{"gene":"ERLIN2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2006,"finding":"Erlin-2 (C8orf2) localizes to the ER membrane and is enriched in detergent-insoluble, buoyant (lipid-raft-like) fractions in a cholesterol-dependent manner. The extreme N-terminus is sufficient for ER targeting in the absence of classical ER retrieval motifs.","method":"Sucrose gradient fractionation, cholesterol depletion, GFP-fusion subcellular targeting assay, monoclonal antibody generation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence (N-terminal targeting domain identified), replicated across multiple cell types and orthogonal methods","pmids":["16835267"],"is_preprint":false},{"year":2007,"finding":"SPFH2 (ERLIN2) rapidly associates with activated IP3Rs prior to their polyubiquitination and p97 recruitment, and RNAi-mediated suppression of SPFH2 markedly inhibits IP3R polyubiquitination and degradation as well as the processing of other ERAD substrates, identifying ERLIN2 as a key ERAD substrate recognition factor.","method":"Co-immunoprecipitation, RNA interference (siRNA knockdown), pulse-chase degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional RNAi knockdown with specific degradation readouts, replicated in follow-up studies","pmids":["17502376"],"is_preprint":false},{"year":2009,"finding":"SPFH1 (erlin-1) and SPFH2 (erlin-2) form a heteromeric ~2 MDa ring-shaped complex (diameter ~250 Å) that binds to IP3R tetramers immediately after their activation and is required for their polyubiquitination and degradation; RNAi depletion of either subunit blocks IP3R ERAD.","method":"Co-immunoprecipitation, sucrose gradient sedimentation, electron microscopy of native complex, RNA interference","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — complex size and ring morphology determined by EM, functional requirement confirmed by RNAi, replicated across labs","pmids":["19240031"],"is_preprint":false},{"year":2009,"finding":"SPFH1/SPFH2 (erlin-1/erlin-2) hetero-oligomeric complex associates with IP3Rs after their activation but before polyubiquitination and p97 association, selectively mediating IP3R ERAD but not HMG-CoA reductase sterol-induced ERAD; suppression of both subunits inhibits IP3R polyubiquitination and degradation without affecting IP3R-mediated calcium mobilization.","method":"Stable m3 muscarinic receptor-expressing HeLa cells, co-immunoprecipitation, RNA interference, calcium mobilization assay, IκBα processing assay as negative control","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, substrate specificity defined with negative controls, independent replication of earlier findings","pmids":["19751772"],"is_preprint":false},{"year":2012,"finding":"Erlin-2 physically associates with active γ-secretase in detergent-resistant ER membranes (DRMs) of brain, and siRNA knockdown of erlin-2 reduces Aβ production with limited effect on Notch processing, identifying erlin-2 as a γ-secretase-associated protein (GSAP) that affects APP substrate selectivity.","method":"γ-secretase inhibitor affinity purification, tandem mass spectrometry, proximity ligation assay, co-immunoprecipitation, siRNA knockdown with Aβ and Notch processing readouts","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (affinity purification, PLA, co-IP, functional knockdown) in a single lab","pmids":["22771797"],"is_preprint":false},{"year":2012,"finding":"ERLIN2 overexpression promotes breast cancer cell survival and adaptation to ER stress; IRE1α/XBP1 axis modulates ERLIN2 protein levels; gain- and loss-of-function show ERLIN2 facilitates cytoprotective response to ER stress.","method":"Stable overexpression (pLenti6/V5-ERLIN2), RNAi knockdown, ER stress induction assays, IRE1α inhibition","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined ER stress pathway readouts, single lab","pmids":["22681620"],"is_preprint":false},{"year":2012,"finding":"ERLIN2 binds to INSIG1 at the ER membrane and promotes SREBP1c activation, leading to increased cytosolic lipid droplet accumulation; ERLIN2 expression is induced by insulin signaling or lipoprotein-deficient medium.","method":"Co-immunoprecipitation (ERLIN2–INSIG1 binding), siRNA knockdown, lipid droplet quantification, SREBP1c activation assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional knockdown with lipid droplet and SREBP1c readouts, single lab","pmids":["22690709"],"is_preprint":false},{"year":2015,"finding":"ERLIN2 acts as an ER-microtubule-binding protein that interacts with α-tubulin and simultaneously binds the Cyclin B1/Cdk1 mitosis-promoting complex during G2/M phase; ERLIN2 facilitates K63-linked ubiquitination and stabilization of Cyclin B1, and its downregulation causes cell cycle arrest.","method":"Co-immunoprecipitation (ERLIN2–α-tubulin and ERLIN2–Cyclin B1/Cdk1), ubiquitination assay (K63-linkage specific), cell cycle analysis (FACS), siRNA knockdown","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay and cell cycle readout, single lab","pmids":["27462423"],"is_preprint":false},{"year":2018,"finding":"Erlin2 is the dominant mediator of IP3R binding within the erlin1/2 complex; the disease-linked T65I mutation (spastic paraplegia) dramatically inhibits erlin2–IP3R interaction and IP3R ubiquitination/degradation. The erlin1/2 complex specifically binds phosphatidylinositol 3-phosphate (PI(3)P), erlin2 binds PI(3)P much more strongly than erlin1, and the T65I mutation inhibits this PI(3)P binding; multiple determinants within the erlin2 polypeptide comprise the PI(3)P-binding site.","method":"Gene editing (CRISPR ablation of erlin1 or erlin2), PI(3)P lipid-binding assay, co-immunoprecipitation (erlin2–IP3R), ubiquitination assay, T65I mutant functional analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — gene editing plus lipid-binding assay plus mutagenesis plus functional ubiquitination readout in a single rigorous study","pmids":["30135210"],"is_preprint":false},{"year":2021,"finding":"ERLIN2 links EVI/WLS (WNT secretory factor) to the ubiquitylation machinery within the ERAD pathway; EVI/WLS undergoes K11-, K48- and K63-linked ubiquitylation mediated by UBE2J2, UBE2K, and UBE2N, and this ubiquitylation is independent of E3 ligases HRD1 and GP78.","method":"Immunoblot-based RNAi screen, co-immunoprecipitation (ERLIN2–EVI/WLS), ubiquitin linkage-specific antibodies, E2/E3 