{"gene":"ERLIN1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2006,"finding":"ERLIN1 (KE04p) localizes to the endoplasmic reticulum and is highly enriched in detergent-insoluble, buoyant (lipid raft-like) fractions in a cholesterol-dependent manner. The extreme N-terminus of ERLIN1 is sufficient to target heterologous GFP to the ER in the absence of classical ER retrieval motifs, identifying the N-terminus as the ER-targeting domain.","method":"Sucrose gradient fractionation, cholesterol depletion, GFP-fusion targeting experiments, confocal microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, cholesterol dependence, GFP targeting), replicated across constructs in a single focused study","pmids":["16835267"],"is_preprint":false},{"year":2009,"finding":"ERLIN1 (SPFH1) and ERLIN2 (SPFH2) form a heteromeric ~2 MDa ring-shaped complex (~250 Å diameter) on the ER membrane that binds to activated IP3R tetramers and is required for their polyubiquitination and proteasomal degradation (ERAD). RNAi-mediated depletion of SPFH1/2 blocks IP3R polyubiquitination and degradation.","method":"Co-immunoprecipitation, sucrose gradient sedimentation, electron microscopy, RNA interference knockdown with IP3R ubiquitination and degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, EM structure of complex, functional RNAi rescue, replicated in independent study (PMID:19751772)","pmids":["19240031","19751772"],"is_preprint":false},{"year":2009,"finding":"In muscarinic receptor-expressing HeLa cells, the ERLIN1/ERLIN2 (SPFH1/2) hetero-oligomeric complex rapidly associates with activated IP3Rs prior to their polyubiquitination and prior to p97 recruitment, acting as a selective recognition factor for activated IP3Rs in ERAD. Suppression of SPFH1/2 did not affect carbachol-induced calcium mobilization or IκBα processing, nor did it affect ERAD of HMG-CoA reductase, indicating substrate specificity.","method":"Stable transfection, RNA interference, co-immunoprecipitation, ubiquitination and degradation assays, calcium mobilization assays","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal assays (Co-IP, RNAi, functional calcium assay, specificity controls), consistent with PMID:19240031","pmids":["19751772"],"is_preprint":false},{"year":2018,"finding":"The erlin1/2 complex selectively binds phosphatidylinositol 3-phosphate (PI(3)P), with erlin2 binding more strongly than erlin1. The disease-linked erlin2 T65I mutation inhibits both PI(3)P binding and the erlin1/2 complex interaction with IP3Rs, blocking IP3R ubiquitination and degradation. Gene editing showed erlin2 is the dominant mediator of IP3R interaction within the complex.","method":"CRISPR/gene editing to ablate erlin1 or erlin2, lipid-binding assays, co-immunoprecipitation, ubiquitination/degradation assays with T65I mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (gene editing, lipid binding, mutagenesis, Co-IP, functional assays) in a single rigorous study","pmids":["30135210"],"is_preprint":false},{"year":2020,"finding":"ERLIN1 localizes to mitochondria-associated membranes (MAMs) within raft-like microdomains and interacts with AMBRA1 at this location. This ERLIN1-AMBRA1 interaction is required for autophagosome formation upon nutrient starvation. The interaction depends on ganglioside GD3 and MFN2 integrity; knockdown of ST8SIA1 (GD3-synthase) or MFN2 impairs AMBRA1-ERLIN1 interaction at MAMs and inhibits autophagy.","method":"Co-immunoprecipitation, FRET, siRNA knockdown, autophagy flux assays, subcellular fractionation to isolate MAMs","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET and Co-IP plus functional knockdown with autophagy readout, single lab, multiple orthogonal methods","pmids":["33034545"],"is_preprint":false},{"year":2022,"finding":"The erlin1/2 complex binds to IP3R1 via the third intralumenal loop (IL3), specifically the region close to transmembrane helix 5 (TM5), with amino acids D2471 and R2472 being critical for erlin1/2 complex association. Additional mutations in IL3 adjacent to TM5 (e.g., D2465N) abolish IP3R1 Ca2+ channel activity. Inhibition of UBE1 (ubiquitin-activating enzyme) blocked IP3R1 ubiquitination and degradation without altering erlin1/2 complex association, confirming erlin1/2 binding is the primary and upstream event.","method":"IP3R1 site-directed mutagenesis, co-immunoprecipitation, UBE1 inhibitor (TAK-243), IP3R1 ubiquitination and degradation assays, calcium channel activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of binding site with orthogonal pharmacological inhibition and functional assays, rigorous epistasis established, single lab","pmids":["35568199"],"is_preprint":false},{"year":2022,"finding":"A splicing site mutation in ERLIN1 (c.504+1G>A) causes erroneous deletion of Exon 7, which alters the conserved prohibitin (PHB) domain of erlin-1, disrupting erlin1/2 complex function in hereditary spastic paraplegia (SPG62).","method":"Whole-exome sequencing, minigene splicing assay, bioinformatic analysis","journal":"European journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — minigene experiment validates splicing defect, but downstream functional consequence on complex inferred rather than directly measured","pmids":["36100157"],"is_preprint":false},{"year":2024,"finding":"ERLIN1/2 scaffolds bridge TMUB1 and RNF170 via a luminal N-terminal conserved region in TMUB1 and RNF170 that binds the SPFH domain of adjacent ERLIN subunits. Loss of both ERLINs limits cholesterol esterification, thereby promoting cholesterol transport from the ER to the Golgi and regulating Golgi morphology and the secretory pathway.","method":"Proteomics/omics approaches, 3D structural modelling, co-immunoprecipitation, phenotypic characterization of ERLIN1/2 double-knockout