{"gene":"MYLIP","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2009,"finding":"IDOL (MYLIP) is an E3 ubiquitin ligase transcriptionally induced by LXR that triggers ubiquitination of the LDLR on its cytoplasmic domain, targeting it for degradation, thereby suppressing LDL uptake. LXR ligand reduces LDLR protein levels in vivo; Idol knockdown increases LDLR protein and promotes LDL uptake; adenoviral Idol expression in mouse liver promotes LDLR degradation and elevates plasma LDL levels.","method":"Co-IP/ubiquitination assay, siRNA knockdown, adenoviral overexpression in vivo, LXR knockout mice","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (ubiquitination assays, KD, KO, in vivo overexpression) in a single highly-cited foundational paper","pmids":["19520913"],"is_preprint":false},{"year":2010,"finding":"IDOL also targets VLDLR and ApoER2 (in addition to LDLR), triggering ubiquitination of their cytoplasmic tails and lysosomal degradation. LXR activation in mice increases Idol expression and decreases Vldlr levels in vivo. IDOL-dependent reduction of VLDLR decreases Reelin binding and Dab1 phosphorylation, linking LXR-IDOL to Reelin signaling.","method":"Ubiquitination assays, siRNA knockdown, LXR agonist treatment in vivo, Dab1 phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro ubiquitination, in vivo pharmacological activation, functional signaling readout; strong mechanistic follow-up paper","pmids":["20427281"],"is_preprint":false},{"year":2011,"finding":"IDOL contains conserved FERM and RING domains both required for LDLR degradation. The RING domain promotes ubiquitination in vitro and Lys-63-specific LDLR ubiquitination in vivo. The FERM domain binds the LDLR and co-localizes with it at the plasma membrane; a phosphotyrosine-binding element in the FERM domain and residues in the LDLR preceding the NPVY endocytosis motif are critical for degradation.","method":"In vitro ubiquitination assay, domain mutagenesis, fluorescence co-localization, homology modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis plus cellular imaging; multiple orthogonal methods","pmids":["21734303"],"is_preprint":false},{"year":2011,"finding":"IDOL forms a complex with the E2 ubiquitin-conjugating enzyme UBE2D family (UBE2D1-4). NMR chemical shift mapping and a 2.1 Å crystal structure of the IDOL RING domain–UBE2D1 complex revealed the structural basis for E2 selectivity. Mutations disrupting IDOL dimerization or IDOL–UBE2D interaction block IDOL-dependent LDLR ubiquitination and degradation; dominant-negative UBE2D inhibits IDOL-mediated LDLR degradation in cells.","method":"Cell-free ubiquitination assay, NMR chemical shift mapping, X-ray crystallography (2.1 Å), structure-guided mutagenesis, dominant-negative expression","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — crystal structure + NMR + mutagenesis + in vitro reconstitution in a single study","pmids":["21685362"],"is_preprint":false},{"year":2011,"finding":"The MYLIP N342S polymorphism (rs9370867) is associated with high total cholesterol in a Mexican population. Functional characterization showed that the Asn-encoding allele supports more potent LDLR degradation and decreased LDL uptake; mutagenesis of residue 342 does not affect intrinsic E3 ligase activity but is critical for LDLR targeting.","method":"Population genetics fine-mapping, cell-based LDLR degradation assay, site-directed mutagenesis, LDL uptake assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — human genetics combined with functional mutagenesis and cellular assays","pmids":["21765216"],"is_preprint":false},{"year":2012,"finding":"FGF21 reduces MYLIP/IDOL at the RNA and protein level and increases LDLR levels and stability. FGF21 also enhances expression of Canopy2/Msap, which interacts with MYLIP/IDOL. Cnpy2/Msap knockdown abolishes the FGF21 effect on LDLR levels, and FGF21 increases LDL particle uptake additively with statins.","method":"siRNA knockdown, Western blot, DiI-LDL uptake assay, overexpression in hepatocyte and macrophage cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in single lab study; identifies novel regulatory input to MYLIP/IDOL","pmids":["22378787"],"is_preprint":false},{"year":2013,"finding":"IDOL stimulates clathrin-independent, caveolae-independent endocytosis of the LDLR. IDOL is recruited to the plasma membrane by