id: O94905
gene_symbol: ERLIN2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ERLIN2 (SPFH2, ER lipid raft-associated protein 2) is a single-pass type II
  endoplasmic reticulum (ER) membrane protein with a lumenal SPFH/prohibitin
  (band 7) domain, belonging to the band 7/mec-2 (stomatin-prohibitin-flotillin)
  family. It associates with lipid-raft-like domains of the ER membrane and
  functions as a scaffold rather than an enzyme. ERLIN2 forms a large
  ring-shaped heteromeric complex with its homolog ERLIN1 (SPFH1); the
  ERLIN1/ERLIN2 complex binds inositol 1,4,5-trisphosphate receptor (IP3R)
  tetramers and, together with the ER ubiquitin ligase RNF170, mediates the
  ER-associated degradation (ERAD) of activated IP3Rs, controlling calcium
  signaling. ERLIN2 also promotes sterol-accelerated ERAD of HMG-CoA reductase
  through an AMFR/gp78-containing ubiquitin ligase complex (with TMUB1 bridging
  ERLIN2 to gp78), and it binds cholesterol and restricts SREBP activation by
  associating with the SCAP-SREBP-Insig machinery, thereby negatively regulating
  cholesterol and fatty acid biosynthesis. Through these activities it recruits
  and binds multiple ER ubiquitin ligases (RNF170, AMFR/gp78, SYVN1, RNF139,
  RNF185/RNF5). Loss-of-function variants in ERLIN2 cause hereditary spastic
  paraplegia (SPG18A/SPG18B) and a recessive intellectual disability syndrome.
alternative_products:
- name: '1'
  id: O94905-1
- name: '2'
  id: O94905-2
  sequence_note: VSP_008713, VSP_008714
- name: '3'
  id: O94905-3
  sequence_note: VSP_013940, VSP_013941
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference that ERLIN2 acts at the ER membrane, consistent with strong experimental evidence that it is an ER membrane SPFH protein.
    action: ACCEPT
    reason: Core compartment and site of action; ERLIN2 is an integral ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0015485
    label: cholesterol binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of cholesterol binding for ERLIN2, consistent with the experimental demonstration that erlins are cooperative cholesterol-binding proteins.
    action: ACCEPT
    reason: Core molecular function of the erlin family; underlies sterol-sensing regulation of SREBP.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: Erlins bound cholesterol with specificity and strong cooperativity
- term:
    id: GO:0032933
    label: SREBP signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of involvement in SREBP signaling, consistent with experimental evidence that erlins restrict SREBP activation.
    action: ACCEPT
    reason: Core biological process; redundant with experimental IMP evidence.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: directly involved in regulating the SREBP machinery
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro-based electronic ER localization; the more specific ER membrane term is preferred.
    action: ACCEPT
    reason: Correct compartment; redundant with the ER membrane annotations.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-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: Electronic assignment of ER membrane localization from the UniProt subcellular location.
    action: ACCEPT
    reason: Core compartment; redundant with experimental IDA evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based assignment of ubiquitin protein ligase binding, consistent with ERLIN2 binding the ER ubiquitin ligases RNF170, AMFR/gp78, SYVN1, RNF139 and the RNF185/RNF5 module.
    action: ACCEPT
    reason: Informative molecular function; ERLIN2 recruits E3 ubiquitin ligases to the ERAD complex.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: Interacts with SYVN1 and RNF139
- term:
    id: GO:0032933
    label: SREBP signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of SREBP signaling involvement, consistent with experimental evidence.
    action: ACCEPT
    reason: Correct biological process; redundant with IMP/IBA evidence.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: directly involved in regulating the SREBP machinery
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: Generic protein-containing complex assignment; ERLIN2 forms the specific ERLIN1/ERLIN2 complex.
    action: KEEP_AS_NON_CORE
    reason: Correct but uninformative; the specific ERLIN1/ERLIN2 complex membership is captured elsewhere.
    supported_by:
    - reference_id: PMID:19240031
      supporting_text: SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of ERAD involvement, consistent with the experimentally demonstrated role in ERAD of IP3 receptors and HMGCR.
    action: ACCEPT
    reason: Core biological process; redundant with experimental IDA evidence.