HeLa cells, cholesterol esterification assays","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell phenotype with multiple omics readouts and structural modeling, single lab","pmids":["38782601"],"is_preprint":false},{"year":2024,"finding":"The erlin1/2 complex directly and selectively binds PI(3)P; disruption or deletion of the complex reduces HeLa cell PI(3)P levels by ~50%, which correlates with decreased autophagic flux without affecting the endocytic pathway or VPS34 kinase activity. This establishes a role for erlin1/2 in maintaining steady-state PI(3)P levels to sustain autophagy.","method":"Recombinant protein lipid-binding assay, PI(3)P quantification in KO/knockdown cells, autophagic flux assays, VPS34 kinase activity assay, pharmacological VPS34 inhibition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding of recombinant protein plus cellular PI(3)P quantification and autophagic flux, single lab, multiple orthogonal methods","pmids":["39018973"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structure of the human erlin1/2 complex reveals it forms a 26-mer cage assembly of alternating erlin1 and erlin2 subunits, defining a nanometer-sized microdomain on the luminal leaflet of the ER. Each subunit contains a phosphatidylinositol-binding pocket in the intramembrane region. The cage can recruit ER proteins to both interior and exterior surfaces, physically secluding cargoes from binding partners to regulate their function. Individual cages can cluster to organize functional membrane microdomains of different sizes.","method":"Single-particle cryo-electron microscopy (cryo-EM), structural analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution cryo-EM structure with identification of PI-binding pockets and cage assembly mechanism, peer-reviewed publication","pmids":["41887216"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of the ER-resident erlin1/2 complex reveals an assembly of 13 heterodimers (26-mer) with defined key interactions underlying the architecture. Key interactions between erlin1 and erlin2 subunits determine the complex's stoichiometry distinct from the mitochondrial PHB1/2 complex (22-mer).","method":"Single-particle cryo-EM structure determination","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-quality structural method (cryo-EM) but preprint, not yet peer-reviewed; corroborated by PMID:41887216","pmids":[],"is_preprint":true},{"year":2019,"finding":"Erlin-1 is required for efficient hepatitis C virus (HCV) infection. siRNA-mediated silencing of erlin-1 reduced intracellular HCV RNA accumulation, protein expression, and virus production. Mechanistic studies showed erlin-1 is required early in infection to initiate RNA replication (downstream of cell entry and primary translation) and later to support infectious virus production.","method":"siRNA knockdown, HCV infection assays, intracellular RNA quantification, viral protein expression, virus production assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional RNAi knockdown with multiple stage-specific readouts, single lab","pmids":["31810281"],"is_preprint":false},{"year":2025,"finding":"Erlin-1 interacts with CYP1A2 in detergent-resistant ER microdomains (DRMs/MAMs) via their N-terminal signal-anchor domains, as demonstrated by a split fluorogenic bifunctional complementation assay (SURF). siRNA knockdown of erlin-1 in HepG2 cells relocates CYP1A2 from DRMs to non-DRMs, impairs CYP1A2 ERLAD (ER-to-lysosomal-associated degradation), and causes insoluble CYP1A2 aggregates. ERLAD of CYP1A2 can be rescued by co-expression of siRNA-resistant erlin-1 or its N-terminal 1-30 residue signal-anchor domain alone.","method":"SURF split-fluorescence assay, siRNA knockdown, sucrose gradient DRM fractionation, ERLAD/ERAD assays, rescue with truncated erlin-1 constructs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including protein-protein interaction assay and functional rescue, preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"ERLIN1 is an ER-resident SPFH/prohibitin-family protein that, together with ERLIN2, assembles into a large (~2 MDa, 26-mer) ring/cage complex on the ER membrane within lipid raft-like microdomains; this complex acts as a recognition scaffold that binds activated IP3Rs at their third intralumenal loop (near TM5), recruits the E3 ubiquitin ligase RNF170 (via TMUB1), and drives IP3R polyubiquitination and proteasomal degradation (ERAD), while also binding PI(3)P to maintain cellular PI(3)P levels and sustain autophagic flux, interacting with AMBRA1 at mitochondria-associated membranes to promote autophagosome formation, regulating cholesterol esterification and Golgi secretory pathway, and supporting HCV RNA replication."},"narrative":{"mechanistic_narrative":"ERLIN1 is an ER-resident SPFH/prohibitin-family protein that, together with ERLIN2, assembles into a large ~2 MDa ring/cage complex within cholesterol-dependent, detergent-insoluble (lipid raft-like) ER microdomains [PMID:16835267, PMID:19240031, PMID:19751772, PMID:41887216]. Cryo-EM defines this complex as a 26-mer cage of alternating ERLIN1 and ERLIN2 subunits that forms a discrete luminal-leaflet microdomain and can recruit ER proteins to both its interior and exterior surfaces, secluding cargoes from their partners; each subunit carries an intramembrane phosphatidylinositol-binding pocket [PMID:41887216]. Functionally, the ERLIN1/2 complex acts as a selective recognition scaffold in ER-associated degradation (ERAD): it binds activated IP3R tetramers — via the third intralumenal loop near transmembrane helix 5, with residues D2471/R2472 critical for association — as the primary upstream event that precedes polyubiquitination and proteasomal degradation [PMID:19240031, PMID:19751772, PMID:35568199]. The