LDLR and facilitates LDLR entry into the multivesicular body (MVB)/ESCRT pathway for lysosomal degradation. siRNA knockdown of ESCRT-0 (HGS) or ESCRT-I (TSG101) prevents IDOL-mediated LDLR degradation. USP8 deubiquitinates LDLR downstream of IDOL and is required for LDLR entry into the MVB pathway.","method":"Real-time single-particle tracking, electron microscopy, siRNA knockdown of ESCRT components, live-cell imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — single-particle tracking + EM + genetic knockdown of pathway components; multiple orthogonal methods","pmids":["23382078"],"is_preprint":false},{"year":2013,"finding":"IDOL-dependent LDLR internalization is clathrin-, caveolin-, macroautophagy-, and dynamin-independent, targeting a LDLR pool in lipid rafts. It depends on the endocytic protein epsin, and degradation can be blocked by perturbation of ESCRT or by USP8.","method":"Pharmacological and genetic inhibition of endocytic pathways, lipid raft fractionation, LDL uptake assay","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological dissection of endocytic pathway; replicated findings from companion paper","pmids":["23733886"],"is_preprint":false},{"year":2013,"finding":"Reelin decreases VLDLR levels in hippocampal neurons via upregulation of the E3 ligase Mylip/IDOL; shRNA knockdown of Mylip/IDOL abrogates the Reelin-induced decrease in VLDLRs. BDNF increases VLDLR levels by increasing gene expression, acting through a transcriptional mechanism.","method":"shRNA knockdown, Western blot, primary hippocampal neuron culture","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific cellular readout in primary neurons, single lab","pmids":["23990472"],"is_preprint":false},{"year":2014,"finding":"The LXR-IDOL axis is tissue- and species-specific. In mice, LXR agonist induces Idol in peripheral tissues but not liver, and does not raise plasma LDL; Idol-deficient mice have elevated LDLR in peripheral but not hepatic tissues. In cynomolgus monkeys, LXR activation induces hepatic IDOL, reduces hepatic LDLR protein, and raises plasma LDL; antisense oligonucleotide knockdown of IDOL in monkeys blunts LXR-induced LDL elevation.","method":"Idol knockout mice, antisense oligonucleotide knockdown in nonhuman primates, plasma lipid measurement, tissue LDLR protein quantification","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — KO mouse + primate ASO knockdown with in vivo lipid readout; replicated across two species","pmids":["25440061"],"is_preprint":false},{"year":2014,"finding":"Liver-specific expression of a degradation-resistant, dominant-active IDOL (sIDOL) in mice dramatically reduces hepatic LDLR protein, elevates plasma LDL cholesterol on chow and Western diet, and causes marked atherosclerotic lesion formation, demonstrating that increased hepatic IDOL activity is sufficient to cause hypercholesterolemia and atherosclerosis.","method":"Albumin-promoter transgenic mice, Western diet feeding, atherosclerosis lesion quantification, plasma lipid measurement","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo transgenic model with quantitative disease endpoints","pmids":["24935961"],"is_preprint":false},{"year":2015,"finding":"USP2 (both isoforms USP2-69 and USP2-45) interacts with IDOL, promotes its deubiquitylation in an activity-dependent manner, and paradoxically stabilizes IDOL while attenuating IDOL-mediated LDLR degradation. A tripartite IDOL–USP2–LDLR complex was identified in which USP2 deubiquitylates LDLR and prevents its degradation. Loss of USP2 reduces LDLR in an IDOL-dependent manner.","method":"Genetic screen, reciprocal Co-IP, deubiquitylation assay, siRNA knockdown, LDL uptake assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 — enzymatic activity assay + reciprocal Co-IP + genetic KD with functional readout; identification of tripartite complex","pmids":["26666640"],"is_preprint":false},{"year":2015,"finding":"MARCH6 indirectly regulates LDLR levels by inducing IDOL expression. Loss of MARCH6 increases SREBP-regulated gene expression but decreases cellular lipoprotein uptake due to enhanced lysosomal LDLR degradation driven by IDOL induction.","method":"Genetic knockdown/knockout, SREBP reporter, LDLR protein measurement, LDL uptake assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic approach with mechanistic follow-up identifying IDOL