ERLIN2

UniProt ID: O94905
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005789 endoplasmic reticulum membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference that ERLIN2 acts at the ER membrane, consistent with strong experimental evidence that it is an ER membrane SPFH protein.
Reason: Core compartment and site of action; ERLIN2 is an integral ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0015485 cholesterol binding
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference of cholesterol binding for ERLIN2, consistent with the experimental demonstration that erlins are cooperative cholesterol-binding proteins.
Reason: Core molecular function of the erlin family; underlies sterol-sensing regulation of SREBP.
Supporting Evidence:
PMID:24217618
Erlins bound cholesterol with specificity and strong cooperativity
GO:0032933 SREBP signaling pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference of involvement in SREBP signaling, consistent with experimental evidence that erlins restrict SREBP activation.
Reason: Core biological process; redundant with experimental IMP evidence.
Supporting Evidence:
PMID:24217618
directly involved in regulating the SREBP machinery
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic ER localization; the more specific ER membrane term is preferred.
Reason: Correct compartment; redundant with the ER membrane annotations.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of ER membrane localization from the UniProt subcellular location.
Reason: Core compartment; redundant with experimental IDA evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0031625 ubiquitin protein ligase binding
IEA
GO_REF:0000002 		ACCEPT
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.
Reason: Informative molecular function; ERLIN2 recruits E3 ubiquitin ligases to the ERAD complex.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
Interacts with SYVN1 and RNF139
GO:0032933 SREBP signaling pathway
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA machine-learning assignment of SREBP signaling involvement, consistent with experimental evidence.
Reason: Correct biological process; redundant with IMP/IBA evidence.
Supporting Evidence:
PMID:24217618
directly involved in regulating the SREBP machinery
GO:0032991 protein-containing complex
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Generic protein-containing complex assignment; ERLIN2 forms the specific ERLIN1/ERLIN2 complex.
Reason: Correct but uninformative; the specific ERLIN1/ERLIN2 complex membership is captured elsewhere.
Supporting Evidence:
PMID:19240031
SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex
GO:0036503 ERAD pathway
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA machine-learning assignment of ERAD involvement, consistent with the experimentally demonstrated role in ERAD of IP3 receptors and HMGCR.
Reason: Core biological process; redundant with experimental IDA evidence.
Supporting Evidence:
PMID:19240031
mediates the ER-associated degradation of inositol 1,4,5-trisphosphate
GO:0045541 negative regulation of cholesterol biosynthetic process
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA assignment of negative regulation of cholesterol biosynthesis, consistent with the erlins' restriction of SREBP activation.
Reason: Correct biological process; redundant with experimental IMP evidence.
Supporting Evidence:
PMID:24217618
led to canonical activation of SREBPs and their target genes
GO:0045717 negative regulation of fatty acid biosynthetic process
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA assignment of negative regulation of fatty acid biosynthesis, consistent with the erlins restricting SREBP.
Reason: Correct biological process; redundant with experimental IMP evidence.
Supporting Evidence:
PMID:24217618
key transcription factors for cholesterol and fatty acid biosynthetic
GO:0005515 protein binding
IPI
PMID:21343306
Membrane-associated ubiquitin ligase complex containing gp78... 		KEEP AS NON CORE
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.
Reason: Real ERAD-module interactions but uninformative GO term.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
O94905; Q9UKV5: AMFR
GO:0005515 protein binding
IPI
PMID:22119785
Defining human ERAD networks through an integrative mapping ... 		KEEP AS NON CORE
Summary: ERAD-network interactome capture (ERLIN1, SYVN1, AMFR). Bare protein binding is uninformative.
Reason: Real ERAD-network interactions but uninformative GO term.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
O94905; O75477: ERLIN1
GO:0005515 protein binding
IPI
PMID:30021884
Histone Interaction Landscapes Visualized by Crosslinking Ma... 		KEEP AS NON CORE
Summary: Crosslinking mass-spectrometry capture of an ERLIN2-ERLIN1 interaction. Bare protein binding is uninformative.
Reason: Real ERLIN1 interaction but uninformative GO term.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
O94905; O75477: ERLIN1
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: Dual proteome-scale network captures of ERLIN2 interactions (ERLIN1, TMUB1). Bare protein binding is uninformative.
Reason: Real interactions but uninformative GO term.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
O94905; O75477: ERLIN1
GO:0005783 endoplasmic reticulum
IDA
GO_REF:0000052 		ACCEPT
Summary: Direct immunofluorescence (HPA) evidence for ER localization.
Reason: Core compartment; directly demonstrated.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:19240031
An endoplasmic reticulum (ER) membrane complex composed of S... 		ACCEPT
Summary: Direct evidence that ERLIN2/SPFH2 is an ER membrane protein, the site of the ERLIN1/ERLIN2 ERAD complex.
Reason: Core compartment; directly demonstrated.
Supporting Evidence:
PMID:19240031
the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric
GO:0036503 ERAD pathway
IDA
PMID:19240031
An endoplasmic reticulum (ER) membrane complex composed of S... 		ACCEPT
Summary: The ERLIN1/ERLIN2 complex binds IP3R tetramers and mediates their ER-associated degradation.
Reason: Core biological process with direct (IDA) support; the defining function of the ERLIN complex.
Supporting Evidence:
PMID:19240031
mediates the ER-associated degradation of inositol 1,4,5-trisphosphate
GO:0045121 membrane raft
NAS
PMID:34572057
Role of ERLINs in the Control of Cell Fate through Lipid Raf... 		KEEP AS NON CORE
Summary: Erlins associate with lipid-raft-like domains of the ER membrane; the NAS membrane-raft localization reflects this SPFH-domain raft association.
Reason: Supported by the lipid-raft characterization of erlins but secondary to the core ER-membrane ERAD/SREBP roles.
Supporting Evidence:
PMID:16835267
define lipid-raft-like domains of the ER
GO:0045540 regulation of cholesterol biosynthetic process
IDA
PMID:24217618
Erlins restrict SREBP activation in the ER and regulate cell... 		ACCEPT
Summary: ERLIN2 regulates cholesterol biosynthesis via the SREBP/SCAP/Insig machinery; the erlins restrict SREBP activation in response to ER cholesterol.
Reason: Core biological process; directly supported.
Supporting Evidence:
PMID:24217618
regulate cellular cholesterol
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-1839094 		MARK AS OVER ANNOTATED
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.
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.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-1839098 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-1839100 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5655240 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5655263 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5655266 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5655269 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5655278 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5655290 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5655326 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-signaling annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-8853322 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-fusion annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-8853325 		MARK AS OVER ANNOTATED
Summary: Reactome FGFR1-fusion annotation placing ERLIN2 at the plasma membrane; inconsistent with its ER membrane localization.
Reason: Over-annotation from FGFR1-pathway curation; ERLIN2 is an ER membrane protein.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding
IPI
PMID:30352685
Stasimon/Tmem41b localizes to mitochondria-associated ER mem... 		KEEP AS NON CORE
Summary: IPI capture of the ERLIN2-TMEM41B interaction (a MAM/ER protein). Bare protein binding is uninformative.
Reason: Real interaction (TMEM41B) but uninformative GO term.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
Interacts with TMEM41B
GO:0032991 protein-containing complex
IDA
PMID:18468998
Blood pressure is regulated by an alpha1D-adrenergic recepto... 		KEEP AS NON CORE
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.
Reason: Experimentally supported but uninformative generic complex term; not the core ERLIN1/ERLIN2 complex.
Supporting Evidence:
PMID:19240031
SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-8866542 		ACCEPT
Summary: Reactome curation placing ERLIN2 at the ER membrane within the CFTR ERAD machinery pathway.
Reason: Correct compartment; redundant with experimental ER membrane annotations.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-8866546 		ACCEPT
Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR ERAD pathway).
Reason: Correct compartment; redundant with experimental evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-8866551 		ACCEPT
Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR ERAD pathway).
Reason: Correct compartment; redundant with experimental evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-8866854 		ACCEPT
Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway).
Reason: Correct compartment; redundant with experimental evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-8866856 		ACCEPT
Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway).
Reason: Correct compartment; redundant with experimental evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-8866857 		ACCEPT
Summary: Reactome curation of ERLIN2 ER membrane localization (CFTR F508del ERAD pathway).
Reason: Correct compartment; redundant with experimental evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-9931264 		ACCEPT
Summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway).
Reason: Correct compartment; redundant with experimental evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-9931298 		ACCEPT
Summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway).
Reason: Correct compartment; redundant with experimental evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-9931313 		ACCEPT
Summary: Reactome curation of ERLIN2 ER membrane localization (CD274/PD-L1 ERAD pathway).
Reason: Correct compartment; redundant with experimental evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0031625 ubiquitin protein ligase binding
IPI
PMID:24019521
RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... 		ACCEPT
Summary: ERLIN2 interacts with the ER ubiquitin ligases RNF185 and RNF5, an informative molecular function reflecting its recruitment of E3 ligases to ERAD.
Reason: Directly supported (IPI); ERLIN2 binds ER ubiquitin ligases, consistent with its ERAD scaffold role.
Supporting Evidence:
PMID:24019521
RNF185 and RNF5 as a novel E3 ligase module
GO:0032933 SREBP signaling pathway
IMP
PMID:24217618
Erlins restrict SREBP activation in the ER and regulate cell... 		ACCEPT
Summary: Depletion of erlins led to canonical activation of SREBPs and their target genes, demonstrating that ERLIN2 restricts SREBP signaling.
Reason: Core biological process with direct depletion (IMP) support.
Supporting Evidence:
PMID:24217618
led to canonical activation of SREBPs and their target genes
GO:0045541 negative regulation of cholesterol biosynthetic process
IMP
PMID:24217618
Erlins restrict SREBP activation in the ER and regulate cell... 		ACCEPT
Summary: By restricting SREBP activation, ERLIN2 negatively regulates cholesterol biosynthesis.
Reason: Core biological process with direct (IMP) support.
Supporting Evidence:
PMID:24217618
led to canonical activation of SREBPs and their target genes
GO:0045717 negative regulation of fatty acid biosynthetic process
IMP
PMID:24217618
Erlins restrict SREBP activation in the ER and regulate cell... 		ACCEPT
Summary: ERLIN2 negatively regulates fatty acid biosynthesis through restriction of SREBP, which activates fatty-acid biosynthetic genes.
Reason: Directly supported (IMP); a consequence of the erlins' SREBP restriction.
Supporting Evidence:
PMID:24217618
key transcription factors for cholesterol and fatty acid biosynthetic
GO:0045121 membrane raft
IDA
PMID:25204797
Flotillin-1 facilitates toll-like receptor 3 signaling in hu... 		KEEP AS NON CORE
Summary: IDA membrane-raft localization of ERLIN2, consistent with the erlins associating with lipid-raft-like domains of the ER membrane.
Reason: Experimentally supported raft association but secondary to the core ER-membrane ERAD/SREBP roles.
Supporting Evidence:
PMID:16835267
define lipid-raft-like domains of the ER
GO:0005783 endoplasmic reticulum
IDA
GO_REF:0000054 		ACCEPT
Summary: Fusion-protein localization (LIFEdb) evidence for ER localization of ERLIN2.
Reason: Correct compartment; redundant with experimental ER membrane evidence.
Supporting Evidence:
file:human/ERLIN2/ERLIN2-uniprot.txt
SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding
IPI
PMID:19240031
An endoplasmic reticulum (ER) membrane complex composed of S... 		KEEP AS NON CORE
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.
Reason: Real ERLIN1 interaction but uninformative GO term.
Supporting Evidence:
PMID:19240031
SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:16835267
Erlin-1 and erlin-2 are novel members of the prohibitin fami... 		ACCEPT
Summary: Direct evidence that erlin-2 localizes to lipid-raft-like domains of the ER membrane.
Reason: Core compartment; directly demonstrated.
Supporting Evidence:
PMID:16835267
define lipid-raft-like domains of the ER