complex bridges the E3 ubiquitin ligase RNF170 and TMUB1 through their luminal N-terminal regions binding the SPFH domain of adjacent ERLIN subunits, completing the degradation machinery [PMID:38782601]. Beyond ERAD, the complex selectively binds PI(3)P and is required to maintain steady-state cellular PI(3)P levels and sustain autophagic flux, independent of VPS34 kinase activity [PMID:30135210, PMID:39018973]; ERLIN1 also localizes to mitochondria-associated membranes where it interacts with AMBRA1 in a GD3- and MFN2-dependent manner to promote starvation-induced autophagosome formation [PMID:33034545]. Loss of both ERLINs limits cholesterol esterification, thereby influencing ER-to-Golgi cholesterol transport, Golgi morphology and the secretory pathway [PMID:38782601]. A splicing mutation in ERLIN1 (c.504+1G>A) that deletes exon 7 and disrupts the prohibitin domain causes hereditary spastic paraplegia (SPG62) [PMID:36100157].","teleology":[{"year":2006,"claim":"Established where ERLIN1 resides and how it is targeted, defining it as an ER protein that partitions into cholesterol-dependent raft-like microdomains.","evidence":"Sucrose gradient fractionation, cholesterol depletion, and GFP-fusion targeting in cells","pmids":["16835267"],"confidence":"High","gaps":["No binding partners or molecular function identified","Functional role of raft partitioning not yet defined"]},{"year":2009,"claim":"Showed ERLIN1 functions as a heteromeric ~2 MDa ring complex with ERLIN2 that recognizes activated IP3Rs and is required for their ERAD, defining the complex's core substrate-recognition role.","evidence":"Reciprocal Co-IP, sucrose sedimentation, EM of the complex, and RNAi with IP3R ubiquitination/degradation assays in HeLa cells","pmids":["19240031","19751772"],"confidence":"High","gaps":["E3 ligase and ubiquitination machinery not yet identified","IP3R binding site on the receptor not mapped","Substrate selectivity mechanism unknown"]},{"year":2009,"claim":"Defined the temporal logic of ERAD, placing ERLIN1/2 binding as an early, substrate-selective recognition event upstream of ubiquitination and p97 recruitment.","evidence":"Stable transfection, RNAi, Co-IP, and specificity controls (calcium mobilization, IkBa, HMG-CoA reductase ERAD) in muscarinic-receptor HeLa cells","pmids":["19751772"],"confidence":"High","gaps":["The ligase linking recognition to ubiquitination still unidentified","Structural basis of complex–IP3R contact unknown"]},{"year":2018,"claim":"Identified PI(3)P as a ligand of the complex and showed a disease mutation couples lipid binding to substrate engagement, linking lipid recognition to ERAD function.","evidence":"CRISPR ablation of erlin1 or erlin2, lipid-binding assays, Co-IP, and degradation assays with the erlin2 T65I mutant","pmids":["30135210"],"confidence":"High","gaps":["Physiological consequence of PI(3)P binding not established here","Why erlin2 dominates IP3R binding structurally unclear"]},{"year":2022,"claim":"Mapped the IP3R binding determinant to intralumenal loop 3 near TM5 and used epistasis to confirm ERLIN1/2 binding is the primary event upstream of ubiquitination.","evidence":"IP3R1 site-directed mutagenesis, Co-IP, UBE1 inhibition (TAK-243), and channel activity/degradation assays","pmids":["35568199"],"confidence":"High","gaps":["Structure of the complex–IP3R interface not resolved","How binding signals ligase recruitment unknown"]},{"year":2022,"claim":"Tied an ERLIN1 splicing mutation disrupting the prohibitin domain to hereditary spastic paraplegia (SPG62), connecting complex integrity to human disease.","evidence":"Whole-exome sequencing, minigene splicing assay, and bioinformatic analysis","pmids":["36100157"],"confidence":"Medium","gaps":["Downstream functional consequence on the complex inferred, not directly measured","Mechanism linking ERAD defect to motor neuron degeneration unestablished"]},{"year":2020,"claim":"Extended ERLIN1's role to autophagy by showing it acts at MAMs with AMBRA1 to drive starvation-induced autophagosome formation.","evidence":"Co-IP, FRET, siRNA of ST8SIA1/MFN2, MAM fractionation, and autophagy flux assays","pmids":["33034545"],"confidence":"Medium","gaps":["Single lab","Molecular mechanism by which the interaction nucleates autophagosomes unclear","Relationship to the ERLIN1/2 ERAD complex not addressed"]},{"year":2024,"claim":"Defined how the complex incorporates the ubiquitin ligase machinery and uncovered a role in cholesterol esterification and secretory pathway regulation.","evidence":"Proteomics, 3D structural modeling, Co-IP, and ERLIN1/2 double-KO HeLa phenotyping with cholesterol esterification assays","pmids":["38782601"],"confidence":"Medium","gaps":["Single lab","Direct enzymatic mechanism of cholesterol esterification regulation not established"]},{"year":2024,"claim":"Established a direct mechanistic basis for the autophagy role by showing the complex maintains steady-state PI(3)P levels independent of VPS34.","evidence":"Recombinant protein lipid binding, PI(3)P quantification in KO/knockdown cells, autophagic flux, and VPS34 activity assays","pmids":["39018973"],"confidence":"Medium","gaps":["Single lab","Mechanism by which the complex maintains PI(3)P pools unresolved"]},{"year":2026,"claim":"Resolved the complex architecture by cryo-EM as a 26-mer cage with intramembrane PI-binding pockets, providing a structural model for how it organizes microdomains and seclude cargoes.","evidence":"Single-particle cryo-EM and structural analysis of the human erlin1/2 complex","pmids":["41887216"],"confidence":"High","gaps":["Structures of substrate- or partner-bound states not determined","How cage clustering is regulated unknown"]},{"year":2019,"claim":"Implicated ERLIN1 in