as mediator, single lab","pmids":["26527619"],"is_preprint":false},{"year":2015,"finding":"DUB inhibition transcriptionally induces IDOL expression through an LXR-independent mechanism mediated by a 70-bp proximal promoter region distinct from the LXR-responsive element, leading to LDLR ubiquitylation and lysosomal degradation.","method":"Pharmacological DUB inhibition, promoter deletion analysis, Lxrαβ−/− MEFs, LDLR protein/mRNA measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — promoter mapping + genetic (Lxrαβ KO) validation; identifies novel regulatory mechanism","pmids":["26719329"],"is_preprint":false},{"year":2017,"finding":"IDOL determines synaptic ApoER2 protein levels in response to neuronal activation and regulates dendritic spine morphogenesis and plasticity. Loss of IDOL in neurons causes constitutive ApoER2 overexpression, impairs activity-dependent structural remodeling of spines, and produces defective LTP. IDOL-deficient mice show impaired experience-dependent reorganization of barrel cortex synaptic circuits and diminished spatial and associative learning.","method":"Neuronal IDOL knockout, LTP recording in hippocampal slices, dendritic spine imaging, barrel cortex mapping, behavioral learning assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with electrophysiological, structural, and behavioral readouts; multiple orthogonal methods","pmids":["28891791"],"is_preprint":false},{"year":2018,"finding":"Deletion of Idol in mice protects from diet-induced obesity and metabolic dysfunction, reducing circulating cholesterol, triglycerides, glucose, and insulin. Idol-KO mice show protection from weight gain, reduced hepatosteatosis, increased UCP1/TH in brown adipose tissue, and increased locomotion and lipoprotein particle clearance.","method":"Idol knockout mice, Western diet feeding, indirect calorimetry, tissue gene expression, in vivo lipoprotein clearance","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO model with multiple metabolic readouts; identifies broader metabolic role","pmids":["29903737"],"is_preprint":false},{"year":2019,"finding":"IDOL controls systemic energy balance through regulation of VLDLR (not LDLR) abundance in neurons, not in peripheral metabolic tissues. Tissue-specific knockout analysis showed that neuronal IDOL deletion alters hypothalamic gene expression linked to metabolic control. VLDLR is identified as the primary mediator of IDOL effects on food intake, thermogenesis, and diet-induced obesity.","method":"Tissue-specific (neuron, liver, adipose, endothelium, intestine, skeletal muscle) conditional KO mice, single-cell RNA sequencing of hypothalamus, metabolic phenotyping","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — systematic tissue-specific KO combined with scRNA-seq; identifies neuronal VLDLR as key substrate","pmids":["32072135"],"is_preprint":false},{"year":2020,"finding":"IDOL is SUMOylated at least at K293 by SUMO1. SUMOylation counteracts IDOL autoubiquitination at K293, stabilizing IDOL protein and increasing its levels. SENP1 reverses SUMOylation of IDOL in an activity-dependent manner, thereby decreasing IDOL levels, increasing LDLR protein, and enhancing LDL uptake. Loss of SENP1 lowers LDLR in an IDOL-dependent manner.","method":"SUMOylation assay, site-directed mutagenesis (K293), SENP1 overexpression and siRNA knockdown, LDLR protein measurement, LDL endocytosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical SUMOylation assay + mutagenesis + genetic KD with functional readout; identifies novel PTM","pmids":["33154164"],"is_preprint":false},{"year":2010,"finding":"Statin treatment rapidly and dose-dependently decreases Idol mRNA in human hepatoma cells and primary hepatocytes, in contrast to its induction of PCSK9. Idol siRNA transfection increases basal LDLR protein by ~60% in HepG2 cells, and the statin-induced increase in LDLR is partially dependent on Idol suppression.","method":"siRNA knockdown, qRT-PCR, Western blot in hepatocyte cell lines and primary hepatocytes","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA epistasis with pharmacological treatment; single lab, two orthogonal readouts","pmids":["21069265"],"is_preprint":false},{"year":2012,"finding":"LXR agonist treatment of HCV-infected Huh7.5.1 cells inhibits HCV infection in a dose-dependent manner; exogenous expression of Idol