    supported_by:
    - reference_id: PMID:19240031
      supporting_text: mediates the ER-associated degradation of inositol 1,4,5-trisphosphate
- term:
    id: GO:0045541
    label: negative regulation of cholesterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA assignment of negative regulation of cholesterol biosynthesis, consistent with the erlins' restriction of SREBP activation.
    action: ACCEPT
    reason: Correct biological process; redundant with experimental IMP evidence.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: led to canonical activation of SREBPs and their target genes
- term:
    id: GO:0045717
    label: negative regulation of fatty acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA assignment of negative regulation of fatty acid biosynthesis, consistent with the erlins restricting SREBP.
    action: ACCEPT
    reason: Correct biological process; redundant with experimental IMP evidence.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: key transcription factors for cholesterol and fatty acid biosynthetic
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21343306
  qualifier: enables
  review:
    summary: IPI interactions with the gp78/AMFR ERAD module (AMFR, SYVN1, TMUB1, ERLIN1, HMGCR). Bare protein binding is uninformative; the E3-ligase binding is captured by the ubiquitin-protein-ligase-binding annotation.
    action: KEEP_AS_NON_CORE
    reason: Real ERAD-module interactions but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'O94905; Q9UKV5: AMFR'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: ERAD-network interactome capture (ERLIN1, SYVN1, AMFR). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real ERAD-network interactions but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'O94905; O75477: ERLIN1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: Crosslinking mass-spectrometry capture of an ERLIN2-ERLIN1 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real ERLIN1 interaction but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'O94905; O75477: ERLIN1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Dual proteome-scale network captures of ERLIN2 interactions (ERLIN1, TMUB1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'O94905; O75477: ERLIN1'
- 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.
    action: ACCEPT
    reason: Core compartment; directly demonstrated.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:19240031
  qualifier: located_in
  review:
    summary: Direct evidence that ERLIN2/SPFH2 is an ER membrane protein, the site of the ERLIN1/ERLIN2 ERAD complex.
    action: ACCEPT
    reason: Core compartment; directly demonstrated.
    supported_by:
    - reference_id: PMID:19240031
      supporting_text: the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:19240031
  qualifier: involved_in
  review:
    summary: The ERLIN1/ERLIN2 complex binds IP3R tetramers and mediates their ER-associated degradation.
    action: ACCEPT
    reason: Core biological process with direct (IDA) support; the defining function of the ERLIN complex.
    supported_by:
    - reference_id: PMID:19240031
      supporting_text: mediates the ER-associated degradation of inositol 1,4,5-trisphosphate
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: NAS
  original_reference_id: PMID:34572057
  qualifier: located_in
  review:
    summary: Erlins associate with lipid-raft-like domains of the ER membrane; the NAS membrane-raft localization reflects this SPFH-domain raft association.
    action: KEEP_AS_NON_CORE
    reason: Supported by the lipid-raft characterization of erlins but secondary to the core ER-membrane ERAD/SREBP roles.
    supported_by:
    - reference_id: PMID:16835267
      supporting_text: define lipid-raft-like domains of the ER
- term:
    id: GO:0045540
    label: regulation of cholesterol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:24217618
  qualifier: involved_in
  review:
    summary: ERLIN2 regulates cholesterol biosynthesis via the SREBP/SCAP/Insig machinery; the erlins restrict SREBP activation in response to ER cholesterol.
    action: ACCEPT
    reason: Core biological process; directly supported.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: regulate cellular cholesterol
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1839094
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling pathway annotation placing ERLIN2 at the plasma membrane. ERLIN2 is an integral ER membrane protein; plasma-membrane localization is not supported by the experimental subcellular-location data.
    action: MARK_AS_OVER_ANNOTATED
    reason: ERLIN2 is an ER membrane SPFH protein; the plasma-membrane localizations are over-annotations from FGFR1-pathway bulk-membrane curation, not its biological site.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1839098
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1839100
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655240
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655263
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655266
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655269
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655278
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655290
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5655326
  qualifier: located_in
  review:
    summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8853322
  qualifier: located_in
  review:
    summary: Reactome FGFR1-fusion annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8853325
  qualifier: located_in
  review:
    summary: Reactome FGFR1-fusion annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30352685
  qualifier: enables
  review:
    summary: IPI capture of the ERLIN2-TMEM41B interaction (a MAM/ER protein). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (TMEM41B) but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: Interacts with TMEM41B
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:18468998
  qualifier: part_of
  review:
    summary: IDA placing ERLIN2 in a protein-containing complex (alpha1D-adrenergic receptor/dystrophin signalosome study). The generic complex term is uninformative; ERLIN2's defining complex is the ERLIN1/ERLIN2 complex.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported but uninformative generic complex term; not the core ERLIN1/ERLIN2 complex.
