id: O75477
gene_symbol: ERLIN1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ERLIN1 (SPFH1, ER lipid raft-associated protein 1) 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. ERLIN1 forms a large
  ring-shaped heteromeric complex with its homolog ERLIN2 (SPFH2); 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, thereby controlling
  calcium signaling. The erlins are cholesterol-binding proteins that restrict
  SREBP activation: they associate with the SCAP-SREBP-Insig machinery to
  promote its ER retention and thus negatively regulate cholesterol and fatty
  acid biosynthesis, contributing to cellular cholesterol homeostasis. ERLIN1
  also interacts with the ER ubiquitin ligases AMFR/gp78 and SYVN1/HRD1, linking
  it to sterol-accelerated ERAD. Loss-of-function variants in ERLIN1 cause
  autosomal recessive hereditary spastic paraplegia (SPG62).
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 ERLIN1 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; ERLIN1 is an integral ER membrane protein.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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, consistent with direct experimental evidence that erlins bind cholesterol cooperatively.
    action: ACCEPT
    reason: Core molecular function; redundant with the experimental IDA cholesterol-binding annotation.
    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, consistent with experimental evidence; 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/ERLIN1/ERLIN1-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/ERLIN1/ERLIN1-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 experimental interactions of ERLIN1 with the ER ubiquitin ligases AMFR/gp78, SYVN1/HRD1 and (in complex with ERLIN2) RNF170.
    action: ACCEPT
    reason: Informative molecular function; ERLIN1 recruits E3 ubiquitin ligases to the ERAD complex.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-uniprot.txt
      supporting_text: Interacts with AMFR and SYVN1
- 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; ERLIN1 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.
    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 (which activates fatty-acid biosynthetic genes).
    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 ER ubiquitin ligases AMFR/gp78 and SYVN1 (and ERLIN2). 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 E3-ligase interactions but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-uniprot.txt
      supporting_text: Interacts with AMFR and SYVN1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: ERAD-network interactome capture (including ERLIN2, 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/ERLIN1/ERLIN1-uniprot.txt
      supporting_text: 'O75477; O94905: ERLIN2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome capture. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions from a large-scale interactome but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-uniprot.txt
      supporting_text: 'O75477; Q96IW7: SEC22A'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome capture (C6orf120). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-uniprot.txt
      supporting_text: 'O75477; Q7Z4R8: C6orf120'
- 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 ERLIN1-ERLIN2 interaction. Bare protein binding is uninformative; the ERLIN1/ERLIN2 complex is captured by complex annotations.
    action: KEEP_AS_NON_CORE
    reason: Real ERLIN2 interaction but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-uniprot.txt
      supporting_text: 'O75477; O94905: ERLIN2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary-interactome (HuRI) captures of ERLIN1 interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real binary interactions but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-uniprot.txt
      supporting_text: 'O75477; Q15436: SEC23A'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Dual proteome-scale network capture (ERLIN2, C6orf120). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions but uninformative GO term.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-uniprot.txt
      supporting_text: 'O75477; O94905: ERLIN2'
- 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/ERLIN1/ERLIN1-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-8866542
  qualifier: located_in
  review:
    summary: Reactome curation placing ERLIN1 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/ERLIN1/ERLIN1-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 ERLIN1 ER membrane localization (CFTR ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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 ERLIN1 ER membrane localization (CFTR ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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 ERLIN1 ER membrane localization (CFTR F508del ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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 ERLIN1 ER membrane localization (CFTR F508del ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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 ERLIN1 ER membrane localization (CFTR F508del ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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 ERLIN1 ER membrane localization (CD274/PD-L1 ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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 ERLIN1 ER membrane localization (CD274/PD-L1 ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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 ERLIN1 ER membrane localization (CD274/PD-L1 ERAD pathway).
    action: ACCEPT
    reason: Correct compartment; redundant with experimental evidence.
    supported_by:
    - reference_id: file:human/ERLIN1/ERLIN1-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 ERLIN1/SPFH1 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; depletion of ERLIN1/ERLIN2 blocks IP3R 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: ERLIN1 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:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:18468998
  qualifier: part_of
  review:
    summary: IDA placing ERLIN1 in a protein-containing complex (alpha1D-adrenergic receptor/dystrophin signalosome study). The generic complex term is uninformative; ERLIN1'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:0015485
    label: cholesterol binding
  evidence_type: IDA
  original_reference_id: PMID:24217618
  qualifier: enables
  review:
    summary: Erlins bind cholesterol with specificity and strong cooperativity, a core molecular function underlying their sterol-sensing regulation of SREBP.
    action: ACCEPT
    reason: Core molecular function with direct (IDA) support.
    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: 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 ERLIN1 restricts SREBP signaling.
    action: ACCEPT
    reason: Core biological process with direct mutant/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, ERLIN1 negatively regulates cholesterol biosynthesis; erlin depletion derepresses SREBP target genes.
    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: ERLIN1 negatively regulates fatty acid biosynthesis through restriction of SREBP, which activates both cholesterol and 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:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19240031
  qualifier: enables
  review:
    summary: IPI capture of the ERLIN1-ERLIN2 (SPFH1-SPFH2) interaction. Bare protein binding is uninformative; the ERLIN1/ERLIN2 complex is captured by the ERAD/complex annotations.
    action: KEEP_AS_NON_CORE
    reason: Real ERLIN2 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-1 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: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 ERLIN1'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; depletion blocks IP3R 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; ERLIN1 interacts with AMFR and SYVN1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the ERLIN1-AMFR/SYVN1 IPI interactions; the abstract names SPFH2/TMUB1 but UniProt records ERLIN1 interaction with AMFR and SYVN1.