confers resistance to HCV infection. This defines an LXR-IDOL-LDLR pathway relevant to HCV entry, as LDLR is required for HCV particle entry.","method":"Adenoviral IDOL overexpression, LXR agonist treatment, HCV infection assay in Huh7.5.1 cells","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with viral infection readout; single lab, mechanistic link to LDLR","pmids":["22713431"],"is_preprint":false},{"year":2020,"finding":"miR-224 and miR-520d directly repress IDOL (as well as PCSK9 and HMGCR) through their 3'-UTR response elements. Overexpression of miR-224 or miR-520d in hepatocytes reduces IDOL mRNA and protein, leading to increased LDLR protein and cell-surface expression and enhanced LDL binding. In vivo delivery of miR-224 to Ldlr+/- mice decreases plasma LDL cholesterol by 15%.","method":"3'-UTR luciferase reporter assays with response element mutagenesis, gain/loss-of-function in hepatocytes, in vivo lipid nanoparticle delivery in mice","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay with mutagenesis + in vivo delivery; identifies miRNA-mediated post-transcriptional regulation of IDOL","pmids":["32528976"],"is_preprint":false},{"year":2020,"finding":"Platycodin D reduces IDOL mRNA, decreasing IDOL-mediated LDLR ubiquitination, increasing LDLR protein half-life (cycloheximide chase), and enhancing LDL-C uptake in HepG2 cells; effects are synergistic with simvastatin.","method":"Cycloheximide chase assay, in vivo ubiquitination assay, LDL-C uptake assay, qRT-PCR","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical assays demonstrating IDOL-mediated mechanism; single lab","pmids":["33199761"],"is_preprint":false},{"year":2017,"finding":"miR-19b directly downregulates MYLIP through its 3'-UTR, promoting breast cancer cell migration and metastasis. Overexpression of miR-19b or inhibition of MYLIP facilitates migration/invasion; MYLIP suppression by miR-19b alters cell adhesion molecule expression (E-Cadherin down, ICAM-1 and Integrin β1 up) and activates Ras-MAPK and PI3K-AKT pathways in vitro and in vivo.","method":"3'-UTR luciferase reporter assay, wound healing and transwell invasion assay, mouse tumor growth model, Western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — reporter assay confirms direct targeting; in vivo tumor model; links MYLIP to cytoskeletal/adhesion function; single lab","pmids":["28969074"],"is_preprint":false},{"year":2020,"finding":"LncRNA TUSC8 functions as a competing endogenous RNA (ceRNA) sponging miR-190b-5p, thereby preventing miR-190b-5p from suppressing MYLIP expression. TUSC8 knockdown promotes breast cancer proliferation, migration, and invasion in vitro and in vivo, at least partly through reducing MYLIP levels and modulating EMT markers.","method":"Luciferase reporter assay, RIP assay, RNA pull-down, siRNA knockdown, mouse xenograft model","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple RNA interaction methods; in vivo model; single lab","pmids":["32039833"],"is_preprint":false}],"current_model":"MYLIP (IDOL) is an LXR-transcriptionally regulated E3 ubiquitin ligase that, together with its obligate E2 partner UBE2D, ubiquitinates the cytoplasmic tails of LDLR, VLDLR, and ApoER2 via its FERM (receptor-binding) and RING (catalytic) domains, routing these receptors through a clathrin-independent, epsin/ESCRT-dependent pathway for lysosomal degradation; IDOL activity is modulated post-translationally by SUMOylation (stabilizing) and deubiquitylation by USP2 (paradoxically reducing LDLR degradation), and in neurons it governs ApoER2/VLDLR abundance to control synaptic plasticity and, via hypothalamic VLDLR, systemic energy balance."},"narrative":{"teleology":[{"year":2009,"claim":"Identification of MYLIP/IDOL as an LXR-inducible E3 ligase that ubiquitinates LDLR and promotes its degradation established the first sterol-regulated, post-translational pathway for LDLR turnover independent of PCSK9.","evidence":"Co-IP/ubiquitination assays, siRNA, adenoviral overexpression in mouse liver, LXR-knockout mice","pmids":["19520913"],"confidence":"High","gaps":["Catalytic domain requirements and E2 partner not yet defined","Substrate specificity beyond LDLR unknown","Endocytic route not characterized"]},{"year":2010,"claim":"Extension of IDOL substrate scope to VLDLR and ApoER2 linked the LXR-IDOL axis to Reelin signaling and