knockdown","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — focused RNAi screen plus Co-IP plus linkage-specific ubiquitination assays, single lab","pmids":["34406391"],"is_preprint":false},{"year":2023,"finding":"The ERLIN2 heterozygous missense variant p.Val71Ala recruits the ubiquitin E3 ligase RNF213 to IP3R1, leading to IP3R1 degradation, reduced intracellular free calcium, ER stress-mediated apoptosis, and inhibition of the MAPK signaling pathway reducing cell proliferation.","method":"Patient-derived iPSC models, IP-mass spectrometry (identifying RNF213 interaction), IP3R1 degradation assay, calcium imaging, MAPK pathway analysis","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus iPSC disease model plus calcium and signaling readouts, single lab","pmids":["40225166"],"is_preprint":false},{"year":2023,"finding":"ERLIN2 heterozygous variant (V71A) causes altered ER morphology and increased XBP-1S mRNA (ER stress activation), and promotes axon growth when overexpressed in primary cortical neurons.","method":"HeLa cell immunofluorescence, RT-PCR (XBP-1 splicing), mouse primary cortical neuron overexpression with axon morphology quantification","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ER morphology imaging plus ER stress molecular readout plus neuronal functional assay, single lab","pmids":["37752894"],"is_preprint":false},{"year":2024,"finding":"The erlin1/2 complex directly and selectively binds PI(3)P; disruption or deletion of the complex reduces cellular PI(3)P levels by ~50%, which correlates with decreased autophagic flux but no effect on the endocytic pathway; the reduction is not due to decreased VPS34 kinase activity, indicating erlin1/2 stabilizes PI(3)P pools to sustain autophagy.","method":"In vitro PI(3)P binding assay with recombinant erlins, PI(3)P quantification in cells with erlin KO/disruption, autophagic flux assay, VPS34 kinase activity measurement, pharmacological VPS34 inhibition","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted lipid-binding with recombinant protein plus cellular KO with orthogonal pathway readouts, single lab but multiple methods","pmids":["39018973"],"is_preprint":false},{"year":2025,"finding":"ERLIN2 assists in cholesterol trafficking from the ER to the outer mitochondrial membrane via MAM by facilitating intermediate folding of the cholesterol transporter StAR; ERLIN2–StAR interactions are transient and increase progressively from ER to MAM; absence of ERLIN2 ablates mitochondrial cholesterol transport.","method":"Co-immunoprecipitation (ERLIN2–StAR at ER and MAM), ERLIN2 knockout/knockdown, mitochondrial cholesterol transport assay, StAR folding assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional transport assay with KO, single lab","pmids":["41251286"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of the human erlin1/2 complex reveal a 26-mer (13 heterodimers of erlin1 and erlin2) ring-shaped assembly; the complex defines a nanodomain on the ER membrane that can cage cargo proteins (physically secluding them from binding partners) and interact with other cages to organize functional membrane microdomains of varying sizes.","method":"Single-particle cryo-EM structure determination under multiple detergent conditions, structural analysis of subunit interactions and conformational heterogeneity","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure at atomic/near-atomic resolution with two independent structural studies reporting consistent 26-mer stoichiometry","pmids":["bio_10.1101_2025.04.21.649849"],"is_preprint":true},{"year":2025,"finding":"A second independent cryo-EM study confirms the erlin1/2 complex forms a 26-mer cage-like structure of alternating erlin1 and erlin2 subunits; the cage recruits proteins to both interior and exterior membrane regions, physically sequesters cargo, and individual cages further oligomerize to organize larger functional membrane microdomains on the ER.","method":"Single-particle cryo-EM under different detergent conditions, functional analysis of cargo sequestration and cage-cage interaction","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus functional mechanistic characterization; replicates stoichiometry finding from independent concurrent study","pmids":["bio_10.1101_2025.06.14.659634"],"is_preprint":true},{"year":2026,"finding":"ERLIN2 regulates IP3R-mediated Ca2+ release and activates the CaMKII-MAPK-CREB signaling pathway, positively regulating CRY1/2 transcription and maintaining circadian rhythmicity in skeletal muscle cells; ERLIN2 knockdown or overexpression alters circadian amplitude, and ATP-induced IP3R-dependent Ca2+ transients that reshape circadian phase are blocked by IP3R, Ca2+, or CaMKII inhibition.","method":"C2C12 skeletal muscle cell knockdown and overexpression, circadian reporter assays, Ca2+ imaging, pharmacological inhibition of IP3R/CaMKII/MAPK, CREB phosphorylation assay, CRY1/2 transcription measurement","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal pharmacological and genetic approaches in single lab with defined pathway readouts","pmids":["41572931"],"is_preprint":false},{"year":2026,"finding":"ERLIN2 undergoes N-glycosylation at asparagine 106 (N106); the E3 ubiquitin ligase MARCHF6 mediates ubiquitination and degradation of ERLIN2, with this effect enhanced when N106 glycosylation is inhibited (N106Q mutant); N-glycosylation at N106 enhances ERLIN2 interaction with Cyclin B1 (CCNB1) and promotes CCNB1 stabilization.","method":"Site-directed mutagenesis (N106Q), co-immunoprecipitation (ERLIN2–CCNB1), MARCHF6 knockdown/overexpression with ERLIN2 ubiquitination assay, N-glycosylation inhibition","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus Co-IP plus functional ubiquitination assay, single lab","pmids":["42166002"],"is_preprint":false},{"year":2025,"finding":"CLPTM1L interacts with ERLIN2 to cooperatively stabilize SREBP1 protein levels by inhibiting its ubiquitination; knockdown of ERLIN2 reduces SREBP1 levels and suppresses NPC cell proliferation and migration.","method":"Co-immunoprecipitation (CLPTM1L–ERLIN2), RNAi knockdown of ERLIN2 with SREBP1 ubiquitination and stability assays, cell proliferation/migration assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional ubiquitination assay plus rescue experiment, single lab","pmids":["40550808"],"is_preprint":false},{"year":2023,"finding":"KCNN1 interacts with ERLIN2 