- 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 ERLIN1 IPI interactions (ERLIN2, SYVN1, AMFR).
- 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 and promoting its ER retention; 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.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome; source of ERLIN1 IPI annotations.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of an ERLIN1 IPI 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 ERLIN1-ERLIN2 IPI annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome (HuRI); source of ERLIN1 IPI annotations.
- 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 ERLIN1 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:37683630
  title: Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection.
  findings:
  - statement: USP25 deubiquitinates and stabilizes ERLIN1; Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Not in publication cache; cited in UniProt for ERLIN1 stabilization by USP25 and cholesterol/SREBP regulation.
- 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 scaffolds that mediate the interaction between the full-length isoform of TMUB1 and the E3 ligase RNF170 (binding their conserved luminal N-terminal motif via the SPFH domains of adjacent ERLIN subunits); these scaffolds limit cholesterol esterification, favouring ER-to-Golgi cholesterol transport and regulating Golgi morphology and the secretory pathway. Variants that preclude these interactions have been linked to hereditary spastic paraplegia.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:38782601, doi:10.26508/lsa.202402620; Veronese
      et al. 2024, Life Sci Alliance). Mechanistic study extending ERLIN1/2 scaffold
      function to TMUB1-L/RNF170 bridging, restriction of cholesterol esterification
      (SOAT1), ER-to-Golgi cholesterol transport, and secretory-pathway/Golgi morphology
      regulation. Connects SPG62 disease variants to disruption of these interfaces.
      Not in publication cache; supporting_text not added to annotations to satisfy
      verbatim-substring validation.
- id: PMID:39367212
  title: 'Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis.'
  findings:
  - statement: Largest series to date of biallelic ERLIN1 variants (13 individuals from six families) causing SPG62 spastic paraparesis; childhood-onset, slowly progressive, predominantly pure paraparesis with possible cerebellar and peripheral-nerve involvement. Three new variants are predicted to alter the bell-shaped ring formed by the ERLIN1/ERLIN2 complex.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:39367212, doi:10.1007/s00439-024-02702-0;
      Cogan et al. 2024, Hum Genet). Expands the SPG62 disease genetics beyond the
      single G50V variant previously noted; variants interpreted as disrupting ERLIN1/ERLIN2
      ring assembly. Not in publication cache.
- id: PMID:31810281
  title: The Host Factor Erlin-1 is Required for Efficient Hepatitis C Virus Infection.
  findings:
  - statement: ERLIN1 is a cholesterol-binding, ER detergent-resistant-membrane protein required for efficient hepatitis C virus infection; its silencing reduces HCV RNA replication initiation, viral protein expression, and infectious virus production, acting downstream of entry and primary translation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:31810281, doi:10.3390/cells8121555; Whitten-Bauer
      et al. 2019, Cells). ERLIN1 as an HCV host factor; corroborates its cholesterol-homeostasis/ER
      detergent-resistant-membrane role. Peripheral to core ERAD/SREBP functions.
      Not in publication cache.
- 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/ERLIN1/ERLIN1-uniprot.txt
  title: UniProt entry O75477 (ERLN1_HUMAN), Erlin-1 / SPFH1
  findings:
  - statement: ERLIN1 is a single-pass type II ER membrane SPFH/prohibitin protein that forms the ERLIN1/ERLIN2 complex mediating ERAD of IP3 receptors, binds cholesterol, restricts SREBP activation, and interacts with the ER ubiquitin ligases AMFR/gp78, SYVN1 and (with ERLIN2) RNF170; variants cause SPG62.
    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 and stabilizing the SREBP-SCAP-Insig complex, thereby negatively regulating cholesterol and fatty acid biosynthesis and contributing to cellular cholesterol homeostasis.
  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:24217618
    supporting_text: directly involved in regulating the SREBP machinery
proposed_new_terms: []
suggested_questions:
- question: What is the stoichiometry and architecture of the ERLIN1/ERLIN2 ring complex (recently resolved by cryo-EM), and how does it select activated/ubiquitinated IP3R tetramers as substrates?
- question: How does cholesterol binding to the erlin SPFH domain mechanistically couple ER sterol levels to retention of the SCAP-SREBP-Insig complex?
- question: How do ERLIN1 SPG62 disease variants (e.g. G50V) impair complex assembly or substrate handling to cause corticospinal motor neuron degeneration?
suggested_experiments:
- description: Reconstitute the ERLIN1/ERLIN2 complex with RNF170 and a model IP3R substrate to test whether ERLIN1 is required for substrate binding versus ligase recruitment in IP3R ERAD.
- description: Use cholesterol photoaffinity probes and SPFH-domain point mutants of ERLIN1 to map the cholesterol-binding site and test whether abolishing cholesterol binding derepresses SREBP target genes.
- description: Introduce the SPG62 G50V variant into neurons and assay ERLIN1/ERLIN2 complex assembly, IP3R degradation, and ER cholesterol/SREBP signaling to link the molecular defect to disease.