ERLIN1 (SPFH1, ER lipid raft-associated protein 1) is a single-pass type II endoplasmic reticulum (ER) membrane protein with a lumenal SPFH/prohibitin (band 7) domain, belonging to the band 7/mec-2 (stomatin-prohibitin-flotillin) family. It associates with lipid-raft-like domains of the ER membrane and functions as a scaffold rather than an enzyme. ERLIN1 forms a large ring-shaped heteromeric complex with its homolog ERLIN2 (SPFH2); the ERLIN1/ERLIN2 complex binds inositol 1,4,5-trisphosphate receptor (IP3R) tetramers and, together with the ER ubiquitin ligase RNF170, mediates the ER-associated degradation (ERAD) of activated IP3Rs, thereby controlling calcium signaling. The erlins are cholesterol-binding proteins that restrict SREBP activation: they associate with the SCAP-SREBP-Insig machinery to promote its ER retention and thus negatively regulate cholesterol and fatty acid biosynthesis, contributing to cellular cholesterol homeostasis. ERLIN1 also interacts with the ER ubiquitin ligases AMFR/gp78 and SYVN1/HRD1, linking it to sterol-accelerated ERAD. Loss-of-function variants in ERLIN1 cause autosomal recessive hereditary spastic paraplegia (SPG62).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that ERLIN1 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; ERLIN1 is an integral ER membrane protein. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0015485 cholesterol binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of cholesterol binding, consistent with direct experimental evidence that erlins bind cholesterol cooperatively. Reason: Core molecular function; redundant with the experimental IDA cholesterol-binding annotation. 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, consistent with experimental evidence; the more specific ER membrane term is preferred. Reason: Correct compartment; redundant with the ER membrane annotations. Supporting Evidence: file:human/ERLIN1/ERLIN1-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/ERLIN1/ERLIN1-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 experimental interactions of ERLIN1 with the ER ubiquitin ligases AMFR/gp78, SYVN1/HRD1 and (in complex with ERLIN2) RNF170. Reason: Informative molecular function; ERLIN1 recruits E3 ubiquitin ligases to the ERAD complex. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt Interacts with AMFR and SYVN1 |
| 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; ERLIN1 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. 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 (which activates fatty-acid biosynthetic genes). 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 ER ubiquitin ligases AMFR/gp78 and SYVN1 (and ERLIN2). Bare protein binding is uninformative; the E3-ligase binding is captured by the ubiquitin-protein-ligase-binding annotation. Reason: Real E3-ligase interactions but uninformative GO term. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt Interacts with AMFR and SYVN1 |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | Summary: ERAD-network interactome capture (including ERLIN2, SYVN1, AMFR). Bare protein binding is uninformative. Reason: Real ERAD-network interactions but uninformative GO term. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt O75477; O94905: ERLIN2 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Proteome-scale interactome capture. Bare protein binding is uninformative. Reason: Real interactions from a large-scale interactome but uninformative GO term. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt O75477; Q96IW7: SEC22A |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: High-throughput interactome capture (C6orf120). Bare protein binding is uninformative. Reason: Real interaction but uninformative GO term. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt O75477; Q7Z4R8: C6orf120 |
| 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 ERLIN1-ERLIN2 interaction. Bare protein binding is uninformative; the ERLIN1/ERLIN2 complex is captured by complex annotations. Reason: Real ERLIN2 interaction but uninformative GO term. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt O75477; O94905: ERLIN2 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary-interactome (HuRI) captures of ERLIN1 interactions. Bare protein binding is uninformative. Reason: Real binary interactions but uninformative GO term. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt O75477; Q15436: SEC23A |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Dual proteome-scale network capture (ERLIN2, C6orf120). Bare protein binding is uninformative. Reason: Real interactions but uninformative GO term. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt O75477; O94905: ERLIN2 |