    supported_by:
    - reference_id: PMID:19240031
      supporting_text: SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866542
  qualifier: located_in
  review:
    summary: Reactome curation placing ERLIN2 at the ER membrane within the CFTR ERAD machinery pathway.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental ER membrane annotations.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866546
  qualifier: located_in
  review:
    summary: Reactome curation of ERLIN2 ER membrane localization (CFTR ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866551
  qualifier: located_in
  review:
    summary: Reactome curation of ERLIN2 ER membrane localization (CFTR ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866854
  qualifier: located_in
  review:
    summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866856
  qualifier: located_in
  review:
    summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866857
  qualifier: located_in
  review:
    summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931264
  qualifier: located_in
  review:
    summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931298
  qualifier: located_in
  review:
    summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9931313
  qualifier: located_in
  review:
    summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:24019521
  qualifier: enables
  review:
    summary: ERLIN2 interacts with the ER ubiquitin ligases RNF185 and RNF5, an informative molecular function reflecting its recruitment of E3 ligases to ERAD.
    action: ACCEPT
    reason: Directly supported (IPI); ERLIN2 binds ER ubiquitin ligases, consistent with its ERAD scaffold role.
    supported_by:
    - reference_id: PMID:24019521
      supporting_text: RNF185 and RNF5 as a novel E3 ligase module
- term:
    id: GO:0032933
    label: SREBP signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:24217618
  qualifier: involved_in
  review:
    summary: Depletion of erlins led to canonical activation of SREBPs and their target genes, demonstrating that ERLIN2 restricts SREBP signaling.
    action: ACCEPT
    reason: Core biological process with direct depletion (IMP) support.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: led to canonical activation of SREBPs and their target genes
- term:
    id: GO:0045541
    label: negative regulation of cholesterol biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:24217618
  qualifier: involved_in
  review:
    summary: By restricting SREBP activation, ERLIN2 negatively regulates cholesterol biosynthesis.
    action: ACCEPT
    reason: Core biological process with direct (IMP) support.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: led to canonical activation of SREBPs and their target genes
- term:
    id: GO:0045717
    label: negative regulation of fatty acid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:24217618
  qualifier: involved_in
  review:
    summary: ERLIN2 negatively regulates fatty acid biosynthesis through restriction of SREBP, which activates fatty-acid biosynthetic genes.
    action: ACCEPT
    reason: Directly supported (IMP); a consequence of the erlins' SREBP restriction.
    supported_by:
    - reference_id: PMID:24217618
      supporting_text: key transcription factors for cholesterol and fatty acid biosynthetic
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IDA
  original_reference_id: PMID:25204797
  qualifier: located_in
  review:
    summary: IDA membrane-raft localization of ERLIN2, consistent with the erlins associating with lipid-raft-like domains of the ER membrane.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported raft association but secondary to the core ER-membrane ERAD/SREBP roles.
    supported_by:
    - reference_id: PMID:16835267
      supporting_text: define lipid-raft-like domains of the ER
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: Fusion-protein localization (LIFEdb) evidence for ER localization of ERLIN2.
    action: ACCEPT
    reason: Correct compartment; redundant with experimental ER membrane evidence.
    supported_by:
    - reference_id: file:human/ERLIN2/ERLIN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19240031
  qualifier: enables
  review:
    summary: IPI capture of the ERLIN2-ERLIN1 (SPFH2-SPFH1) interaction. Bare protein binding is uninformative; the ERLIN1/ERLIN2 complex is captured by the ERAD/complex annotations.
    action: KEEP_AS_NON_CORE
    reason: Real ERLIN1 interaction but uninformative GO term.