pathogen biology, showing it is required at distinct stages of HCV infection including initiation of RNA replication.","evidence":"siRNA knockdown with stage-specific HCV RNA, protein, and virus production readouts","pmids":["31810281"],"confidence":"Medium","gaps":["Single lab","Direct molecular interaction with HCV components not shown","Whether the ERAD/microdomain function underlies this role unknown"]},{"year":null,"claim":"How the ERLIN1/2 cage's distinct functions — IP3R ERAD, PI(3)P maintenance, cholesterol handling, MAM autophagy, and substrate sequestration — are coordinated and selectively triggered remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking microdomain organization to substrate choice","Structural basis of partner/cargo selection not determined","In vivo physiological consequences of each function not separately tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,8,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,5,7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,5,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7]}],"complexes":["ERLIN1/ERLIN2 complex"],"partners":["ERLIN2","ITPR1","RNF170","TMUB1","AMBRA1","CYP1A2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75477","full_name":"Erlin-1","aliases":["Endoplasmic reticulum lipid raft-associated protein 1","Protein KE04","Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 1","SPFH domain-containing protein 1"],"length_aa":348,"mass_kda":39.2,"function":"Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway (PubMed:37683630). Binds cholesterol and may promote ER retention of the SCAP-SREBF complex (PubMed:24217618) (Microbial infection) Required early in hepatitis C virus (HCV) infection to initiate RNA replication, and later in the infection to support infectious virus production","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O75477/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERLIN1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BAG6","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"OSBPL8","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2},{"gene":"VCP","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ERLIN1","total_profiled":1310},"omim":[{"mim_id":"615681","title":"SPASTIC PARAPLEGIA 62, AUTOSOMAL RECESSIVE; SPG62","url":"https://www.omim.org/entry/615681"},{"mim_id":"614649","title":"RING FINGER PROTEIN 170; RNF170","url":"https://www.omim.org/entry/614649"},{"mim_id":"612363","title":"ALANINE AMINOTRANSFERASE, PLASMA LEVEL OF, QUANTITATIVE TRAIT LOCUS 1","url":"https://www.omim.org/entry/612363"},{"mim_id":"611605","title":"ENDOPLASMIC RETICULUM LIPID RAFT-ASSOCIATED PROTEIN 2; ERLIN2","url":"https://www.omim.org/entry/611605"},{"mim_id":"611604","title":"ENDOPLASMIC RETICULUM LIPID RAFT-ASSOCIATED PROTEIN 1; ERLIN1","url":"https://www.omim.org/entry/611604"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":106.7}],"url":"https://www.proteinatlas.org/search/ERLIN1"},"hgnc":{"alias_symbol":["KE04","Erlin-1","SPG62"],"prev_symbol":["C10orf69","SPFH1"]},"alphafold":{"accession":"O75477","domains":[{"cath_id":"-","chopping":"1-65","consensus_level":"medium","plddt":90.6669,"start":1,"end":65},{"cath_id":"3.30.479.30","chopping":"66-177","consensus_level":"medium","plddt":93.7297,"start":66,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75477","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75477-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75477-F1-predicted_aligned_error_v6.png","plddt_mean":85.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERLIN1","jax_strain_url":"https://www.jax.org/strain/search?query=ERLIN1"},"sequence":{"accession":"O75477","fasta_url":"https://rest.uniprot.org/uniprotkb/O75477.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75477/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75477"}},"corpus_meta":[{"pmid":"16835267","id":"PMC_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.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16835267","citation_count":198,"is_preprint":false},{"pmid":"19240031","id":"PMC_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.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19240031","citation_count":95,"is_preprint":false},{"pmid":"33034545","id":"PMC_33034545","title":"Raft-like lipid microdomains drive autophagy initiation via AMBRA1-ERLIN1 molecular association within MAMs.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33034545","citation_count":69,"is_preprint":false},{"pmid":"23477746","id":"PMC_23477746","title":"The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study.","date":"2013","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/23477746","citation_count":43,"is_preprint":false},{"pmid":"29453415","id":"PMC_29453415","title":"ERLIN1 mutations cause teenage-onset slowly progressive ALS in a large Turkish pedigree.","date":"2018","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/29453415","citation_count":30,"is_preprint":false},{"pmid":"30135210","id":"PMC_30135210","title":"The erlin2 T65I mutation inhibits erlin1/2 complex-mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30135210","citation_count":27,"is_preprint":false},{"pmid":"19751772","id":"PMC_19751772","title":"SPFH1 and SPFH2 mediate the ubiquitination and degradation of inositol 1,4,5-trisphosphate receptors in muscarinic receptor-expressing HeLa cells.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19751772","citation_count":24,"is_preprint":false},{"pmid":"36100157","id":"PMC_36100157","title":"A novel homozygous mutation in ERLIN1 gene causing spastic paraplegia 62 and literature review.","date":"2022","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36100157","citation_count":10,"is_preprint":false},{"pmid":"35568199","id":"PMC_35568199","title":"Binding of the erlin1/2 complex to the third intralumenal loop of IP3R1 triggers its ubiquitin-proteasomal degradation.