and enhances ERLIN2-mediated Cyclin B1 stabilization and K63-linked ubiquitination; ERLIN2 knockdown partially reverses the KCNN1 overexpression-induced increase in Cyclin B1 stability, placing ERLIN2 downstream of KCNN1 in a KCNN1/ERLIN2/Cyclin B1 axis.","method":"Co-immunoprecipitation (KCNN1–ERLIN2), K63-ubiquitin-specific assay for Cyclin B1, epistasis by double knockdown/overexpression","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus epistasis experiments with ubiquitination readout, single lab","pmids":["37831636"],"is_preprint":false}],"current_model":"ERLIN2 (erlin-2/SPFH2) is an ER membrane protein that assembles with erlin-1 into a cryo-EM-resolved 26-mer ring/cage complex (~2 MDa) that organizes lipid-raft-like microdomains on the ER; the complex binds and stabilizes phosphatidylinositol 3-phosphate (PI(3)P) to sustain autophagic flux, acts as a substrate-recognition factor for ERAD by associating with activated IP3Rs prior to their polyubiquitination and proteasomal degradation (a function inhibited by the disease-linked T65I mutation), regulates IP3R-mediated calcium release to activate CaMKII-MAPK-CREB-CRY1/2 circadian signaling, facilitates cholesterol trafficking from the ER to mitochondria via StAR interaction, promotes SREBP1c activation by binding INSIG1, and stabilizes Cyclin B1 through K63-linked ubiquitination during G2/M phase; loss-of-function mutations in ERLIN2 cause SPG18 hereditary spastic paraplegia and related motor neuron diseases."},"narrative":{"mechanistic_narrative":"ERLIN2 (erlin-2/SPFH2) is an ER membrane protein that, together with erlin-1, assembles into a large ring/cage-shaped hetero-oligomeric complex (~2 MDa, a 26-mer of alternating erlin-1/erlin-2 subunits) that organizes lipid-raft-like microdomains on the ER and physically sequesters cargo proteins from their binding partners [PMID:19240031, PMID:bio_10.1101_2025.04.21.649849, PMID:bio_10.1101_2025.06.14.659634]. It resides in detergent-resistant, cholesterol-dependent ER membrane fractions, with its extreme N-terminus directing ER targeting [PMID:16835267]. A central function of the complex is substrate recognition in ER-associated degradation (ERAD): erlin-2 (the dominant IP3R-binding subunit) associates with activated IP3R tetramers prior to their polyubiquitination and p97 recruitment, and is required for IP3R ubiquitination and proteasomal degradation while leaving calcium mobilization intact [PMID:17502376, PMID:19240031, PMID:19751772, PMID:30135210]. The erlin-1/2 complex directly and selectively binds phosphatidylinositol 3-phosphate (PI(3)P) through determinants within erlin-2, and this PI(3)P binding stabilizes cellular PI(3)P pools to sustain autophagic flux without altering VPS34 kinase activity or endocytosis [PMID:30135210, PMID:39018973]. Beyond ERAD, ERLIN2 participates in lipid and sterol regulation by binding INSIG1 to promote SREBP1c activation and lipid droplet accumulation [PMID:22690709], cooperating with CLPTM1L to stabilize SREBP1 by inhibiting its ubiquitination [PMID:40550808], and facilitating StAR-mediated cholesterol transport from the ER to mitochondria via MAM contact sites [PMID:41251286]. ERLIN2 also stabilizes Cyclin B1 through K63-linked ubiquitination during G2/M, associating with α-tubulin and the Cyclin B1/Cdk1 complex such that its loss causes cell cycle arrest [PMID:27462423], and it regulates IP3R-mediated Ca2+ release that activates CaMKII-MAPK-CREB signaling to maintain circadian rhythmicity [PMID:41572931]. Disease-linked ERLIN2 variants (T65I and V71A) impair erlin-2–IP3R interaction, PI(3)P binding, and calcium homeostasis, linking ERLIN2 dysfunction to spastic paraplegia and motor neuron disease [PMID:30135210, PMID:40225166, PMID:37752894].","teleology":[{"year":2006,"claim":"Established where ERLIN2 acts and how it is targeted, defining it as a cholesterol-dependent, lipid-raft-associated ER membrane protein.","evidence":"Sucrose gradient fractionation, cholesterol depletion, and GFP-fusion targeting assays in multiple cell types","pmids":["16835267"],"confidence":"High","gaps":["Function of the raft-like microdomain not yet defined","No binding partners identified at this stage"]},{"year":2007,"claim":"Answered what ERLIN2 does mechanistically by showing it acts as an ERAD substrate-recognition factor that engages activated IP3Rs before their ubiquitination.","evidence":"Co-immunoprecipitation, siRNA knockdown, and pulse-chase degradation assays","pmids":["17502376"],"confidence":"High","gaps":["E3 ligase and how recognition triggers ubiquitination unknown","Whether ERLIN2 acts alone or in a complex unresolved"]},{"year":2009,"claim":"Resolved that ERLIN2 functions within a large erlin-1/erlin-2 ring complex required for IP3R ERAD, defining the structural unit and its substrate selectivity.","evidence":"Co-IP, sucrose gradient sedimentation, EM of native complex, RNAi, and substrate-specificity controls (no effect on HMG-CoA reductase or IκBα)","pmids":["19240031","19751772"],"confidence":"High","gaps":["Atomic stoichiometry not yet determined","How the complex distinguishes activated from inactive IP3R unknown"]},{"year":2012,"claim":"Extended ERLIN2 function beyond IP3R ERAD to membrane-protein complexes and lipid metabolism, including γ-secretase association, ER-stress cytoprotection, and INSIG1-dependent SREBP1c activation.","evidence":"Affinity purification/MS, PLA, Co-IP, RNAi with Aβ/Notch readouts; ER-stress gain/loss-of-function; INSIG1 Co-IP with lipid droplet and SREBP1c assays","pmids":["22771797","22681620","22690709"],"confidence":"Medium","gaps":["Each link reported from a single lab","Mechanistic relationship between ERAD role and lipid/secretase functions unclear"]},{"year":2015,"claim":"Showed ERLIN2 has a cell-cycle role distinct from degradation, stabilizing Cyclin B1 via K63-linked ubiquitination at the ER-microtubule interface.","evidence":"Reciprocal Co-IP (α-tubulin, Cyclin B1/Cdk1), K63-linkage-specific ubiquitination assay, FACS cell-cycle analysis, siRNA","pmids":["27462423"],"confidence":"Medium","gaps":["E3 ligase mediating K63 ubiquitination not identified","How a degradation-associated factor switches to stabilization unexplained"]},{"year":2018,"claim":"Defined ERLIN2 as the dominant IP3R- and PI(3)P-binding subunit and linked a disease mutation (T65I) mechanistically to loss of both