Core Functions

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.

Directly Involved In:
ERAD pathway
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • PMID:19240031
    mediates the ER-associated degradation of inositol 1,4,5-trisphosphate
  • PMID:19240031
    SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex

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:
cholesterol binding
Directly Involved In:
SREBP signaling pathway negative regulation of cholesterol biosynthetic process
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:

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:
ubiquitin protein ligase binding
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000054
Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:16835267
Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER.
  • Erlin-1 and erlin-2 are prohibitin-family ER membrane proteins that define lipid-raft-like domains of the ER.
PMID:18468998
Blood pressure is regulated by an alpha1D-adrenergic receptor/dystrophin signalosome.
PMID:19240031
An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate receptors.
  • 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.
PMID:21343306
Membrane-associated ubiquitin ligase complex containing gp78 mediates sterol-accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
  • SPFH2 (ERLIN2) and TMUB1 associate with the ER ubiquitin ligase gp78/AMFR in sterol-accelerated ERAD of HMG-CoA reductase.
PMID:22119785
Defining human ERAD networks through an integrative mapping strategy.
PMID:24019521
RNF185 is a novel E3 ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR).
  • RNF185 and RNF5 form a novel ER-associated E3 ligase module central to CFTR degradation; ERLIN2 interacts with these E3 ligases.
PMID:24217618
Erlins restrict SREBP activation in the ER and regulate cellular cholesterol homeostasis.
  • Erlins are cholesterol-binding proteins that restrict SREBP activation by stabilizing the SREBP-Scap-Insig complex; erlin depletion activates SREBP target genes.
PMID:25204797
Flotillin-1 facilitates toll-like receptor 3 signaling in human endothelial cells.
PMID:30021884
Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
PMID:30352685
Stasimon/Tmem41b localizes to mitochondria-associated ER membranes and is essential for mouse embryonic development.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34572057
Role of ERLINs in the Control of Cell Fate through Lipid Rafts.
  • Review of ERLIN1/2 as ER lipid-raft-associated proteins controlling cell fate.
PMID:38782601
ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway.
  • 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.
PMID:40225166
Disruption of Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary Spastic Paraplegia in Patient-Derived Stem Cell Models.
  • 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.
PMID:38427163
Hereditary spastic paraparesis type 18 (SPG18): new ERLIN2 variants in a series of Italian patients, shedding light upon genetic and phenotypic variability.
  • 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.
PMID:38607533
Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.
  • 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.
Reactome:R-HSA-1839094
Activated FGFR1 mutants and fusions bind PLCG1
Reactome:R-HSA-1839098
Activated FGFR1 mutants and fusions phosphorylate PLCG1
Reactome:R-HSA-1839100
p-4Y- PLCG1 dissociates from activated FGFR1 mutants and fusions
Reactome:R-HSA-5655240
Activated FGFR1 mutants:p-FRS2 binds GRB2:GAB1:PIK3R1
Reactome:R-HSA-5655263
Activated FGFR1 mutants:p-FRS2:GRB2:GAB1:PIK3R1 binds PIK3CA
Reactome:R-HSA-5655266
Activated FGFR1 mutants:p-FRS2 binds GRB2-SOS1
Reactome:R-HSA-5655269
Activated FGFR1 mutants bind FRS2
Reactome:R-HSA-5655278
Activated FGFR1 mutants phosphorylate FRS2
Reactome:R-HSA-5655290
Activated FGFR1 mutant-associated PI3K phosphorylates PIP2 to PIP3
Reactome:R-HSA-5655326
Activated FGFR1 mutants:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange
Reactome:R-HSA-8853322
Plasma membrane FGFR1 fusions dimerize
Reactome:R-HSA-8853325
Plasma membrane FGFR1 fusions autophosphorylate
Reactome:R-HSA-8866542
VCP-catalyzed ATP hydrolysis promotes the translocation of misfolded CFTR into the cytosol
Reactome:R-HSA-8866546
RNF5 and RNF185 ubiquitinate misfolded CFTR
Reactome:R-HSA-8866551
CFTR binds components of the ERAD machinery for ubiquitination and degradation
Reactome:R-HSA-8866854
VCP-catalyzed ATP hydrolysis promotes the translocation of CFTR F508del into the cytosol
Reactome:R-HSA-8866856
RNF5 and RNF185 ubiquitinate CFTR F508del
Reactome:R-HSA-8866857
CFTR F508del binds components of the ERAD machinery for ubiquitination and degradation
Reactome:R-HSA-9931264
Active transport of ubiquitinated CD274 from ER to cytosol
Reactome:R-HSA-9931298
Ubiquitination of CD274 by ERAD complex
Reactome:R-HSA-9931313
p-S195-CD274 binds ERAD complex
file:human/ERLIN2/ERLIN2-uniprot.txt
UniProt entry O94905 (ERLN2_HUMAN), Erlin-2 / SPFH2
  • 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.