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35568199","citation_count":9,"is_preprint":false},{"pmid":"31810281","id":"PMC_31810281","title":"The Host Factor Erlin-1 is Required for Efficient Hepatitis C Virus Infection.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31810281","citation_count":8,"is_preprint":false},{"pmid":"38776916","id":"PMC_38776916","title":"The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD.","date":"2024","source":"Med (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/38776916","citation_count":7,"is_preprint":false},{"pmid":"38782601","id":"PMC_38782601","title":"ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/38782601","citation_count":6,"is_preprint":false},{"pmid":"11118313","id":"PMC_11118313","title":"Identification and characterization of a novel gene KE04 differentially expressed by activated human dendritic cells.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11118313","citation_count":6,"is_preprint":false},{"pmid":"34439987","id":"PMC_34439987","title":"Transcriptome and Literature Mining Highlight the Differential Expression of ERLIN1 in Immune Cells during Sepsis.","date":"2021","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34439987","citation_count":6,"is_preprint":false},{"pmid":"39367212","id":"PMC_39367212","title":"Biallelic variants in ERLIN1: a series of 13 individuals with spastic paraparesis.","date":"2024","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39367212","citation_count":3,"is_preprint":false},{"pmid":"39018973","id":"PMC_39018973","title":"The erlin1/erlin2 complex binds to and stabilizes phosphatidylinositol 3-phosphate and regulates autophagy.","date":"2024","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/39018973","citation_count":2,"is_preprint":false},{"pmid":"41887216","id":"PMC_41887216","title":"The Erlin1/2 complex is a dynamic scaffold for membrane microdomain assembly on the endoplasmic reticulum.","date":"2026","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/41887216","citation_count":1,"is_preprint":false},{"pmid":"41205880","id":"PMC_41205880","title":"ERLIN1: A central regulator of protein quality control, lipid homeostasis, and cellular signaling at the endoplasmic reticulum.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41205880","citation_count":0,"is_preprint":false},{"pmid":"42219074","id":"PMC_42219074","title":"circCrebrf modulates the miR-3562/ERLIN1 axis to suppress neuronal oxidative stress and apoptosis following traumatic brain injury.","date":"2026","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/42219074","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.25.678692","title":"Hepatic cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): Topological determinants and cellular partnerships that dictate the preferential P450 proteolytic sorting into macroautophagy rather than UPS","date":"2025-09-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.25.678692","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.14.659634","title":"Erlin1/2 Complex is a Dynamic Scaffold for Membrane Protein Sequestration and Microdomain Assembly on the Endoplasmic Reticulum","date":"2025-06-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.14.659634","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.21.649849","title":"Structures of human organellar SPFH protein complexes","date":"2025-04-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.21.649849","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14004,"output_tokens":3725,"usd":0.048944,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11333,"output_tokens":3763,"usd":0.07537,"stage2_stop_reason":"end_turn"},"total_usd":0.124314,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"ERLIN1 (KE04p) localizes to the endoplasmic reticulum and is highly enriched in detergent-insoluble, buoyant (lipid raft-like) fractions in a cholesterol-dependent manner. The extreme N-terminus of ERLIN1 is sufficient to target heterologous GFP to the ER in the absence of classical ER retrieval motifs, identifying the N-terminus as the ER-targeting domain.\",\n      \"method\": \"Sucrose gradient fractionation, cholesterol depletion, GFP-fusion targeting experiments, confocal microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, cholesterol dependence, GFP targeting), replicated across constructs in a single focused study\",\n      \"pmids\": [\"16835267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ERLIN1 (SPFH1) and ERLIN2 (SPFH2) form a heteromeric ~2 MDa ring-shaped complex (~250 Å diameter) on the ER membrane that binds to activated IP3R tetramers and is required for their polyubiquitination and proteasomal degradation (ERAD). RNAi-mediated depletion of SPFH1/2 blocks IP3R polyubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, sucrose gradient sedimentation, electron microscopy, RNA interference knockdown with IP3R ubiquitination and degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, EM structure of complex, functional RNAi rescue, replicated in independent study (PMID:19751772)\",\n      \"pmids\": [\"19240031\", \"19751772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In muscarinic receptor-expressing HeLa cells, the ERLIN1/ERLIN2 (SPFH1/2) hetero-oligomeric complex rapidly associates with activated IP3Rs prior to their polyubiquitination and prior to p97 recruitment, acting as a selective recognition factor for activated IP3Rs in ERAD. Suppression of SPFH1/2 did not affect carbachol-induced calcium mobilization or IκBα processing, nor did it affect ERAD of HMG-CoA reductase, indicating substrate specificity.