interactions.","evidence":"CRISPR ablation of erlin-1 or erlin-2, PI(3)P lipid-binding assays, Co-IP, ubiquitination assay, T65I mutagenesis","pmids":["30135210"],"confidence":"High","gaps":["Structural basis of the PI(3)P-binding site not resolved","Functional consequence of PI(3)P binding not yet established"]},{"year":2021,"claim":"Broadened ERLIN2's ERAD substrate repertoire to the WNT secretory factor EVI/WLS and connected it to specific E2 enzymes independent of canonical ER E3 ligases.","evidence":"RNAi screen, Co-IP, ubiquitin-linkage-specific antibodies, E2/E3 knockdown","pmids":["34406391"],"confidence":"Medium","gaps":["The E3 ligase for EVI/WLS not identified","Single-lab finding"]},{"year":2024,"claim":"Linked ERLIN2's PI(3)P binding to a physiological output, showing the complex stabilizes cellular PI(3)P pools to sustain autophagic flux.","evidence":"In vitro PI(3)P binding with recombinant erlins, PI(3)P quantification in KO/disrupted cells, autophagic flux assay, VPS34 activity measurement","pmids":["39018973"],"confidence":"High","gaps":["Molecular mechanism by which bound PI(3)P is protected from turnover unknown","Single-lab study"]},{"year":2025,"claim":"Provided the atomic architecture of the complex, defining it as a 26-mer cage that sequesters cargo and oligomerizes into membrane microdomains.","evidence":"Two independent single-particle cryo-EM studies under multiple detergent conditions (preprints)","pmids":["bio_10.1101_2025.04.21.649849","bio_10.1101_2025.06.14.659634"],"confidence":"High","gaps":["Structures of cargo-bound complex not resolved","Preprint status, not peer-reviewed"]},{"year":2025,"claim":"Added sterol-trafficking and SREBP1-stabilization roles, showing ERLIN2 chaperones StAR folding for ER-to-mitochondria cholesterol transport and cooperates with CLPTM1L to stabilize SREBP1.","evidence":"Co-IP (ERLIN2-StAR at ER/MAM; CLPTM1L-ERLIN2), KO/knockdown, mitochondrial cholesterol transport and SREBP1 ubiquitination assays","pmids":["41251286","40550808"],"confidence":"Medium","gaps":["How a cage/sequestration function relates to folding chaperone activity unclear","Single-lab findings"]},{"year":2026,"claim":"Connected ERLIN2-regulated IP3R Ca2+ signaling to downstream circadian control and defined post-translational regulation of ERLIN2 itself.","evidence":"C2C12 circadian reporter and Ca2+ imaging with IP3R/CaMKII/MAPK inhibition; N106Q mutagenesis, MARCHF6 knockdown/overexpression, CCNB1 Co-IP","pmids":["41572931","42166002"],"confidence":"Medium","gaps":["Whether circadian role generalizes beyond skeletal muscle untested","Single-lab findings"]},{"year":2023,"claim":"Tied ERLIN2 dysfunction to human disease through patient-derived variants that disrupt IP3R handling and ER homeostasis.","evidence":"Patient iPSC models, IP-MS identifying RNF213 recruitment to IP3R1, Ca2+ imaging, MAPK analysis, ER morphology imaging, neuronal axon assays","pmids":["40225166","37752894"],"confidence":"Medium","gaps":["Variant V71A studied in single labs","How aberrant RNF213 recruitment relates to normal ERAD pathway unresolved"]},{"year":null,"claim":"How the single cage complex integrates its diverse roles — ERAD substrate selection, PI(3)P stabilization, sterol trafficking, and Cyclin B1 stabilization — into a coherent regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking cargo sequestration to the multiple downstream pathways","Identity of E3 ligases for several substrates unknown","Structural basis for substrate vs. lipid selectivity undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,7,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,3,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,13,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,17,19]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[16]}],"complexes":["erlin-1/erlin-2 (SPFH1/SPFH2) cage complex"],"partners":["ERLIN1","ITPR1","INSIG1","CCNB1","STARD1","CLPTM1L","KCNN1","MARCHF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94905","full_name":"Erlin-2","aliases":["Endoplasmic reticulum lipid raft-associated protein 2","Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 2","SPFH domain-containing protein 2"],"length_aa":339,"mass_kda":37.8,"function":"Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1 (PubMed:17502376, PubMed:19240031). Promotes sterol-accelerated ERAD of HMGCR probably implicating an AMFR/gp78-containing ubiquitin ligase complex (PubMed:21343306). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. May promote ER retention of the SCAP-SREBF complex (PubMed:24217618)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O94905/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERLIN2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GET4","stoichiometry":4.0},{"gene":"AHCY","stoichiometry":0.2},{"gene":"BAG6","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"GAPDH","stoichiometry":0.2},{"gene":"GORASP2","stoichiometry":0.2},{"gene":"OSBPL8","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ERLIN2","total_profiled":1310},"omim":[{"mim_id":"620512","title":"SPASTIC PARAPLEGIA 18A, AUTOSOMAL DOMINANT; SPG18A","url":"https://www.omim.org/entry/620512"},{"mim_id":"614649","title":"RING FINGER PROTEIN 170; RNF170","url":"https://www.omim.org/entry/614649"},{"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"},{"mim_id":"611225","title":"SPASTIC PARAPLEGIA 18B, AUTOSOMAL RECESSIVE; SPG18B","url":"https://www.omim.org/entry/611225"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ERLIN2"},"hgnc":{"alias_symbol":["NET32","Erlin-2"],"prev_symbol":["C8orf2","SPFH2","SPG18"]},"alphafold":{"accession":"O94905","domains":[{"cath_id":"-","chopping":"1-63","consensus_level":"medium","plddt":89.9762,"start":1,"end":63},{"cath_id":"3.30.479.30","chopping":"64-175","consensus_level":"high","plddt":93.4661,"start":64,"end":175}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94905","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94905-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94905-F1-predicted_aligned_error_v6.png","plddt_mean":85.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERLIN2","jax_strain_url":"https://www.jax.org/strain/search?query=ERLIN2"},"sequence":{"accession":"O94905","fasta_url":"https://rest.uniprot.org/uniprotkb/O94905.