| 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/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866542 | ACCEPT | Summary: Reactome curation placing ERLIN1 at the ER membrane within the CFTR ERAD machinery pathway. Reason: Correct compartment; redundant with experimental ER membrane annotations. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866546 | ACCEPT | Summary: Reactome curation of ERLIN1 ER membrane localization (CFTR ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866551 | ACCEPT | Summary: Reactome curation of ERLIN1 ER membrane localization (CFTR ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866854 | ACCEPT | Summary: Reactome curation of ERLIN1 ER membrane localization (CFTR F508del ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866856 | ACCEPT | Summary: Reactome curation of ERLIN1 ER membrane localization (CFTR F508del ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866857 | ACCEPT | Summary: Reactome curation of ERLIN1 ER membrane localization (CFTR F508del ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931264 | ACCEPT | Summary: Reactome curation of ERLIN1 ER membrane localization (CD274/PD-L1 ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931298 | ACCEPT | Summary: Reactome curation of ERLIN1 ER membrane localization (CD274/PD-L1 ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN1/ERLIN1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931313 | ACCEPT | Summary: Reactome curation of ERLIN1 ER membrane localization (CD274/PD-L1 ERAD pathway). Reason: Correct compartment; redundant with experimental evidence. Supporting Evidence: file:human/ERLIN1/ERLIN1-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 ERLIN1/SPFH1 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; depletion of ERLIN1/ERLIN2 blocks IP3R 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: ERLIN1 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:0032991 protein-containing complex | IDA PMID:18468998 Blood pressure is regulated by an alpha1D-adrenergic recepto... | KEEP AS NON CORE | Summary: IDA placing ERLIN1 in a protein-containing complex (alpha1D-adrenergic receptor/dystrophin signalosome study). The generic complex term is uninformative; ERLIN1's defining complex is the ERLIN1/ERLIN2 complex. 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:0015485 cholesterol binding | IDA PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | ACCEPT | Summary: Erlins bind cholesterol with specificity and strong cooperativity, a core molecular function underlying their sterol-sensing regulation of SREBP. Reason: Core molecular function with direct (IDA) support. Supporting Evidence: PMID:24217618 Erlins bound cholesterol with specificity and strong cooperativity |
| 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 ERLIN1 restricts SREBP signaling. Reason: Core biological process with direct mutant/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, ERLIN1 negatively regulates cholesterol biosynthesis; erlin depletion derepresses SREBP target genes. 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: ERLIN1 negatively regulates fatty acid biosynthesis through restriction of SREBP, which activates both cholesterol and 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:0005515 protein binding | IPI PMID:19240031 An endoplasmic reticulum (ER) membrane complex composed of S... | KEEP AS NON CORE | Summary: IPI capture of the ERLIN1-ERLIN2 (SPFH1-SPFH2) interaction. Bare protein binding is uninformative; the ERLIN1/ERLIN2 complex is captured by the ERAD/complex annotations. Reason: Real ERLIN2 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-1 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 |
Loading supporting content…
Download this section (compressed HTML)Q: What is the stoichiometry and architecture of the ERLIN1/ERLIN2 ring complex (recently resolved by cryo-EM), and how does it select activated/ubiquitinated IP3R tetramers as substrates?
Q: How does cholesterol binding to the erlin SPFH domain mechanistically couple ER sterol levels to retention of the SCAP-SREBP-Insig complex?
Q: How do ERLIN1 SPG62 disease variants (e.g. G50V) impair complex assembly or substrate handling to cause corticospinal motor neuron degeneration?
Experiment: Reconstitute the ERLIN1/ERLIN2 complex with RNF170 and a model IP3R substrate to test whether ERLIN1 is required for substrate binding versus ligase recruitment in IP3R ERAD.
Experiment: Use cholesterol photoaffinity probes and SPFH-domain point mutants of ERLIN1 to map the cholesterol-binding site and test whether abolishing cholesterol binding derepresses SREBP target genes.
Experiment: Introduce the SPG62 G50V variant into neurons and assay ERLIN1/ERLIN2 complex assembly, IP3R degradation, and ER cholesterol/SREBP signaling to link the molecular defect to disease.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)