\",\n      \"method\": \"Stable transfection, RNA interference, co-immunoprecipitation, ubiquitination and degradation assays, calcium mobilization assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal assays (Co-IP, RNAi, functional calcium assay, specificity controls), consistent with PMID:19240031\",\n      \"pmids\": [\"19751772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The erlin1/2 complex selectively binds phosphatidylinositol 3-phosphate (PI(3)P), with erlin2 binding more strongly than erlin1. The disease-linked erlin2 T65I mutation inhibits both PI(3)P binding and the erlin1/2 complex interaction with IP3Rs, blocking IP3R ubiquitination and degradation. Gene editing showed erlin2 is the dominant mediator of IP3R interaction within the complex.\",\n      \"method\": \"CRISPR/gene editing to ablate erlin1 or erlin2, lipid-binding assays, co-immunoprecipitation, ubiquitination/degradation assays with T65I mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (gene editing, lipid binding, mutagenesis, Co-IP, functional assays) in a single rigorous study\",\n      \"pmids\": [\"30135210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ERLIN1 localizes to mitochondria-associated membranes (MAMs) within raft-like microdomains and interacts with AMBRA1 at this location. This ERLIN1-AMBRA1 interaction is required for autophagosome formation upon nutrient starvation. The interaction depends on ganglioside GD3 and MFN2 integrity; knockdown of ST8SIA1 (GD3-synthase) or MFN2 impairs AMBRA1-ERLIN1 interaction at MAMs and inhibits autophagy.\",\n      \"method\": \"Co-immunoprecipitation, FRET, siRNA knockdown, autophagy flux assays, subcellular fractionation to isolate MAMs\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET and Co-IP plus functional knockdown with autophagy readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33034545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The erlin1/2 complex binds to IP3R1 via the third intralumenal loop (IL3), specifically the region close to transmembrane helix 5 (TM5), with amino acids D2471 and R2472 being critical for erlin1/2 complex association. Additional mutations in IL3 adjacent to TM5 (e.g., D2465N) abolish IP3R1 Ca2+ channel activity. Inhibition of UBE1 (ubiquitin-activating enzyme) blocked IP3R1 ubiquitination and degradation without altering erlin1/2 complex association, confirming erlin1/2 binding is the primary and upstream event.\",\n      \"method\": \"IP3R1 site-directed mutagenesis, co-immunoprecipitation, UBE1 inhibitor (TAK-243), IP3R1 ubiquitination and degradation assays, calcium channel activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of binding site with orthogonal pharmacological inhibition and functional assays, rigorous epistasis established, single lab\",\n      \"pmids\": [\"35568199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A splicing site mutation in ERLIN1 (c.504+1G>A) causes erroneous deletion of Exon 7, which alters the conserved prohibitin (PHB) domain of erlin-1, disrupting erlin1/2 complex function in hereditary spastic paraplegia (SPG62).\",\n      \"method\": \"Whole-exome sequencing, minigene splicing assay, bioinformatic analysis\",\n      \"journal\": \"European journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — minigene experiment validates splicing defect, but downstream functional consequence on complex inferred rather than directly measured\",\n      \"pmids\": [\"36100157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ERLIN1/2 scaffolds bridge TMUB1 and RNF170 via a luminal N-terminal conserved region in TMUB1 and RNF170 that binds the SPFH domain of adjacent ERLIN subunits. Loss of both ERLINs limits cholesterol esterification, thereby promoting cholesterol transport from the ER to the Golgi and regulating Golgi morphology and the secretory pathway.\",\n      \"method\": \"Proteomics/omics approaches, 3D structural modelling, co-immunoprecipitation, phenotypic characterization of ERLIN1/2 double-knockout HeLa cells, cholesterol esterification assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell phenotype with multiple omics readouts and structural modeling, single lab\",\n      \"pmids\": [\"38782601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The erlin1/2 complex directly and selectively binds PI(3)P; disruption or deletion of the complex reduces HeLa cell PI(3)P levels by ~50%, which correlates with decreased autophagic flux without affecting the endocytic pathway or VPS34 kinase activity. This establishes a role for erlin1/2 in maintaining steady-state PI(3)P levels to sustain autophagy.\",\n      \"method\": \"Recombinant protein lipid-binding assay, PI(3)P quantification in KO/knockdown cells, autophagic flux assays, VPS34 kinase activity assay, pharmacological VPS34 inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding of recombinant protein plus cellular PI(3)P quantification and autophagic flux, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39018973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structure of the human erlin1/2 complex reveals it forms a 26-mer cage assembly of alternating erlin1 and erlin2 subunits, defining a nanometer-sized microdomain on the luminal leaflet of the ER. Each subunit contains a phosphatidylinositol-binding pocket in the intramembrane region. The cage can recruit ER proteins to both interior and exterior surfaces, physically secluding cargoes from binding partners to regulate their function. Individual cages can cluster to organize functional membrane microdomains of different sizes.