Suggested Questions for Experts

Q: 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?

Q: How do ERLIN2 SPG18A/SPG18B disease variants impair complex assembly, IP3R ERAD, or cholesterol/SREBP regulation to cause corticospinal motor neuron degeneration?

Q: 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

Experiment: 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.

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(ERLIN2-deep-research-falcon.md)
Research Report: Functional Annotation of Human **ERLIN2** (UniProt O94905) Falcon Edison Scientific Literature 14 citations 2 artifacts 2026-06-12T05:09:52.133371
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000009 The requested information is provided in Figures 3, 7, and 8. - **ERLIN1/2 Scaffold Model:** Figure 3 shows the schematic (A) and t (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

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Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Functional Annotation of Human ERLIN2 (UniProt O94905)

0. Target verification (critical identity check)

The literature reviewed here matches the UniProt-provided target: ERLIN2 (ER lipid raft-associated protein 2; “Erlin-2”), encoded by ERLIN2 in Homo sapiens, a ~40 kDa band 7/SPFH-domain ER membrane protein that forms an ERLIN1/2 hetero-oligomeric complex in cholesterol-rich ER membrane nanodomains. This description is consistent across mechanistic cell biology and disease genetics literature used in this report, supporting correct gene/protein identity alignment with UniProt accession O94905. (veronese2024erlin12scaffoldsbridge pages 1-2, manganelli2021roleoferlins pages 5-7)

1. Key concepts and current understanding

1.1 ERLIN2 as an ER “lipid-raft-like” nanodomain scaffold (definition)

“ER lipid rafts” (also described as detergent-resistant membranes/nanodomains) refer to cholesterol-enriched microdomains within the endoplasmic reticulum that organize specific proteins and lipids into functional assemblies. ERLIN2 (with ERLIN1) is widely treated as a marker and organizer of these ER raft-like domains, functioning as a non-enzymatic scaffold rather than a catalytic enzyme. (veronese2024erlin12scaffoldsbridge pages 1-2, manganelli2021roleoferlins pages 5-7)

1.2 ERLIN2 in ER-associated degradation (ERAD): adaptor/scaffold role

ER-associated degradation (ERAD) removes specific ER and ER membrane proteins by ubiquitination and extraction (often via p97/VCP) followed by proteasomal degradation. ERLIN2 contributes to ERAD primarily by organizing client proteins and ubiquitination/extraction machinery within ER nanodomains, rather than directly ubiquitinating substrates. The best-supported example is activated inositol 1,4,5-trisphosphate receptors (IP3Rs), which undergo ubiquitination and ERAD after activation. (veronese2024erlin12scaffoldsbridge pages 1-2, manganelli2021roleoferlins pages 5-7)

1.3 ERLIN2 and lipid/cholesterol homeostasis

A major theme is that ERLIN2 binds cholesterol and participates in pathways that connect ER cholesterol status to (i) regulation of SREBP (sterol regulatory element-binding proteins) activation and (ii) downstream effects on lipid storage (e.g., cholesteryl ester formation) and secretory pathway function. (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 12-12, manganelli2021roleoferlins pages 5-7)

2. Molecular function, subcellular localization, complexes, and pathways (experimental evidence)

2.1 Subcellular localization

ERLIN2 localizes to the endoplasmic reticulum membrane, enriched in cholesterol-rich ER detergent-resistant membrane fractions/nanodomains. Evidence from recent mechanistic work also supports functional presence near ER–Golgi contact regions, consistent with roles in cholesterol flux to the Golgi and regulation of Golgi morphology/secretory trafficking. (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 12-12)

2.2 Core molecular function: large ERLIN1/2 scaffold complex

ERLIN2 assembles with ERLIN1 into large ring-like hetero-oligomeric scaffold structures on the ER membrane. These scaffolds provide multivalent binding surfaces that can recruit luminal motifs and stabilize interactions among client proteins and regulators. A 2024 study (Life Science Alliance) directly connects this scaffolding role to the formation of an interaction bridge between the ER proteins TMUB1 and RNF170. (veronese2024erlin12scaffoldsbridge pages 1-2)

Visual evidence (mechanistic model and phenotype): ERLIN1/2 scaffold organization and its link to cholesterol esterification phenotypes and rescue by SOAT1 inhibition are summarized in the figures retrieved from Veronese et al. 2024. (veronese2024erlin12scaffoldsbridge media 30054738, veronese2024erlin12scaffoldsbridge media bd5fdacb, veronese2024erlin12scaffoldsbridge media 2c4467d5, veronese2024erlin12scaffoldsbridge media bf33204b, veronese2024erlin12scaffoldsbridge media c1b3c978)

2.3 Interaction partners and mechanistic pathway context

RNF170 and IP3R ERAD. RNF170 is an ER membrane ubiquitin ligase implicated in ubiquitination of activated IP3Rs, with ERLIN scaffolds serving as platforms that recruit or support RNF170 function toward IP3Rs. This supports ERLIN2’s role in the IP3R ubiquitination → extraction → degradation axis, linking ERLIN2 to calcium signaling control via IP3R abundance. (veronese2024erlin12scaffoldsbridge pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2, manganelli2021roleoferlins pages 5-7)

TMUB1, p97/VCP extraction, and ERAD coupling. TMUB1 is described as an ER-resident escort factor that promotes p97-mediated extraction of membrane proteins. The 2024 mechanistic study shows ERLIN scaffolds bridging TMUB1 and RNF170 via conserved luminal motifs, providing a concrete model for how ERLIN2-containing scaffolds can couple ubiquitination (RNF170) with extraction (TMUB1/p97) within ER nanodomains. (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 19-20)

Lipid regulation module (INSIG/SREBP/SCAP). Erlins physically interact with components of the SREBP regulatory system (SREBP–SCAP–INSIG) and are proposed to contribute to sterol-dependent retention/processing, thereby connecting ERLIN2 scaffolds to sterol-sensing control of lipid biosynthesis. (manganelli2021roleoferlins pages 5-7)

2.4 Cholesterol esterification control and secretory pathway regulation (2024 primary research)

Veronese et al. (May 2024) provide direct functional evidence that ERLIN1/2 scaffolds restrict cholesterol esterification and influence Golgi morphology and the secretory pathway.