    supported_by:
    - reference_id: PMID:19240031
      supporting_text: SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:16835267
  qualifier: located_in
  review:
    summary: Direct evidence that erlin-2 localizes to lipid-raft-like domains of the ER membrane.
    action: ACCEPT
    reason: Core compartment; directly demonstrated.
    supported_by:
    - reference_id: PMID:16835267
      supporting_text: define lipid-raft-like domains of the ER
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  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:16835267
  title: Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins
    that define lipid-raft-like domains of the ER.
  findings:
  - statement: Erlin-1 and erlin-2 are prohibitin-family ER membrane proteins that define lipid-raft-like domains of the ER.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes ERLIN1/2 as prohibitin-family ER lipid-raft proteins; source of ER membrane and membrane-raft localization.
- id: PMID:18468998
  title: Blood pressure is regulated by an alpha1D-adrenergic receptor/dystrophin
    signalosome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: alpha1D-AR/dystrophin signalosome study; source of a generic protein-containing-complex IDA annotation, peripheral to ERLIN2's core function.
- id: PMID:19240031
  title: An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and SPFH2
    mediates the ER-associated degradation of inositol 1,4,5-trisphosphate receptors.
  findings:
  - statement: SPFH1 (ERLIN1) and SPFH2 (ERLIN2) form a ring-shaped ~2 MDa heteromeric ER membrane complex that binds IP3R tetramers and mediates their ER-associated degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive study establishing the ERLIN1/ERLIN2 complex and its role in ERAD of IP3 receptors.
- id: PMID:21343306
  title: Membrane-associated ubiquitin ligase complex containing gp78 mediates sterol-accelerated
    degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
  findings:
  - statement: SPFH2 (ERLIN2) and TMUB1 associate with the ER ubiquitin ligase gp78/AMFR in sterol-accelerated ERAD of HMG-CoA reductase.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes ERLIN2's role in sterol-accelerated HMGCR ERAD and its gp78/AMFR/SYVN1/TMUB1 interactions.
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: ERAD interactome mapping; source of ERLIN2 IPI interactions (ERLIN1, SYVN1, AMFR).
- id: PMID:24019521
  title: RNF185 is a novel E3 ligase of endoplasmic reticulum-associated degradation
    (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR).
  findings:
  - statement: RNF185 and RNF5 form a novel ER-associated E3 ligase module central to CFTR degradation; ERLIN2 interacts with these E3 ligases.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the ERLIN2-RNF185/RNF5 ubiquitin-protein-ligase-binding IPI annotation.
- id: PMID:24217618
  title: Erlins restrict SREBP activation in the ER and regulate cellular cholesterol
    homeostasis.
  findings:
  - statement: Erlins are cholesterol-binding proteins that restrict SREBP activation by stabilizing the SREBP-Scap-Insig complex; erlin depletion activates SREBP target genes.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the cholesterol-binding and SREBP-restricting functions of erlins; ERLIN2 interacts with SCAP/INSIG1/SREBF1/SREBF2.
- id: PMID:25204797
  title: Flotillin-1 facilitates toll-like receptor 3 signaling in human endothelial
    cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Endothelial flotillin/membrane-raft study; source of an ERLIN2 membrane-raft IDA annotation.
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry
    in Intact Cell Nuclei.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Crosslinking MS study; source of an ERLIN2-ERLIN1 IPI annotation.
- id: PMID:30352685
  title: Stasimon/Tmem41b localizes to mitochondria-associated ER membranes and is
    essential for mouse embryonic development.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: TMEM41B/MAM study; source of an ERLIN2-TMEM41B IPI annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome; source of ERLIN2 IPI annotations.
- id: PMID:34572057
  title: Role of ERLINs in the Control of Cell Fate through Lipid Rafts.
  findings:
  - statement: Review of ERLIN1/2 as ER lipid-raft-associated proteins controlling cell fate.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review used by ComplexPortal for the membrane-raft NAS annotation.
