrane
  findings: []
- id: Reactome:R-HSA-5387389
  title: Hh processing variants are translocated to the cytosol in a VCP-dependent
    manner
  findings: []
- id: Reactome:R-HSA-5483238
  title: Hh processing variants are ubiquitinated
  findings: []
- id: Reactome:R-HSA-8866542
  title: VCP-catalyzed ATP hydrolysis promotes the translocation of misfolded CFTR
    into the cytosol
  findings: []
- id: Reactome:R-HSA-8866546
  title: RNF5 and RNF185 ubiquitinate misfolded CFTR
  findings: []
- id: Reactome:R-HSA-8866551
  title: CFTR binds components of the ERAD machinery for ubiquitination and degradation
  findings: []
- id: Reactome:R-HSA-8866854
  title: VCP-catalyzed ATP hydrolysis promotes the translocation of CFTR F508del into
    the cytosol
  findings: []
- id: Reactome:R-HSA-8866856
  title: RNF5 and RNF185 ubiquitinate CFTR F508del
  findings: []
- id: Reactome:R-HSA-8866857
  title: CFTR F508del binds components of the ERAD machinery for ubiquitination and
    degradation
  findings: []
- id: Reactome:R-HSA-9931264
  title: Active transport of ubiquitinated CD274 from ER to cytosol
  findings: []
- id: Reactome:R-HSA-9931298
  title: Ubiquitination of CD274 by ERAD complex
  findings: []
- id: Reactome:R-HSA-9931313
  title: p-S195-CD274 binds ERAD complex
  findings: []