  • Mechanistic model: ERLIN scaffolds bind cholesterol and modulate its accessibility to the ER cholesterol esterification enzyme SOAT1, thereby favoring ER-to-Golgi cholesterol transport and maintaining secretory pathway organization. (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 12-12)
  • Pharmacologic intervention: the study reports that SOAT1 inhibition (using avasimibe) can rescue ERLIN-deficiency-associated phenotypes, including excessive large lipid droplets and Golgi fragmentation, supporting causality of cholesterol esterification imbalance downstream of ERLIN loss. (veronese2024erlin12scaffoldsbridge media 30054738, veronese2024erlin12scaffoldsbridge media bf33204b)
  • Quantitative datapoint explicitly available in the retrieved text: ERLIN double knockout cells showed a tendency toward increased SOAT1 abundance (log2FC = 0.40; q = 0.07). (veronese2024erlin12scaffoldsbridge pages 12-12)

3. Recent developments (prioritizing 2023–2024)

3.1 Patient-derived stem cell models implicate Ca2+ dysregulation in ERLIN2-linked HSP (2023)

Zhu et al. (Jun 2023) used patient-derived iPSC models and identified a heterozygous ERLIN2 missense variant (p.Val71Ala) in an HSP family. Their mechanistic interpretation was that mutant ERLIN2 recruited the E3 ligase RNF213, promoting degradation of IP3R1, which lowered intracellular free Ca2+, induced ER-stress-mediated apoptosis, and suppressed MAPK signaling, reducing proliferation in patient-derived neural cells. This work proposes a specific autosomal-dominant disease mechanism via altered IP3R abundance and calcium homeostasis. (zhu2023disruptionofintracellular pages 1-2)

3.2 Clinical expansion and inheritance patterns in SPG18 (2024)

Two 2024 clinical genetics studies expand phenotype and inheritance considerations for ERLIN2-related spastic paraplegia:

  • Cioffi et al. (Mar 2024) emphasize that SPG18 is classically recessive but that monoallelic/autosomal dominant presentations have been described; they also report HSP-to-ALS phenoconversion in 2 of 5 cases in their series. They note screening scale in one diagnostic workflow: 944 clinically suspected HSP patients tested over 8 years. (cioffi2024hereditaryspasticparaparesis pages 1-2)
  • Trinchillo et al. (Apr 2024) report an autosomal dominant ERLIN2 mutation segregating in a large family with variable expressivity, including complicated presentations, further supporting phenotypic breadth beyond “pure” HSP in some ERLIN2 variant contexts. (trinchillo2024expandingspg18clinical pages 8-9)

3.3 Connecting ERLIN scaffolds to neurologic disease mechanisms (2024 cell biology)

The 2024 scaffold study explicitly links ERLIN complex biology (TMUB1/RNF170 and cholesterol esterification control) to variants previously linked to hereditary spastic paraplegia, framing disease as potentially involving disruption of nanodomain scaffold interactions that couple lipid handling and ERAD/client processing. (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 12-12)

4. Current applications and real-world implementations

4.1 Clinical genetics and diagnostics

ERLIN2 is now a recognized disease gene in hereditary spastic paraplegia gene panels and exome/genome sequencing workflows; the 2024 Italian series provides real-world scale metrics (944 suspected HSP patients screened over 8 years) and highlights the practical diagnostic implication that HSP gene panels may be relevant even in familial ALS-like presentations due to observed phenoconversion in some ERLIN2-linked cases. (cioffi2024hereditaryspasticparaparesis pages 1-2)

4.2 Experimental pharmacology / pathway “druggability” signals

While no approved ERLIN2-targeted therapy exists in the evidence reviewed, Veronese et al. provide a proof-of-principle that modulating downstream lipid metabolism can correct ERLIN-loss phenotypes: SOAT1 inhibition (avasimibe) rescued lipid droplet and Golgi phenotypes in ERLIN-deficient cells. This suggests a potential translational direction (pathway-level intervention rather than direct ERLIN2 targeting) for disorders where cholesterol esterification imbalance is a driver. (veronese2024erlin12scaffoldsbridge media 30054738, veronese2024erlin12scaffoldsbridge media bf33204b)

4.3 Knowledgebase integration (target–disease association)

Open Targets aggregates literature-based evidence linking ERLIN2 to hereditary spastic paraplegia 18 and broader hereditary spastic paraplegia disease concepts, as well as cancer-related associations (likely reflecting ERLIN2 amplification/ER-stress literature). This is useful for prioritization but should be interpreted as an evidence aggregation layer rather than direct mechanistic proof. (OpenTargets Search: -ERLIN2)

5. Expert synthesis and analysis (mechanism-focused)

5.1 Primary functional annotation (non-enzymatic scaffold)

The most defensible primary function for ERLIN2 is that of an ER membrane nanodomain scaffold/adaptor that integrates two major functional themes:

  1. Quality control / receptor turnover: organizing ERAD machinery around activated clients such as IP3Rs, in coordination with ubiquitin ligases (e.g., RNF170) and extraction factors (p97/VCP machinery via TMUB1). (veronese2024erlin12scaffoldsbridge pages 1-2, manganelli2021roleoferlins pages 5-7)
  2. Lipid handling coupled to trafficking: shaping local ER cholesterol accessibility and routing (restricting esterification; promoting ER-to-Golgi cholesterol movement), impacting Golgi morphology and secretion. (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 12-12)

This dual role provides a plausible bridge between (i) neurologic phenotypes driven by altered Ca2+ homeostasis (via IP3R regulation) and (ii) broader cell biology phenotypes involving secretory pathway dysfunction and lipid droplet accumulation.

5.2 Disease mechanism models supported by 2023–2024 evidence

Two non-mutually exclusive mechanisms are supported:

  • Ca2+ signaling perturbation via IP3R abundance: patient-derived iPSC work supports a model where mutant ERLIN2 drives abnormal IP3R1 degradation and downstream Ca2+ depletion/ER stress and apoptosis in neural contexts. (zhu2023disruptionofintracellular pages 1-2)
  • Cholesterol esterification/secretory pathway imbalance: ERLIN loss shifts cholesterol toward esterification and lipid droplet accumulation and disrupts Golgi morphology; SOAT1 inhibition rescues phenotypes, supporting causal linkage. (veronese2024erlin12scaffoldsbridge media 30054738, veronese2024erlin12scaffoldsbridge media bf33204b)

6. Key statistics and data points (from retrieved sources)

  • SOAT1 abundance trend in ERLIN DKO cells: log2FC 0.40; q 0.07. (veronese2024erlin12scaffoldsbridge pages 12-12)
  • Phenoconversion in a 2024 SPG18 series: 2/5 cases reported with HSP→ALS phenoconversion. (cioffi2024hereditaryspasticparaparesis pages 1-2)
  • Diagnostic workflow scale: 944 clinically suspected HSP patients screened over 8 years in a single laboratory setting (contextualizing rarity and diagnostic throughput). (cioffi2024hereditaryspasticparaparesis pages 1-2)

7. Evidence summary table

The following table provides a structured evidence map linking ERLIN2 functional annotation components to key sources, including URLs/DOIs and explicitly captured quantitative points.