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94905/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94905"}},"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":"17502376","id":"PMC_17502376","title":"SPFH2 mediates the endoplasmic reticulum-associated degradation of inositol 1,4,5-trisphosphate receptors and other substrates in mammalian cells.","date":"2007","source":"The Journal of biological 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The first AD-SPG18 pedigree in Chinese and literature review.","date":"2021","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/34734492","citation_count":8,"is_preprint":false},{"pmid":"37752894","id":"PMC_37752894","title":"A novel autosomal dominant ERLIN2 variant activates endoplasmic reticulum stress in a Chinese HSP family.","date":"2023","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37752894","citation_count":4,"is_preprint":false},{"pmid":"37831636","id":"PMC_37831636","title":"KCNN1 promotes proliferation and metastasis of breast cancer via ERLIN2-mediated stabilization and K63-dependent ubiquitination of Cyclin B1.","date":"2023","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37831636","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 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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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20149,"output_tokens":5269,"usd":0.069741,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13659,"output_tokens":4427,"usd":0.089485,"stage2_stop_reason":"end_turn"},"total_usd":0.159226,"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\": \"Erlin-2 (C8orf2) localizes to the ER membrane and is enriched in detergent-insoluble, buoyant (lipid-raft-like) fractions in a cholesterol-dependent manner. The extreme N-terminus is sufficient for ER targeting in the absence of classical ER retrieval motifs.\",\n      \"method\": \"Sucrose gradient fractionation, cholesterol depletion, GFP-fusion subcellular targeting assay, monoclonal antibody generation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence (N-terminal targeting domain identified), replicated across multiple cell types and orthogonal methods\",\n      \"pmids\": [\"16835267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SPFH2 (ERLIN2) rapidly associates with activated IP3Rs prior to their polyubiquitination and p97 recruitment, and RNAi-mediated suppression of SPFH2 markedly inhibits IP3R polyubiquitination and degradation as well as the processing of other ERAD substrates, identifying ERLIN2 as a key ERAD substrate recognition factor.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference (siRNA knockdown), pulse-chase degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional RNAi knockdown with specific degradation readouts, replicated in follow-up studies\",\n      \"pmids\": [\"17502376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SPFH1 (erlin-1) and SPFH2 (erlin-2) form a heteromeric ~2 MDa ring-shaped complex (diameter ~250 Å) that binds to IP3R tetramers immediately after their activation and is required for their polyubiquitination and degradation; RNAi depletion of either subunit blocks IP3R ERAD.\",\n      \"method\": \"Co-immunoprecipitation, sucrose gradient sedimentation, electron microscopy of native complex, RNA interference\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — complex size and ring morphology determined by EM, functional requirement confirmed by RNAi, replicated across labs\",\n      \"pmids\": [\"19240031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SPFH1/SPFH2 (erlin-1/erlin-2) hetero-oligomeric complex associates with IP3Rs after their activation but before polyubiquitination and p97 association, selectively mediating IP3R ERAD but not HMG-CoA reductase sterol-induced ERAD; suppression of both subunits inhibits IP3R polyubiquitination and degradation without affecting IP3R-mediated calcium mobilization.\",\n      \"method\": \"Stable m3 muscarinic receptor-expressing HeLa cells, co-immunoprecipitation, RNA interference, calcium mobilization assay, IκBα processing assay as negative control\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, substrate specificity defined with negative controls, independent replication of earlier findings\",\n      \"pmids\": [\"19751772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Erlin-2 physically associates with active γ-secretase in detergent-resistant ER membranes (DRMs) of brain, and siRNA knockdown of erlin-2 reduces Aβ production with limited effect on Notch processing, identifying erlin-2 as a γ-secretase-associated protein (GSAP) that affects APP substrate selectivity.\",\n      \"method\": \"γ-secretase inhibitor affinity purification, tandem mass spectrometry, proximity ligation assay, co-immunoprecipitation, siRNA knockdown with Aβ and Notch processing readouts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (affinity purification, PLA, co-IP, functional knockdown) in a single lab\",\n      \"pmids\": [\"22771797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERLIN2 overexpression promotes breast cancer cell survival and adaptation to ER stress; IRE1α/XBP1 axis modulates ERLIN2 protein levels; gain- and loss-of-function show ERLIN2 facilitates cytoprotective response to ER stress.\",\n      \"method\": \"Stable overexpression (pLenti6/V5-ERLIN2), RNAi knockdown, ER stress induction assays, IRE1α inhibition\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined ER stress pathway readouts, single lab\",\n      \"pmids\": [\"22681620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ERLIN2 binds to INSIG1 at the ER membrane and promotes SREBP1c activation, leading to increased cytosolic lipid droplet accumulation; ERLIN2 expression is induced by insulin signaling or lipoprotein-deficient medium.\",\n      \"method\": \"Co-immunoprecipitation (ERLIN2–INSIG1 binding), siRNA knockdown, lipid droplet quantification, SREBP1c activation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional knockdown with lipid droplet and SREBP1c readouts, single lab\",\n      \"pmids\": [\"22690709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERLIN2 acts as an ER-microtubule-binding protein that interacts with α-tubulin and simultaneously binds the Cyclin B1/Cdk1 mitosis-promoting complex during G2/M phase; ERLIN2 facilitates K63-linked ubiquitination and stabilization of Cyclin B1, and its downregulation causes cell cycle arrest.