revealed IDOL as a general regulator of the LDLR family, while statin treatment was shown to suppress IDOL transcription, adding a pharmacological dimension.","evidence":"Ubiquitination assays, LXR agonist in vivo, Dab1 phosphorylation readout; qRT-PCR and siRNA in hepatocytes","pmids":["20427281","21069265"],"confidence":"High","gaps":["Domain architecture mediating receptor recognition unresolved","Whether Reelin signaling feeds back on IDOL unknown"]},{"year":2011,"claim":"Structural and biochemical dissection of IDOL's FERM and RING domains, identification of UBE2D as the obligate E2 partner (crystal structure at 2.1 Å), and demonstration that RING-mediated dimerization is required for activity defined the minimal catalytic mechanism.","evidence":"X-ray crystallography, NMR, in vitro ubiquitination, domain mutagenesis, fluorescence co-localization","pmids":["21734303","21685362"],"confidence":"High","gaps":["Full-length IDOL structure unavailable","Whether other E2s can substitute in vivo untested","Structural basis of FERM–receptor interaction not resolved at atomic level"]},{"year":2011,"claim":"The MYLIP N342S coding polymorphism was linked to total cholesterol variation in humans and shown to alter LDLR targeting efficiency without affecting intrinsic E3 activity, providing the first human genetic evidence that IDOL variation affects lipid metabolism.","evidence":"Population genetic fine-mapping in Mexican cohort, cell-based LDLR degradation and LDL uptake assays with site-directed mutagenesis","pmids":["21765216"],"confidence":"High","gaps":["Structural mechanism by which N342S alters receptor targeting unclear","Replication in diverse populations incomplete at that time"]},{"year":2013,"claim":"Elucidation of the IDOL-triggered endocytic itinerary showed that LDLR is internalized via a clathrin-, caveolin-, and dynamin-independent route that depends on epsin and the ESCRT machinery, with USP8 acting as a downstream deubiquitinase required for MVB sorting.","evidence":"Single-particle tracking, electron microscopy, siRNA of ESCRT-0/I components and epsin, lipid raft fractionation","pmids":["23382078","23733886"],"confidence":"High","gaps":["Identity of the cargo adaptor linking ubiquitinated LDLR to epsin not defined","Whether the same route applies to VLDLR/ApoER2 not tested"]},{"year":2013,"claim":"Reelin was found to upregulate IDOL in hippocampal neurons to decrease VLDLR, establishing a neuronal activity–IDOL feedback loop that modulates Reelin receptor availability.","evidence":"shRNA knockdown of IDOL in primary hippocampal neurons, Western blot for VLDLR","pmids":["23990472"],"confidence":"Medium","gaps":["Signaling pathway from Reelin to IDOL transcription not mapped","Whether LXR mediates this induction in neurons unresolved","Single-lab finding"]},{"year":2014,"claim":"Species- and tissue-specificity of the LXR–IDOL axis was resolved: in mice IDOL operates peripherally but not in liver, whereas in primates hepatic IDOL is LXR-responsive and its knockdown prevents LXR-driven LDL elevation, clarifying why murine models underestimate IDOL's role in cholesterol homeostasis.","evidence":"Idol-KO mice, antisense oligonucleotide knockdown in cynomolgus monkeys, plasma lipid profiling","pmids":["25440061"],"confidence":"High","gaps":["Molecular basis for species-specific hepatic LXR–IDOL regulation unknown","Whether IDOL ASO is therapeutically viable long-term not assessed"]},{"year":2014,"claim":"Gain-of-function expression of a stabilized IDOL in mouse liver was sufficient to cause hypercholesterolemia and atherosclerosis, establishing IDOL as a causal driver of cardiovascular disease when overactive.","evidence":"Albumin-promoter transgenic mice, Western diet, atherosclerotic lesion quantification","pmids":["24935961"],"confidence":"High","gaps":["Whether endogenous IDOL levels ever reach pathological thresholds in humans unclear","Contribution of non-LDLR substrates to atherosclerosis phenotype not dissected"]},{"year":2015,"claim":"Discovery of USP2 as a deubiquitinase that forms a tripartite complex with IDOL and LDLR revealed a paradoxical regulatory circuit: USP2 stabilizes IDOL yet attenuates LDLR degradation by deubiquitinating LDLR directly.","evidence":"Genetic screen, reciprocal Co-IP, in vitro deubiquitylation, siRNA, LDL uptake assay","pmids":["26666640"],"confidence":"High","gaps":["In