Aspect Key findings Key sources (author year, journal) URL/DOI
Identity/domain/localization ERLIN2 is the verified human protein encoded by ERLIN2 (UniProt O94905), an ER lipid raft-associated membrane protein in the band 7/SPFH family that hetero-oligomerizes with ERLIN1. It localizes mainly to cholesterol-rich ER detergent-resistant nanodomains and has also been linked to ER–Golgi contact regions and, under some conditions, MAM-associated rafts (veronese2024erlin12scaffoldsbridge pages 1-2, manganelli2021roleoferlins pages 5-7). Veronese 2024, Life Science Alliance; Manganelli 2021, Cells https://doi.org/10.26508/lsa.202402620 ; https://doi.org/10.3390/cells10092408
Complex/partners ERLIN2 forms large ring-shaped ERLIN1/2 complexes (likely ~24 subunits) that scaffold membrane proteins. Reported partners include ERLIN1, RNF170, TMUB1, TMEM259, INSIG1, FAF2, VCP/p97, and associations with other ERAD ligases. A 2024 study showed ERLIN scaffolds bridge TMUB1 and RNF170 through a conserved luminal motif that binds adjacent ERLIN SPFH interfaces (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 12-12, veronese2024erlin12scaffoldsbridge pages 19-20). Veronese 2024, Life Science Alliance https://doi.org/10.26508/lsa.202402620
Pathways/mechanism Best-supported mechanism: ERLIN2 acts as a non-enzymatic ER membrane scaffold/adaptor in ER-associated degradation (ERAD), especially for activated IP3 receptors (IP3Rs). ERLIN2 helps recruit RNF170 for IP3R ubiquitination/degradation and binds cholesterol and PI3P, supporting microdomain assembly and client handling. ERLINs also influence SREBP/INSIG/SCAP regulation, HMG-CoA reductase turnover, and cholesterol partitioning/esterification, thereby affecting Golgi morphology and the secretory pathway (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 12-12, manganelli2021roleoferlins pages 5-7). Veronese 2024, Life Science Alliance; Manganelli 2021, Cells https://doi.org/10.26508/lsa.202402620 ; https://doi.org/10.3390/cells10092408
Disease links Human genetics strongly links ERLIN2 to SPG18 / hereditary spastic paraplegia (HSP) with autosomal recessive and some autosomal dominant presentations. Clinical expansion includes developmental delay, seizures, contractures, hearing loss, and reported HSP-to-ALS phenoconversion in some families. Recent work also proposed a dominant mechanism in which mutant ERLIN2 alters IP3R control and Ca2+ homeostasis (cioffi2024hereditaryspasticparaparesis pages 1-2, zhu2023disruptionofintracellular pages 1-2, trinchillo2024expandingspg18clinical pages 8-9, OpenTargets Search: -ERLIN2). Cioffi 2024, Neurological Sciences; Zhu 2023, Human Mutation; Trinchillo 2024, Neurological Sciences; Open Targets https://doi.org/10.1007/s10072-024-07423-w ; https://doi.org/10.1155/2023/4834423 ; https://doi.org/10.1007/s10072-024-07500-0 ; https://platform.opentargets.org/target/ENSG00000147475
Key quantitative findings Explicit quantitative snippets reported in accessible evidence: HeLa ERLIN double-knockout cells showed a tendency toward increased SOAT1 abundance (log2FC = 0.40; q = 0.07), consistent with increased cholesterol esterification pressure; in one 2024 SPG18 clinical series, 2 of 5 cases showed HSP→ALS phenoconversion; the same report noted 944 clinically suspected HSP patients screened over 8 years in one laboratory workflow (veronese2024erlin12scaffoldsbridge pages 12-12, cioffi2024hereditaryspasticparaparesis pages 1-2). Veronese 2024, Life Science Alliance; Cioffi 2024, Neurological Sciences https://doi.org/10.26508/lsa.202402620 ; https://doi.org/10.1007/s10072-024-07423-w
2023–2024 mechanistic update A 2023 patient-derived iPSC study of ERLIN2 p.Val71Ala proposed that mutant ERLIN2 recruits RNF213 to drive IP3R1 degradation, lowering intracellular free Ca2+, triggering ER-stress apoptosis, and suppressing MAPK signaling/cell proliferation. A 2024 cell-biology study extended ERLIN function beyond classical ERAD, showing ERLIN scaffolds restrict cholesterol esterification and favor ER-to-Golgi cholesterol transport to support secretory-pathway organization (zhu2023disruptionofintracellular pages 1-2, veronese2024erlin12scaffoldsbridge pages 1-2). Zhu 2023, Human Mutation; Veronese 2024, Life Science Alliance https://doi.org/10.1155/2023/4834423 ; https://doi.org/10.26508/lsa.202402620

Table: This table summarizes the core functional annotation evidence for human ERLIN2, emphasizing verified identity, molecular mechanism, disease relevance, and the most explicit quantitative findings from recent literature.

8. Key sources (prioritized, with publication dates and URLs)

  • Veronese et al. “ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway.” Life Science Alliance (May 2024). https://doi.org/10.26508/lsa.202402620 (veronese2024erlin12scaffoldsbridge pages 1-2, veronese2024erlin12scaffoldsbridge pages 12-12, veronese2024erlin12scaffoldsbridge media 30054738)
  • Zhu et al. “Disruption of Intracellular Calcium Homeostasis Leads to ERLIN2-Linked Hereditary Spastic Paraplegia in Patient-Derived Stem Cell Models.” Human Mutation (Jun 2023). https://doi.org/10.1155/2023/4834423 (zhu2023disruptionofintracellular pages 1-2)
  • Cioffi et al. “Hereditary spastic paraparesis type 18 (SPG18): new ERLIN2 variants…” Neurological Sciences (Mar 2024). https://doi.org/10.1007/s10072-024-07423-w (cioffi2024hereditaryspasticparaparesis pages 1-2)
  • Trinchillo et al. “Expanding SPG18 clinical spectrum: autosomal dominant mutation…” Neurological Sciences (Apr 2024). https://doi.org/10.1007/s10072-024-07500-0 (trinchillo2024expandingspg18clinical pages 8-9)
  • Manganelli et al. “Role of ERLINs in the control of cell fate through lipid rafts.” Cells (Sep 2021). https://doi.org/10.3390/cells10092408 (manganelli2021roleoferlins pages 5-7)
  • Open Targets Platform (ERLIN2 target page) (accessed via tool output). https://platform.opentargets.org/target/ENSG00000147475 (OpenTargets Search: -ERLIN2)

9. Limitations of this synthesis

Some mechanistic claims widely discussed in the ERLIN literature (e.g., detailed kinetics of IP3R ubiquitination steps, full substrate lists beyond IP3R/HMGR, and structural resolution of the oligomer) are referenced in the review and scaffold work but were not all available as fully inspectable primary evidence snippets in the retrieved text corpus for this run. Therefore, the report emphasizes mechanisms directly supported by the retrieved full-text evidence and figures. (veronese2024erlin12scaffoldsbridge pages 1-2, manganelli2021roleoferlins pages 5-7)

References

  1. (veronese2024erlin12scaffoldsbridge pages 1-2): Matteo Veronese, Sebastian Kallabis, Alexander Tobias Kaczmarek, Anushka Das, Lennart Robers, Simon Schumacher, Alessia Lofrano, Susanne Brodesser, Stefan Müller, Kay Hofmann, Marcus Krüger, and Elena I Rugarli. Erlin1/2 scaffolds bridge tmub1 and rnf170 and restrict cholesterol esterification to regulate the secretory pathway. Life Science Alliance, 7:e202402620, May 2024. URL: https://doi.org/10.26508/lsa.202402620, doi:10.26508/lsa.202402620. This article has 8 citations and is from a peer-reviewed journal.