\",\n      \"method\": \"Co-immunoprecipitation (ERLIN2–α-tubulin and ERLIN2–Cyclin B1/Cdk1), ubiquitination assay (K63-linkage specific), cell cycle analysis (FACS), siRNA knockdown\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay and cell cycle readout, single lab\",\n      \"pmids\": [\"27462423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Erlin2 is the dominant mediator of IP3R binding within the erlin1/2 complex; the disease-linked T65I mutation (spastic paraplegia) dramatically inhibits erlin2–IP3R interaction and IP3R ubiquitination/degradation. The erlin1/2 complex specifically binds phosphatidylinositol 3-phosphate (PI(3)P), erlin2 binds PI(3)P much more strongly than erlin1, and the T65I mutation inhibits this PI(3)P binding; multiple determinants within the erlin2 polypeptide comprise the PI(3)P-binding site.\",\n      \"method\": \"Gene editing (CRISPR ablation of erlin1 or erlin2), PI(3)P lipid-binding assay, co-immunoprecipitation (erlin2–IP3R), ubiquitination assay, T65I mutant functional analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — gene editing plus lipid-binding assay plus mutagenesis plus functional ubiquitination readout in a single rigorous study\",\n      \"pmids\": [\"30135210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERLIN2 links EVI/WLS (WNT secretory factor) to the ubiquitylation machinery within the ERAD pathway; EVI/WLS undergoes K11-, K48- and K63-linked ubiquitylation mediated by UBE2J2, UBE2K, and UBE2N, and this ubiquitylation is independent of E3 ligases HRD1 and GP78.\",\n      \"method\": \"Immunoblot-based RNAi screen, co-immunoprecipitation (ERLIN2–EVI/WLS), ubiquitin linkage-specific antibodies, E2/E3 knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — focused RNAi screen plus Co-IP plus linkage-specific ubiquitination assays, single lab\",\n      \"pmids\": [\"34406391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The ERLIN2 heterozygous missense variant p.Val71Ala recruits the ubiquitin E3 ligase RNF213 to IP3R1, leading to IP3R1 degradation, reduced intracellular free calcium, ER stress-mediated apoptosis, and inhibition of the MAPK signaling pathway reducing cell proliferation.\",\n      \"method\": \"Patient-derived iPSC models, IP-mass spectrometry (identifying RNF213 interaction), IP3R1 degradation assay, calcium imaging, MAPK pathway analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus iPSC disease model plus calcium and signaling readouts, single lab\",\n      \"pmids\": [\"40225166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ERLIN2 heterozygous variant (V71A) causes altered ER morphology and increased XBP-1S mRNA (ER stress activation), and promotes axon growth when overexpressed in primary cortical neurons.\",\n      \"method\": \"HeLa cell immunofluorescence, RT-PCR (XBP-1 splicing), mouse primary cortical neuron overexpression with axon morphology quantification\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ER morphology imaging plus ER stress molecular readout plus neuronal functional assay, single lab\",\n      \"pmids\": [\"37752894\"],\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 cellular PI(3)P levels by ~50%, which correlates with decreased autophagic flux but no effect on the endocytic pathway; the reduction is not due to decreased VPS34 kinase activity, indicating erlin1/2 stabilizes PI(3)P pools to sustain autophagy.\",\n      \"method\": \"In vitro PI(3)P binding assay with recombinant erlins, PI(3)P quantification in cells with erlin KO/disruption, autophagic flux assay, VPS34 kinase activity measurement, pharmacological VPS34 inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted lipid-binding with recombinant protein plus cellular KO with orthogonal pathway readouts, single lab but multiple methods\",\n      \"pmids\": [\"39018973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ERLIN2 assists in cholesterol trafficking from the ER to the outer mitochondrial membrane via MAM by facilitating intermediate folding of the cholesterol transporter StAR; ERLIN2–StAR interactions are transient and increase progressively from ER to MAM; absence of ERLIN2 ablates mitochondrial cholesterol transport.\",\n      \"method\": \"Co-immunoprecipitation (ERLIN2–StAR at ER and MAM), ERLIN2 knockout/knockdown, mitochondrial cholesterol transport assay, StAR folding assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional transport assay with KO, single lab\",\n      \"pmids\": [\"41251286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of the human erlin1/2 complex reveal a 26-mer (13 heterodimers of erlin1 and erlin2) ring-shaped assembly; the complex defines a nanodomain on the ER membrane that can cage cargo proteins (physically secluding them from binding partners) and interact with other cages to organize functional membrane microdomains of varying sizes.\",\n      \"method\": \"Single-particle cryo-EM structure determination under multiple detergent conditions, structural analysis of subunit interactions and conformational heterogeneity\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure at atomic/near-atomic resolution with two independent structural studies reporting consistent 26-mer stoichiometry\",\n      \"pmids\": [\"bio_10.1101_2025.04.21.649849\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A second independent cryo-EM study confirms the erlin1/2 complex forms a 26-mer cage-like structure of alternating erlin1 and erlin2 subunits; the cage recruits proteins to both interior and exterior membrane regions, physically sequesters cargo, and individual cages further oligomerize to organize larger functional membrane microdomains on the ER.\",\n      \"method\": \"Single-particle cryo-EM under different detergent conditions, functional analysis of cargo sequestration and cage-cage interaction\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus functional mechanistic characterization; replicates stoichiometry finding from independent concurrent study\",\n      \"pmids\": [\"bio_10.1101_2025.06.14.659634\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ERLIN2 regulates IP3R-mediated Ca2+ release and activates the CaMKII-MAPK-CREB signaling pathway, positively regulating CRY1/2 transcription and maintaining circadian rhythmicity in skeletal muscle cells; ERLIN2 knockdown or overexpression alters circadian amplitude, and ATP-induced IP3R-dependent Ca2+ transients that reshape circadian phase are blocked by IP3R, Ca2+, or CaMKII inhibition.