- id: PMID:38782601
  title: ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification
    to regulate the secretory pathway.
  findings:
  - statement: ERLIN1/ERLIN2 form large ring-like cup-shaped ER-membrane scaffolds that
      bind cholesterol and E3 ubiquitin ligases and mediate the interaction between full-length
      TMUB1 and RNF170 via a conserved luminal N-terminal motif binding the SPFH/prohibitin
      domains of two adjacent ERLIN subunits; loss of both ERLINs limits cholesterol
      esterification, favouring ER-to-Golgi cholesterol transport and regulating Golgi
      morphology and the secretory pathway. HSP-linked variants map to these interaction
      interfaces.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.26508/lsa.202402620). Key 2024 mechanistic
      study extending ERLIN function beyond classical IP3R/HMGCR ERAD; establishes the
      ERLIN scaffold as the platform bridging TMUB1 and RNF170, identifies the conserved
      luminal motif/SPFH interface used by HSP variants, and shows ERLINs restrict
      cholesterol esterification to support ER-to-Golgi cholesterol transport and
      secretory-pathway/Golgi organization. Not cached, so no verbatim supporting_text
      added.
- id: PMID:40225166
  title: Disruption of Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary
    Spastic Paraplegia in Patient-Derived Stem Cell Models.
  findings:
  - statement: A heterozygous ERLIN2 missense variant (p.Val71Ala) in an HSP family;
      patient-derived iPSC models show the mutant ERLIN2 recruits the E3 ligase RNF213
      to degrade IP3R1, lowering intracellular free calcium, triggering ER-stress-mediated
      apoptosis, and suppressing MAPK signaling and proliferation, proposing an
      autosomal-dominant disease mechanism.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1155/2023/4834423). Proposes a dominant
      ERLIN2 disease mechanism via altered IP3R1 abundance/Ca2+ homeostasis. Note the
      ligase implicated is RNF213 in this mutant context, distinct from the canonical
      RNF170-mediated IP3R ERAD captured in the review. Not cached; no verbatim
      supporting_text added.
- id: PMID:38427163
  title: 'Hereditary spastic paraparesis type 18 (SPG18): new ERLIN2 variants in a series
    of Italian patients, shedding light upon genetic and phenotypic variability.'
  findings:
  - statement: SPG18 from ERLIN2 variants shows both biallelic (complicated) and
      monoallelic/autosomal-dominant (often pure, late-onset) presentations; reports
      HSP-to-ALS phenoconversion (2 of 5 cases) and a recurrent monoallelic c.502G>A
      variant as a potential hotspot for an ALS-like SPG18 phenotype.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1007/s10072-024-07423-w). Clinical-genetics
      expansion of SPG18 phenotype and inheritance, including HSP-ALS phenoconversion.
      Disease-context reference; not cached.
- id: PMID:38607533
  title: 'Expanding SPG18 clinical spectrum: autosomal dominant mutation causes
    complicated hereditary spastic paraplegia in a large family.'
  findings:
  - statement: An autosomal-dominant ERLIN2 p.V168M mutation segregates in a four-generation
      family with variable expressivity (phenoconversion to ALS, pure HSP, and a
      complicated form with psychomotor delay and epilepsy); erlin2 oligomerization was
      normal, arguing against a dominant-negative oligomerization defect for this variant.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (DOI 10.1007/s10072-024-07500-0). Documents AD SPG18
      with complicated phenotype and rules out a dominant-negative effect of V168M on
      erlin2 oligomerization. Disease-context reference; not cached.