\",\n      \"method\": \"Single-particle cryo-electron microscopy (cryo-EM), structural analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution cryo-EM structure with identification of PI-binding pockets and cage assembly mechanism, peer-reviewed publication\",\n      \"pmids\": [\"41887216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of the ER-resident erlin1/2 complex reveals an assembly of 13 heterodimers (26-mer) with defined key interactions underlying the architecture. Key interactions between erlin1 and erlin2 subunits determine the complex's stoichiometry distinct from the mitochondrial PHB1/2 complex (22-mer).\",\n      \"method\": \"Single-particle cryo-EM structure determination\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-quality structural method (cryo-EM) but preprint, not yet peer-reviewed; corroborated by PMID:41887216\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Erlin-1 is required for efficient hepatitis C virus (HCV) infection. siRNA-mediated silencing of erlin-1 reduced intracellular HCV RNA accumulation, protein expression, and virus production. Mechanistic studies showed erlin-1 is required early in infection to initiate RNA replication (downstream of cell entry and primary translation) and later to support infectious virus production.\",\n      \"method\": \"siRNA knockdown, HCV infection assays, intracellular RNA quantification, viral protein expression, virus production assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional RNAi knockdown with multiple stage-specific readouts, single lab\",\n      \"pmids\": [\"31810281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Erlin-1 interacts with CYP1A2 in detergent-resistant ER microdomains (DRMs/MAMs) via their N-terminal signal-anchor domains, as demonstrated by a split fluorogenic bifunctional complementation assay (SURF). siRNA knockdown of erlin-1 in HepG2 cells relocates CYP1A2 from DRMs to non-DRMs, impairs CYP1A2 ERLAD (ER-to-lysosomal-associated degradation), and causes insoluble CYP1A2 aggregates. ERLAD of CYP1A2 can be rescued by co-expression of siRNA-resistant erlin-1 or its N-terminal 1-30 residue signal-anchor domain alone.\",\n      \"method\": \"SURF split-fluorescence assay, siRNA knockdown, sucrose gradient DRM fractionation, ERLAD/ERAD assays, rescue with truncated erlin-1 constructs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including protein-protein interaction assay and functional rescue, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ERLIN1 is an ER-resident SPFH/prohibitin-family protein that, together with ERLIN2, assembles into a large (~2 MDa, 26-mer) ring/cage complex on the ER membrane within lipid raft-like microdomains; this complex acts as a recognition scaffold that binds activated IP3Rs at their third intralumenal loop (near TM5), recruits the E3 ubiquitin ligase RNF170 (via TMUB1), and drives IP3R polyubiquitination and proteasomal degradation (ERAD), while also binding PI(3)P to maintain cellular PI(3)P levels and sustain autophagic flux, interacting with AMBRA1 at mitochondria-associated membranes to promote autophagosome formation, regulating cholesterol esterification and Golgi secretory pathway, and supporting HCV RNA replication.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERLIN1 is an ER-resident SPFH/prohibitin-family protein that, together with ERLIN2, assembles into a large ~2 MDa ring/cage complex within cholesterol-dependent, detergent-insoluble (lipid raft-like) ER microdomains [#0, #1, #9]. Cryo-EM defines this complex as a 26-mer cage of alternating ERLIN1 and ERLIN2 subunits that forms a discrete luminal-leaflet microdomain and can recruit ER proteins to both its interior and exterior surfaces, secluding cargoes from their partners; each subunit carries an intramembrane phosphatidylinositol-binding pocket [#9]. Functionally, the ERLIN1/2 complex acts as a selective recognition scaffold in ER-associated degradation (ERAD): it binds activated IP3R tetramers — via the third intralumenal loop near transmembrane helix 5, with residues D2471/R2472 critical for association — as the primary upstream event that precedes polyubiquitination and proteasomal degradation [#1, #2, #5]. The complex bridges the E3 ubiquitin ligase RNF170 and TMUB1 through their luminal N-terminal regions binding the SPFH domain of adjacent ERLIN subunits, completing the degradation machinery [#7]. Beyond ERAD, the complex selectively binds PI(3)P and is required to maintain steady-state cellular PI(3)P levels and sustain autophagic flux, independent of VPS34 kinase activity [#3, #8]; ERLIN1 also localizes to mitochondria-associated membranes where it interacts with AMBRA1 in a GD3- and MFN2-dependent manner to promote starvation-induced autophagosome formation [#4]. Loss of both ERLINs limits cholesterol esterification, thereby influencing ER-to-Golgi cholesterol transport, Golgi morphology and the secretory pathway [#7]. A splicing mutation in ERLIN1 (c.504+1G>A) that deletes exon 7 and disrupts the prohibitin domain causes hereditary spastic paraplegia (SPG62) [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established where ERLIN1 resides and how it is targeted, defining it as an ER protein that partitions into cholesterol-dependent raft-like microdomains.\",\n      \"evidence\": \"Sucrose gradient fractionation, cholesterol depletion, and GFP-fusion targeting in cells\",\n      \"pmids\": [\"16835267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partners or molecular function identified\", \"Functional role of raft partitioning not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed ERLIN1 functions as a heteromeric ~2 MDa ring complex with ERLIN2 that recognizes activated IP3Rs and is required for their ERAD, defining the complex's core substrate-recognition role.