\",\n      \"method\": \"C2C12 skeletal muscle cell knockdown and overexpression, circadian reporter assays, Ca2+ imaging, pharmacological inhibition of IP3R/CaMKII/MAPK, CREB phosphorylation assay, CRY1/2 transcription measurement\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal pharmacological and genetic approaches in single lab with defined pathway readouts\",\n      \"pmids\": [\"41572931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ERLIN2 undergoes N-glycosylation at asparagine 106 (N106); the E3 ubiquitin ligase MARCHF6 mediates ubiquitination and degradation of ERLIN2, with this effect enhanced when N106 glycosylation is inhibited (N106Q mutant); N-glycosylation at N106 enhances ERLIN2 interaction with Cyclin B1 (CCNB1) and promotes CCNB1 stabilization.\",\n      \"method\": \"Site-directed mutagenesis (N106Q), co-immunoprecipitation (ERLIN2–CCNB1), MARCHF6 knockdown/overexpression with ERLIN2 ubiquitination assay, N-glycosylation inhibition\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus Co-IP plus functional ubiquitination assay, single lab\",\n      \"pmids\": [\"42166002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLPTM1L interacts with ERLIN2 to cooperatively stabilize SREBP1 protein levels by inhibiting its ubiquitination; knockdown of ERLIN2 reduces SREBP1 levels and suppresses NPC cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation (CLPTM1L–ERLIN2), RNAi knockdown of ERLIN2 with SREBP1 ubiquitination and stability assays, cell proliferation/migration assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional ubiquitination assay plus rescue experiment, single lab\",\n      \"pmids\": [\"40550808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KCNN1 interacts with ERLIN2 and enhances ERLIN2-mediated Cyclin B1 stabilization and K63-linked ubiquitination; ERLIN2 knockdown partially reverses the KCNN1 overexpression-induced increase in Cyclin B1 stability, placing ERLIN2 downstream of KCNN1 in a KCNN1/ERLIN2/Cyclin B1 axis.\",\n      \"method\": \"Co-immunoprecipitation (KCNN1–ERLIN2), K63-ubiquitin-specific assay for Cyclin B1, epistasis by double knockdown/overexpression\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus epistasis experiments with ubiquitination readout, single lab\",\n      \"pmids\": [\"37831636\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERLIN2 (erlin-2/SPFH2) is an ER membrane protein that assembles with erlin-1 into a cryo-EM-resolved 26-mer ring/cage complex (~2 MDa) that organizes lipid-raft-like microdomains on the ER; the complex binds and stabilizes phosphatidylinositol 3-phosphate (PI(3)P) to sustain autophagic flux, acts as a substrate-recognition factor for ERAD by associating with activated IP3Rs prior to their polyubiquitination and proteasomal degradation (a function inhibited by the disease-linked T65I mutation), regulates IP3R-mediated calcium release to activate CaMKII-MAPK-CREB-CRY1/2 circadian signaling, facilitates cholesterol trafficking from the ER to mitochondria via StAR interaction, promotes SREBP1c activation by binding INSIG1, and stabilizes Cyclin B1 through K63-linked ubiquitination during G2/M phase; loss-of-function mutations in ERLIN2 cause SPG18 hereditary spastic paraplegia and related motor neuron diseases.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERLIN2 (erlin-2/SPFH2) is an ER membrane protein that, together with erlin-1, assembles into a large ring/cage-shaped hetero-oligomeric complex (~2 MDa, a 26-mer of alternating erlin-1/erlin-2 subunits) that organizes lipid-raft-like microdomains on the ER and physically sequesters cargo proteins from their binding partners [#2, #14, #15]. It resides in detergent-resistant, cholesterol-dependent ER membrane fractions, with its extreme N-terminus directing ER targeting [#0]. A central function of the complex is substrate recognition in ER-associated degradation (ERAD): erlin-2 (the dominant IP3R-binding subunit) associates with activated IP3R tetramers prior to their polyubiquitination and p97 recruitment, and is required for IP3R ubiquitination and proteasomal degradation while leaving calcium mobilization intact [#1, #2, #3, #8]. The erlin-1/2 complex directly and selectively binds phosphatidylinositol 3-phosphate (PI(3)P) through determinants within erlin-2, and this PI(3)P binding stabilizes cellular PI(3)P pools to sustain autophagic flux without altering VPS34 kinase activity or endocytosis [#8, #12]. Beyond ERAD, ERLIN2 participates in lipid and sterol regulation by binding INSIG1 to promote SREBP1c activation and lipid droplet accumulation [#6], cooperating with CLPTM1L to stabilize SREBP1 by inhibiting its ubiquitination [#18], and facilitating StAR-mediated cholesterol transport from the ER to mitochondria via MAM contact sites [#13]. ERLIN2 also stabilizes Cyclin B1 through K63-linked ubiquitination during G2/M, associating with α-tubulin and the Cyclin B1/Cdk1 complex such that its loss causes cell cycle arrest [#7], and it regulates IP3R-mediated Ca2+ release that activates CaMKII-MAPK-CREB signaling to maintain circadian rhythmicity [#16]. Disease-linked ERLIN2 variants (T65I and V71A) impair erlin-2–IP3R interaction, PI(3)P binding, and calcium homeostasis, linking ERLIN2 dysfunction to spastic paraplegia and motor neuron disease [#8, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established where ERLIN2 acts and how it is targeted, defining it as a cholesterol-dependent, lipid-raft-associated ER membrane protein.\",\n      \"evidence\": \"Sucrose gradient fractionation, cholesterol depletion, and GFP-fusion targeting assays in multiple cell types\",\n      \"pmids\": [\"16835267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the raft-like microdomain not yet defined\", \"No binding partners identified at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Answered what ERLIN2 does mechanistically by showing it acts as an ERAD substrate-recognition factor that engages activated IP3Rs before their ubiquitination.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, and pulse-chase degradation assays\",\n      \"pmids\": [\"17502376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase and how recognition triggers ubiquitination unknown\", \"Whether ERLIN2 acts alone or in a complex unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved that ERLIN2 functions within a large erlin-1/erlin-2 ring complex required for IP3R ERAD, defining the structural unit and its substrate selectivity.