  2. (manganelli2021roleoferlins pages 5-7): Valeria Manganelli, Agostina Longo, Vincenzo Mattei, Serena Recalchi, Gloria Riitano, Daniela Caissutti, Antonella Capozzi, Maurizio Sorice, Roberta Misasi, and Tina Garofalo. Role of erlins in the control of cell fate through lipid rafts. Cells, 10:2408, Sep 2021. URL: https://doi.org/10.3390/cells10092408, doi:10.3390/cells10092408. This article has 42 citations.

  3. (veronese2024erlin12scaffoldsbridge pages 12-12): Matteo Veronese, Sebastian Kallabis, Alexander Tobias Kaczmarek, Anushka Das, Lennart Robers, Simon Schumacher, Alessia Lofrano, Susanne Brodesser, Stefan Müller, Kay Hofmann, Marcus Krüger, and Elena I Rugarli. Erlin1/2 scaffolds bridge tmub1 and rnf170 and restrict cholesterol esterification to regulate the secretory pathway. Life Science Alliance, 7:e202402620, May 2024. URL: https://doi.org/10.26508/lsa.202402620, doi:10.26508/lsa.202402620. This article has 8 citations and is from a peer-reviewed journal.

  4. (veronese2024erlin12scaffoldsbridge media 30054738): Matteo Veronese, Sebastian Kallabis, Alexander Tobias Kaczmarek, Anushka Das, Lennart Robers, Simon Schumacher, Alessia Lofrano, Susanne Brodesser, Stefan Müller, Kay Hofmann, Marcus Krüger, and Elena I Rugarli. Erlin1/2 scaffolds bridge tmub1 and rnf170 and restrict cholesterol esterification to regulate the secretory pathway. Life Science Alliance, 7:e202402620, May 2024. URL: https://doi.org/10.26508/lsa.202402620, doi:10.26508/lsa.202402620. This article has 8 citations and is from a peer-reviewed journal.

  5. (veronese2024erlin12scaffoldsbridge media bd5fdacb): Matteo Veronese, Sebastian Kallabis, Alexander Tobias Kaczmarek, Anushka Das, Lennart Robers, Simon Schumacher, Alessia Lofrano, Susanne Brodesser, Stefan Müller, Kay Hofmann, Marcus Krüger, and Elena I Rugarli. Erlin1/2 scaffolds bridge tmub1 and rnf170 and restrict cholesterol esterification to regulate the secretory pathway. Life Science Alliance, 7:e202402620, May 2024. URL: https://doi.org/10.26508/lsa.202402620, doi:10.26508/lsa.202402620. This article has 8 citations and is from a peer-reviewed journal.

  6. (veronese2024erlin12scaffoldsbridge media 2c4467d5): Matteo Veronese, Sebastian Kallabis, Alexander Tobias Kaczmarek, Anushka Das, Lennart Robers, Simon Schumacher, Alessia Lofrano, Susanne Brodesser, Stefan Müller, Kay Hofmann, Marcus Krüger, and Elena I Rugarli. Erlin1/2 scaffolds bridge tmub1 and rnf170 and restrict cholesterol esterification to regulate the secretory pathway. Life Science Alliance, 7:e202402620, May 2024. URL: https://doi.org/10.26508/lsa.202402620, doi:10.26508/lsa.202402620. This article has 8 citations and is from a peer-reviewed journal.

  7. (veronese2024erlin12scaffoldsbridge media bf33204b): Matteo Veronese, Sebastian Kallabis, Alexander Tobias Kaczmarek, Anushka Das, Lennart Robers, Simon Schumacher, Alessia Lofrano, Susanne Brodesser, Stefan Müller, Kay Hofmann, Marcus Krüger, and Elena I Rugarli. Erlin1/2 scaffolds bridge tmub1 and rnf170 and restrict cholesterol esterification to regulate the secretory pathway. Life Science Alliance, 7:e202402620, May 2024. URL: https://doi.org/10.26508/lsa.202402620, doi:10.26508/lsa.202402620. This article has 8 citations and is from a peer-reviewed journal.

  8. (veronese2024erlin12scaffoldsbridge media c1b3c978): Matteo Veronese, Sebastian Kallabis, Alexander Tobias Kaczmarek, Anushka Das, Lennart Robers, Simon Schumacher, Alessia Lofrano, Susanne Brodesser, Stefan Müller, Kay Hofmann, Marcus Krüger, and Elena I Rugarli. Erlin1/2 scaffolds bridge tmub1 and rnf170 and restrict cholesterol esterification to regulate the secretory pathway. Life Science Alliance, 7:e202402620, May 2024. URL: https://doi.org/10.26508/lsa.202402620, doi:10.26508/lsa.202402620. This article has 8 citations and is from a peer-reviewed journal.

  9. (cioffi2024hereditaryspasticparaparesis pages 1-2): Ettore Cioffi, Valeria Gioiosa, Alessandra Tessa, Antonio Petrucci, Rosanna Trovato, Filippo Maria Santorelli, and Carlo Casali. Hereditary spastic paraparesis type 18 (spg18): new erlin2 variants in a series of italian patients, shedding light upon genetic and phenotypic variability. Neurological Sciences, 45:3845-3852, Mar 2024. URL: https://doi.org/10.1007/s10072-024-07423-w, doi:10.1007/s10072-024-07423-w. This article has 3 citations and is from a peer-reviewed journal.

  10. (veronese2024erlin12scaffoldsbridge pages 19-20): Matteo Veronese, Sebastian Kallabis, Alexander Tobias Kaczmarek, Anushka Das, Lennart Robers, Simon Schumacher, Alessia Lofrano, Susanne Brodesser, Stefan Müller, Kay Hofmann, Marcus Krüger, and Elena I Rugarli. Erlin1/2 scaffolds bridge tmub1 and rnf170 and restrict cholesterol esterification to regulate the secretory pathway. Life Science Alliance, 7:e202402620, May 2024. URL: https://doi.org/10.26508/lsa.202402620, doi:10.26508/lsa.202402620. This article has 8 citations and is from a peer-reviewed journal.

  11. (zhu2023disruptionofintracellular pages 1-2): Xin Zhu, Xiaoyin Tan, Junwen Wang, Limeng Dai, Jia Li, Xingying Guan, Ziyi Wang, Mao Zhang, Junyan Hu, Yun Bai, and Hongen Guo. Disruption of intracellular calcium homeostasis leads to erlin2-linked hereditary spastic paraplegia in patient-derived stem cell models. Human Mutation, 2023:1-14, Jun 2023. URL: https://doi.org/10.1155/2023/4834423, doi:10.1155/2023/4834423. This article has 1 citations and is from a domain leading peer-reviewed journal.