- id: Reactome:R-HSA-1839094
  title: Activated FGFR1 mutants and fusions bind PLCG1
  findings: []
- id: Reactome:R-HSA-1839098
  title: Activated FGFR1 mutants and fusions phosphorylate PLCG1
  findings: []
- id: Reactome:R-HSA-1839100
  title: p-4Y- PLCG1 dissociates from activated FGFR1 mutants and fusions
  findings: []
- id: Reactome:R-HSA-5655240
  title: Activated FGFR1 mutants:p-FRS2 binds GRB2:GAB1:PIK3R1
  findings: []
- id: Reactome:R-HSA-5655263
  title: Activated FGFR1 mutants:p-FRS2:GRB2:GAB1:PIK3R1 binds PIK3CA
  findings: []
- id: Reactome:R-HSA-5655266
  title: Activated FGFR1 mutants:p-FRS2 binds GRB2-SOS1
  findings: []
- id: Reactome:R-HSA-5655269
  title: Activated FGFR1 mutants bind FRS2
  findings: []
- id: Reactome:R-HSA-5655278
  title: Activated FGFR1 mutants phosphorylate FRS2
  findings: []
- id: Reactome:R-HSA-5655290
  title: Activated FGFR1 mutant-associated PI3K phosphorylates PIP2 to PIP3
  findings: []
- id: Reactome:R-HSA-5655326
  title: Activated FGFR1 mutants:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange
  findings: []
- id: Reactome:R-HSA-8853322
  title: Plasma membrane FGFR1 fusions dimerize
  findings: []
- id: Reactome:R-HSA-8853325
  title: Plasma membrane FGFR1 fusions autophosphorylate
  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: []
- id: file:human/ERLIN2/ERLIN2-uniprot.txt
  title: UniProt entry O94905 (ERLN2_HUMAN), Erlin-2 / SPFH2
  findings:
  - statement: ERLIN2 is a single-pass type II ER membrane SPFH/prohibitin protein forming the ERLIN1/ERLIN2 complex that mediates ERAD of IP3 receptors and HMGCR, binds cholesterol, restricts SREBP, and interacts with ER ubiquitin ligases (RNF170, AMFR, SYVN1, RNF139, RNF185/RNF5); variants cause SPG18.
    reference_section_type: OTHER
core_functions:
- description: Scaffold subunit of the ring-shaped ERLIN1/ERLIN2 SPFH-domain complex that binds inositol 1,4,5-trisphosphate receptor (IP3R) tetramers and, with the E3 ligase RNF170, mediates their ER-associated degradation, controlling calcium signaling.
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
  supported_by:
  - reference_id: PMID:19240031
    supporting_text: mediates the ER-associated degradation of inositol 1,4,5-trisphosphate
  - reference_id: PMID:19240031
    supporting_text: SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex
- description: Cholesterol-binding ER membrane protein that restricts SREBP activation by associating with the SREBP-SCAP-Insig machinery and that promotes sterol-accelerated ERAD of HMG-CoA reductase via a gp78/AMFR ubiquitin ligase complex, thereby negatively regulating cholesterol and fatty acid biosynthesis.
  molecular_function:
    id: GO:0015485
    label: cholesterol binding
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0032933
    label: SREBP signaling pathway
  - id: GO:0045541
    label: negative regulation of cholesterol biosynthetic process
  supported_by:
  - reference_id: PMID:24217618
    supporting_text: Erlins bound cholesterol with specificity and strong cooperativity
  - reference_id: PMID:21343306
    supporting_text: associated proteins of mammalian gp78
- description: ER-membrane adaptor that binds and recruits multiple ER ubiquitin ligases (RNF170, AMFR/gp78, SYVN1, RNF139, RNF185/RNF5) to the ERLIN complex, coupling substrate recognition to ubiquitination during ERAD.
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:24019521
    supporting_text: RNF185 and RNF5 as a novel E3 ligase module
  - reference_id: PMID:21343306
    supporting_text: associated proteins of mammalian gp78
  - reference_id: PMID:38782601
proposed_new_terms: []
suggested_questions:
- question: What is the architecture and substrate-selection mechanism of the ERLIN1/ERLIN2 ring complex (recently resolved by cryo-EM), and how does ERLIN2 recognize activated/ubiquitinated IP3R tetramers versus HMGCR?
- question: How do ERLIN2 SPG18A/SPG18B disease variants impair complex assembly, IP3R ERAD, or cholesterol/SREBP regulation to cause corticospinal motor neuron degeneration?
- question: How is cholesterol binding by the ERLIN2 SPFH domain coupled to retention of the SCAP-SREBP-Insig complex and to sterol-accelerated HMGCR degradation?
suggested_experiments:
- description: Reconstitute the ERLIN1/ERLIN2 complex with RNF170 and a model IP3R substrate to determine ERLIN2's contribution to substrate binding versus E3-ligase recruitment in IP3R ERAD.
- description: Introduce SPG18 variants (e.g. S129T, R180C, D300V) into neurons and assay ERLIN complex assembly, IP3R degradation, calcium signaling, and ER cholesterol/SREBP signaling to link molecular defects to disease.
- description: Use cholesterol photoaffinity probes and SPFH-domain mutants of ERLIN2 to map the cholesterol-binding site and test its requirement for SREBP restriction and sterol-accelerated HMGCR ERAD.