\",\n      \"evidence\": \"Reciprocal Co-IP, sucrose sedimentation, EM of the complex, and RNAi with IP3R ubiquitination/degradation assays in HeLa cells\",\n      \"pmids\": [\"19240031\", \"19751772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase and ubiquitination machinery not yet identified\", \"IP3R binding site on the receptor not mapped\", \"Substrate selectivity mechanism unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the temporal logic of ERAD, placing ERLIN1/2 binding as an early, substrate-selective recognition event upstream of ubiquitination and p97 recruitment.\",\n      \"evidence\": \"Stable transfection, RNAi, Co-IP, and specificity controls (calcium mobilization, IkBa, HMG-CoA reductase ERAD) in muscarinic-receptor HeLa cells\",\n      \"pmids\": [\"19751772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ligase linking recognition to ubiquitination still unidentified\", \"Structural basis of complex–IP3R contact unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified PI(3)P as a ligand of the complex and showed a disease mutation couples lipid binding to substrate engagement, linking lipid recognition to ERAD function.\",\n      \"evidence\": \"CRISPR ablation of erlin1 or erlin2, lipid-binding assays, Co-IP, and degradation assays with the erlin2 T65I mutant\",\n      \"pmids\": [\"30135210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of PI(3)P binding not established here\", \"Why erlin2 dominates IP3R binding structurally unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the IP3R binding determinant to intralumenal loop 3 near TM5 and used epistasis to confirm ERLIN1/2 binding is the primary event upstream of ubiquitination.\",\n      \"evidence\": \"IP3R1 site-directed mutagenesis, Co-IP, UBE1 inhibition (TAK-243), and channel activity/degradation assays\",\n      \"pmids\": [\"35568199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the complex–IP3R interface not resolved\", \"How binding signals ligase recruitment unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tied an ERLIN1 splicing mutation disrupting the prohibitin domain to hereditary spastic paraplegia (SPG62), connecting complex integrity to human disease.\",\n      \"evidence\": \"Whole-exome sequencing, minigene splicing assay, and bioinformatic analysis\",\n      \"pmids\": [\"36100157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream functional consequence on the complex inferred, not directly measured\", \"Mechanism linking ERAD defect to motor neuron degeneration unestablished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended ERLIN1's role to autophagy by showing it acts at MAMs with AMBRA1 to drive starvation-induced autophagosome formation.\",\n      \"evidence\": \"Co-IP, FRET, siRNA of ST8SIA1/MFN2, MAM fractionation, and autophagy flux assays\",\n      \"pmids\": [\"33034545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular mechanism by which the interaction nucleates autophagosomes unclear\", \"Relationship to the ERLIN1/2 ERAD complex not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined how the complex incorporates the ubiquitin ligase machinery and uncovered a role in cholesterol esterification and secretory pathway regulation.\",\n      \"evidence\": \"Proteomics, 3D structural modeling, Co-IP, and ERLIN1/2 double-KO HeLa phenotyping with cholesterol esterification assays\",\n      \"pmids\": [\"38782601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct enzymatic mechanism of cholesterol esterification regulation not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a direct mechanistic basis for the autophagy role by showing the complex maintains steady-state PI(3)P levels independent of VPS34.\",\n      \"evidence\": \"Recombinant protein lipid binding, PI(3)P quantification in KO/knockdown cells, autophagic flux, and VPS34 activity assays\",\n      \"pmids\": [\"39018973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which the complex maintains PI(3)P pools unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the complex architecture by cryo-EM as a 26-mer cage with intramembrane PI-binding pockets, providing a structural model for how it organizes microdomains and seclude cargoes.\",\n      \"evidence\": \"Single-particle cryo-EM and structural analysis of the human erlin1/2 complex\",\n      \"pmids\": [\"41887216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of substrate- or partner-bound states not determined\", \"How cage clustering is regulated unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated ERLIN1 in pathogen biology, showing it is required at distinct stages of HCV infection including initiation of RNA replication.\",\n      \"evidence\": \"siRNA knockdown with stage-specific HCV RNA, protein, and virus production readouts\",\n      \"pmids\": [\"31810281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct molecular interaction with HCV components not shown\", \"Whether the ERAD/microdomain function underlies this role unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the ERLIN1/2 cage's distinct functions — IP3R ERAD, PI(3)P maintenance, cholesterol handling, MAM autophagy, and substrate sequestration — are coordinated and selectively triggered remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking microdomain organization to substrate choice\", \"Structural basis of partner/cargo selection not determined\", \"In vivo physiological consequences of each function not separately tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 8, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 5, 7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 5, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"ERLIN1/ERLIN2 complex\"],\n    \"partners\": [\"ERLIN2\", \"ITPR1\", \"RNF170\", \"TMUB1\", \"AMBRA1\", \"CYP1A2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}