  12. (trinchillo2024expandingspg18clinical pages 8-9): Assunta Trinchillo, Valeria Valente, Marcello Esposito, Miriana Migliaccio, Aniello Iovino, Michele Picciocchi, Nunzia Cuomo, Carmela Caccavale, Cristofaro Nocerino, Laura De Rosa, Elena Salvatore, Giovanna Maria Pierantoni, Valeria Menchise, Simona Paladino, and Chiara Criscuolo. Expanding spg18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family. Neurological Sciences, 45:4373-4381, Apr 2024. URL: https://doi.org/10.1007/s10072-024-07500-0, doi:10.1007/s10072-024-07500-0. This article has 2 citations and is from a peer-reviewed journal.

  13. (OpenTargets Search: -ERLIN2): Open Targets Query (-ERLIN2, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Citations

  1. manganelli2021roleoferlins pages 5-7
  2. zhu2023disruptionofintracellular pages 1-2
  3. cioffi2024hereditaryspasticparaparesis pages 1-2
  4. https://doi.org/10.26508/lsa.202402620
  5. https://doi.org/10.3390/cells10092408
  6. https://doi.org/10.1007/s10072-024-07423-w
  7. https://doi.org/10.1155/2023/4834423
  8. https://doi.org/10.1007/s10072-024-07500-0
  9. https://platform.opentargets.org/target/ENSG00000147475
  10. https://doi.org/10.26508/lsa.202402620,
  11. https://doi.org/10.3390/cells10092408,
  12. https://doi.org/10.1007/s10072-024-07423-w,
  13. https://doi.org/10.1155/2023/4834423,
  14. https://doi.org/10.1007/s10072-024-07500-0,

📚 Additional Documentation

Notes

(ERLIN2-notes.md)

ERLIN2 (SPFH2 / ER lipid raft-associated protein 2) review notes

UniProt: O94905 (ERLN2_HUMAN), 339 aa. Synonyms SPFH2, C8orf2. HGNC:1356.
Single-pass type II ER membrane protein with a lumenal SPFH/prohibitin (band 7) domain. Band 7/mec-2
family; associates with lipid-raft-like ER domains. Disease: hereditary spastic paraplegia SPG18A/SPG18B
and recessive intellectual disability/joint-contractures syndrome.

Core biology

  1. ERLIN1/ERLIN2 complex mediating ERAD of IP3 receptors. SPFH2 (ERLIN2) and SPFH1 (ERLIN1) form a
    ~2 MDa ring-shaped ER membrane complex that binds IP3R tetramers and mediates their ERAD with RNF170.
    PMID:19240031
    SPFH2 alone was shown to mediate ERAD of IP3 receptors and other substrates (PubMed:17502376, not cached).
    In complex with ERLIN1, interacts with RNF170. ComplexPortal CPX-7121.
  2. Sterol-accelerated ERAD of HMGCR (gp78/AMFR module). ERLIN2 promotes sterol-accelerated ERAD of
    HMG-CoA reductase via an AMFR/gp78-containing ubiquitin ligase complex; TMUB1 bridges ERLIN2 to gp78.
    PMID:21343306
    Interacts with AMFR, SYVN1, RNF139, TMUB1, HMGCR.
  3. Cholesterol binding / SREBP regulation. Like ERLIN1, ERLIN2 restricts SREBP activation and
    regulates cholesterol homeostasis; interacts with SCAP, INSIG1, SREBF1, SREBF2 under sterol sufficiency.
    PMID:24217618
  4. E3-ligase binding. ERLIN2 binds the ER ubiquitin ligases RNF170, AMFR/gp78, SYVN1, RNF139, and the
    RNF185/RNF5 module (PubMed:24019521) — informative ubiquitin protein ligase binding.
  5. Lipid-raft ER domains (PMID:16835267).

Annotation assessment summary

  • ER membrane (GO:0005789) / ER (GO:0005783): core compartment → ACCEPT.
  • ERLIN1/2 complex / ERAD of IP3R (GO:0036503 ERAD pathway IDA): core → ACCEPT.
  • cholesterol binding (GO:0015485 IBA): core MF → ACCEPT (note: only IBA here, no human IDA, but consistent
    with the erlin family cholesterol-binding evidence in PMID:24217618).
  • SREBP signaling / negative regulation cholesterol & fatty acid biosynthesis / regulation cholesterol
    biosynthesis: SREBP/sterol role → ACCEPT.
  • ubiquitin protein ligase binding (GO:0031625 IPI PMID:24019521; IEA InterPro): binds RNF185/RNF5 and other
    ER E3 ligases → ACCEPT (informative).
  • membrane raft (GO:0045121 IDA/NAS): lipid-raft ER domains → KEEP_AS_NON_CORE.
  • plasma membrane (GO:0005886) TAS Reactome (x13, FGFR1 signaling pathways): ERLIN2 is an ER membrane
    protein; plasma-membrane localization is an over-annotation from pathway bulk-membrane curation →
    MARK_AS_OVER_ANNOTATED.
  • protein-containing complex (GO:0032991): generic → KEEP_AS_NON_CORE.
  • protein binding (GO:0005515) IPI: uninformative → KEEP_AS_NON_CORE (TMEM41B interaction PMID:30352685 etc.).
  • Do NOT over-claim catalytic MF: ERLIN2 is a scaffold/lipid-binding SPFH protein.

Falcon deep-research findings (incorporated 2026-06)

All four cited papers below were PMID-verified via PubMed (DOI-to-PMID); none are in the
publications/ cache, so no verbatim supporting_text was added to the review — references
added with reference_review only, plus the Veronese ref id on the E3-ligase/TMUB1 core_function.

  • ERLIN1/2 scaffolds form "large ring-like cup-shaped structures on the ER membrane" that
    "bind cholesterol and E3 ubiquitin ligases, potentially defining functional nanodomains."
    PMID:38782601
  • New mechanistic link: ERLIN scaffolds bridge full-length TMUB1 and RNF170 through a conserved
    luminal N-terminal motif that binds the SPFH/prohibitin domain of two adjacent ERLIN subunits;
    HSP-linked variants map to these interfaces.
    PMID:38782601
  • New cell-biology role beyond classical ERAD: ERLINs limit cholesterol esterification, favouring
    ER-to-Golgi cholesterol transport and regulating Golgi morphology and the secretory pathway
    (HeLa double-KO phenotype).
    PMID:38782601
  • Falcon also notes SOAT1 inhibition (avasimibe) rescues lipid-droplet/Golgi phenotypes in
    ERLIN-deficient cells (from figures); treat as a translational/pharmacology lead, not a GO
    annotation. (Veronese 2024, PMID:38782601)
  • Proposed dominant disease mechanism: a heterozygous ERLIN2 p.Val71Ala recruits the E3 ligase
    RNF213 (NOT RNF170) to degrade IP3R1, lowering free Ca2+, triggering ER-stress apoptosis and
    suppressing MAPK/proliferation in patient-derived iPSC models.
    PMID:40225166
  • SPG18 inheritance is broader than classic recessive: monoallelic/autosomal-dominant ERLIN2
    variants (often pure, late-onset) occur, with HSP-to-ALS phenoconversion (2/5 cases) and a
    recurrent monoallelic c.502G>A hotspot for an ALS-like phenotype.
    PMID:38427163
  • An AD ERLIN2 p.V168M family showed variable expressivity (ALS phenoconversion, pure HSP, and a
    complicated form with psychomotor delay/epilepsy) but NORMAL erlin2 oligomerization, arguing
    against a dominant-negative oligomerization defect for this variant.
    PMID:38607533
  • Caveat: the Falcon report's "cryo-EM of the ERLIN complex" framing is not directly supported by
    a retrieved structural paper; Veronese 2024 uses 3D modelling, not cryo-EM. The existing
    suggested_question about a cryo-EM-resolved architecture remains a forward-looking question.