\",\n      \"evidence\": \"Co-IP, sucrose gradient sedimentation, EM of native complex, RNAi, and substrate-specificity controls (no effect on HMG-CoA reductase or IκBα)\",\n      \"pmids\": [\"19240031\", \"19751772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic stoichiometry not yet determined\", \"How the complex distinguishes activated from inactive IP3R unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended ERLIN2 function beyond IP3R ERAD to membrane-protein complexes and lipid metabolism, including γ-secretase association, ER-stress cytoprotection, and INSIG1-dependent SREBP1c activation.\",\n      \"evidence\": \"Affinity purification/MS, PLA, Co-IP, RNAi with Aβ/Notch readouts; ER-stress gain/loss-of-function; INSIG1 Co-IP with lipid droplet and SREBP1c assays\",\n      \"pmids\": [\"22771797\", \"22681620\", \"22690709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each link reported from a single lab\", \"Mechanistic relationship between ERAD role and lipid/secretase functions unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed ERLIN2 has a cell-cycle role distinct from degradation, stabilizing Cyclin B1 via K63-linked ubiquitination at the ER-microtubule interface.\",\n      \"evidence\": \"Reciprocal Co-IP (α-tubulin, Cyclin B1/Cdk1), K63-linkage-specific ubiquitination assay, FACS cell-cycle analysis, siRNA\",\n      \"pmids\": [\"27462423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating K63 ubiquitination not identified\", \"How a degradation-associated factor switches to stabilization unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined ERLIN2 as the dominant IP3R- and PI(3)P-binding subunit and linked a disease mutation (T65I) mechanistically to loss of both interactions.\",\n      \"evidence\": \"CRISPR ablation of erlin-1 or erlin-2, PI(3)P lipid-binding assays, Co-IP, ubiquitination assay, T65I mutagenesis\",\n      \"pmids\": [\"30135210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PI(3)P-binding site not resolved\", \"Functional consequence of PI(3)P binding not yet established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened ERLIN2's ERAD substrate repertoire to the WNT secretory factor EVI/WLS and connected it to specific E2 enzymes independent of canonical ER E3 ligases.\",\n      \"evidence\": \"RNAi screen, Co-IP, ubiquitin-linkage-specific antibodies, E2/E3 knockdown\",\n      \"pmids\": [\"34406391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase for EVI/WLS not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked ERLIN2's PI(3)P binding to a physiological output, showing the complex stabilizes cellular PI(3)P pools to sustain autophagic flux.\",\n      \"evidence\": \"In vitro PI(3)P binding with recombinant erlins, PI(3)P quantification in KO/disrupted cells, autophagic flux assay, VPS34 activity measurement\",\n      \"pmids\": [\"39018973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which bound PI(3)P is protected from turnover unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the atomic architecture of the complex, defining it as a 26-mer cage that sequesters cargo and oligomerizes into membrane microdomains.\",\n      \"evidence\": \"Two independent single-particle cryo-EM studies under multiple detergent conditions (preprints)\",\n      \"pmids\": [\"bio_10.1101_2025.04.21.649849\", \"bio_10.1101_2025.06.14.659634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of cargo-bound complex not resolved\", \"Preprint status, not peer-reviewed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added sterol-trafficking and SREBP1-stabilization roles, showing ERLIN2 chaperones StAR folding for ER-to-mitochondria cholesterol transport and cooperates with CLPTM1L to stabilize SREBP1.\",\n      \"evidence\": \"Co-IP (ERLIN2-StAR at ER/MAM; CLPTM1L-ERLIN2), KO/knockdown, mitochondrial cholesterol transport and SREBP1 ubiquitination assays\",\n      \"pmids\": [\"41251286\", \"40550808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a cage/sequestration function relates to folding chaperone activity unclear\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected ERLIN2-regulated IP3R Ca2+ signaling to downstream circadian control and defined post-translational regulation of ERLIN2 itself.\",\n      \"evidence\": \"C2C12 circadian reporter and Ca2+ imaging with IP3R/CaMKII/MAPK inhibition; N106Q mutagenesis, MARCHF6 knockdown/overexpression, CCNB1 Co-IP\",\n      \"pmids\": [\"41572931\", \"42166002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether circadian role generalizes beyond skeletal muscle untested\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tied ERLIN2 dysfunction to human disease through patient-derived variants that disrupt IP3R handling and ER homeostasis.\",\n      \"evidence\": \"Patient iPSC models, IP-MS identifying RNF213 recruitment to IP3R1, Ca2+ imaging, MAPK analysis, ER morphology imaging, neuronal axon assays\",\n      \"pmids\": [\"40225166\", \"37752894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Variant V71A studied in single labs\", \"How aberrant RNF213 recruitment relates to normal ERAD pathway unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the single cage complex integrates its diverse roles — ERAD substrate selection, PI(3)P stabilization, sterol trafficking, and Cyclin B1 stabilization — into a coherent regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking cargo sequestration to the multiple downstream pathways\", \"Identity of E3 ligases for several substrates unknown\", \"Structural basis for substrate vs. lipid selectivity undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 7, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"GO:0005789\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 3, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 13, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 17, 19]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\"erlin-1/erlin-2 (SPFH1/SPFH2) cage complex\"],\n    \"partners\": [\"ERLIN1\", \"ITPR1\", \"INSIG1\", \"CCNB1\", \"STARD1\", \"CLPTM1L\", \"KCNN1\", \"MARCHF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}