Pn Notes

(ERLIN2-pn-notes.md)

ERLIN2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O94905
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-11
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 29; KEEP_AS_NON_CORE: 10; MARK_AS_OVER_ANNOTATED: 12

PN Consistency Summary

  • Consistency: Strong. Deep research (Veronese 2024 scaffold/TMUB1-RNF170; Zhu 2023 iPSC Ca2+/IP3R1; Cioffi/Trinchillo 2024 SPG18) ↔ review YAML (ERAD of IP3R + HMGCR via gp78/AMFR, cholesterol binding, SREBP restriction, E3-ligase binding RNF170/AMFR/SYVN1/RNF139/RNF185-RNF5, membrane raft) ↔ PN annotation all agree. No contradictions.
  • PN story / NEW pressure: PN asserts ERAD + non-catalytic E3-complex membership — both already captured (GO:0036503 IDA PMID:19240031; GO:0031625 ubiquitin protein ligase binding has an experimental IPI PMID:24019521, stronger than ERLIN1). Sterol-accelerated HMGCR ERAD (PMID:21343306) and the 2024 scaffold/cholesterol-esterification role (PMID:38782601) extend beyond GOA but are cited. No NEW term forced; optional MF ADD GO:0160072 "ubiquitin ligase complex scaffold activity" (verified real). Verdict: already captured; scaffold-activity term optional.
  • Evidence alignment: PN cites opaque workbook IDs (1610068, 41481136 — not PMIDs). Review anchors to PMID:19240031, 24217618, 21343306, 24019521, 38782601, 40225166 + ComplexPortal CPX-7121. Note review flags RNF213 (Zhu/PMID:40225166) as a mutant-context ligase distinct from canonical RNF170 — correctly not conflated.
  • Verdict: Consistent and high-quality; PN story already captured. GO:0000151 projection mildly over-reaches (non-catalytic scaffold); prefer GO:0000835 / GO:0160072. PM over-annotation correctly handled.

Full Consistency Review

  • UniProt: O94905 (ERLN2_HUMAN, SPFH2; 3 isoforms) · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE (all actioned; 11 plasma-membrane Reactome annotations MARK_AS_OVER_ANNOTATED).
  • PN placement: ER proteostasis|Organelle-specific protein degradation|ER associated degradation|ER handling of ERAD substrates and Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|RNF170 / ERLIN complex|noncatalytic / BAND 7 ; PN-node mapping: [group ERAD] mapped/exact GO:0036503; [type ER-handling] mapped/ok_for_propagation GO:0036503; [group idiosyncratic RING complex] mapped/ok_for_propagation GO:0000151 ubiquitin ligase complex; subtype/type/branch no_mapping; UPS class context_only/too_broad GO:0061630. (Dossier identical to ERLIN1.)
  • Consistency: Strong. Deep research (Veronese 2024 scaffold/TMUB1-RNF170; Zhu 2023 iPSC Ca2+/IP3R1; Cioffi/Trinchillo 2024 SPG18) ↔ review YAML (ERAD of IP3R + HMGCR via gp78/AMFR, cholesterol binding, SREBP restriction, E3-ligase binding RNF170/AMFR/SYVN1/RNF139/RNF185-RNF5, membrane raft) ↔ PN annotation all agree. No contradictions.
  • PN story / NEW pressure: PN asserts ERAD + non-catalytic E3-complex membership — both already captured (GO:0036503 IDA PMID:19240031; GO:0031625 ubiquitin protein ligase binding has an experimental IPI PMID:24019521, stronger than ERLIN1). Sterol-accelerated HMGCR ERAD (PMID:21343306) and the 2024 scaffold/cholesterol-esterification role (PMID:38782601) extend beyond GOA but are cited. No NEW term forced; optional MF ADD GO:0160072 "ubiquitin ligase complex scaffold activity" (verified real). Verdict: already captured; scaffold-activity term optional.
  • Mapping strategy: Same as ERLIN1 — ERAD mapping correct; GO:0000151 over-reaches (catalytic-complex CC projected onto non-catalytic BAND 7 scaffold). Prefer GO:0000835 "ER ubiquitin ligase complex" (verified real). Distinct from ERLIN1: the plasma-membrane annotations are correctly MARK_AS_OVER_ANNOTATED (Reactome FGFR1 bulk-membrane curation), consistent with ER-membrane SPFH biology — handled well, no change needed.
  • Evidence alignment: PN cites opaque workbook IDs (1610068, 41481136 — not PMIDs). Review anchors to PMID:19240031, 24217618, 21343306, 24019521, 38782601, 40225166 + ComplexPortal CPX-7121. Note review flags RNF213 (Zhu/PMID:40225166) as a mutant-context ligase distinct from canonical RNF170 — correctly not conflated.
  • Verdict: Consistent and high-quality; PN story already captured. GO:0000151 projection mildly over-reaches (non-catalytic scaffold); prefer GO:0000835 / GO:0160072. PM over-annotation correctly handled.

Recommended edits: [MAP] Replace/qualify the GO:0000151 group projection with GO:0000835 "ER ubiquitin ligase complex" (CC), noting ERLINs are non-catalytic BAND 7 subunits. [YAML, optional] Consider adding MF GO:0160072 "ubiquitin ligase complex scaffold activity" to core_functions.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-11
  • review_yaml: genes/human/ERLIN2/ERLIN2-ai-review.yaml
  • PN workbook rows: 2

PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | ER handling of ERAD substrates

  • UniProt: O94905
  • In branches: ER, UPS
  • PN-node mapping records (path + ancestors):
    • [type] ER proteostasis|Organelle-specific protein degradation|ER associated degradation|ER handling of ERAD substrates
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0036503 ERAD pathway]
      rationale: This PN type captures ER-lumenal and membrane-local ERAD handling steps prior to retrotranslocation. These steps are mechanistic parts of the broader ERAD pathway, so propagation to ERAD pathway is appropriate.
    • [group] ER proteostasis|Organelle-specific protein degradation|ER associated degradation
      status=mapped scope=exact GO=[GO:0036503 ERAD pathway]
      rationale: The PN group "ER associated degradation" is a direct lexical and biological match to the GO ERAD pathway term. The additional branch and class context disambiguates the source string from any broader degradation language.
    • [class] ER proteostasis|Organelle-specific protein degradation
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [branch] ER proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | idiosyncratic RING complex | RNF170 / ERLIN complex | noncatalytic / BAND 7

  • UniProt: O94905
  • In branches: ER, UPS
  • Signature domains: (none)
  • Auxiliary domains: IPR001107
  • PN references (titles):
    • 1610068
    • 41481136
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|RNF170 / ERLIN complex|noncatalytic / BAND 7
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|RNF170 / ERLIN complex
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0000151 ubiquitin ligase complex]
      rationale: This PN group is an E3 ligase complex bucket. The safest shared GO target is ubiquitin ligase complex membership rather than assigning catalytic activity to every subunit.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (3)

  • GO:0036503 ERAD pathway | scope=exact | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation
  • GO:0036503 ERAD pathway | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation|ER handling of ERAD substrates
  • GO:0000151 ubiquitin ligase complex | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
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.