vivo relevance in animal models not demonstrated","Whether USP2 competes with USP8 at the ESCRT step unknown"]},{"year":2017,"claim":"IDOL was shown to be essential for activity-dependent regulation of synaptic ApoER2, dendritic spine remodeling, LTP, and experience-dependent cortical plasticity, establishing a non-metabolic, neuronal function.","evidence":"Neuronal conditional KO mice, hippocampal slice LTP, spine imaging, barrel cortex mapping, behavioral learning assays","pmids":["28891791"],"confidence":"High","gaps":["Whether LDLR or VLDLR also contributes to the synaptic phenotype not fully excluded","Upstream signals regulating neuronal IDOL during plasticity not identified"]},{"year":2019,"claim":"Systematic tissue-specific knockout and scRNA-seq identified neuronal VLDLR (not hepatic LDLR) as the primary IDOL substrate governing systemic energy balance, linking hypothalamic IDOL to food intake, thermogenesis, and diet-induced obesity.","evidence":"Conditional KO in six tissue compartments, hypothalamic single-cell RNA-seq, metabolic phenotyping","pmids":["32072135"],"confidence":"High","gaps":["Specific hypothalamic neuronal subtype(s) mediating the effect not pinpointed","Whether ApoER2 contributes to hypothalamic energy regulation via IDOL untested"]},{"year":2020,"claim":"SUMOylation at K293 was identified as a stabilizing post-translational modification of IDOL that antagonizes autoubiquitination; SENP1-mediated deSUMOylation destabilizes IDOL and consequently increases LDLR, adding a SUMO-dependent regulatory layer.","evidence":"SUMOylation assay, K293 mutagenesis, SENP1 overexpression/knockdown, LDLR and LDL uptake measurement","pmids":["33154164"],"confidence":"High","gaps":["Physiological signals controlling IDOL SUMOylation unknown","Whether other SUMO sites exist not exhaustively mapped","Interplay between SUMOylation and USP2-mediated regulation unexplored"]},{"year":null,"claim":"Key unresolved questions include the full-length atomic structure of IDOL, the structural basis of FERM domain–receptor selectivity, the signaling pathways that regulate neuronal IDOL during synaptic plasticity, and whether therapeutic IDOL inhibition can safely lower LDL cholesterol in primates without perturbing neuronal or metabolic functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length IDOL structure","No selective small-molecule IDOL inhibitor reported","Crosstalk between SUMO, USP2, and epsin/ESCRT pathways not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,11,17]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,3,6,7,11,17]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,9,10,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,8,14,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["UBE2D1","USP2","LDLR","VLDLR","LRP8","USP8","SENP1"],"other_free_text":[]},"mechanistic_narrative":"MYLIP (also called IDOL) is an E3 ubiquitin ligase that controls the abundance of LDL receptor family members at the plasma membrane, thereby regulating cholesterol uptake, Reelin signaling, and systemic energy balance. Transcriptionally induced by LXR, MYLIP binds LDLR, VLDLR, and ApoER2 through its FERM domain and catalyzes Lys-63-linked ubiquitination of their cytoplasmic tails via its RING domain in partnership with the E2 enzyme UBE2D, routing these receptors through an epsin- and ESCRT-dependent, clathrin-independent pathway to lysosomes for degradation [PMID:19520913, PMID:20427281, PMID:21734303, PMID:21685362, PMID:23382078]. MYLIP protein stability is enhanced by SUMO1 conjugation at K293, which antagonizes autoubiquitination, while the deubiquitinase USP2 forms a tripartite complex with MYLIP and LDLR to deubiquitinate LDLR and restrain its degradation [PMID:33154164, PMID:26666640]. In neurons, MYLIP-dependent turnover of ApoER2 and VLDLR governs dendritic spine plasticity, long-term potentiation, and experience-dependent circuit remodeling, and hypothalamic MYLIP control of VLDLR abundance regulates food intake, thermogenesis, and susceptibility to diet-induced obesity [PMID:28891791, PMID:32072135]."},"prefetch_data":{"uniprot":{"accession":"Q8WY64","full_name":"E3 ubiquitin-protein ligase MYLIP","aliases":["Inducible degrader of the LDL-receptor","Idol","Myosin regulatory light chain interacting protein","MIR","RING-type E3 ubiquitin transferase MYLIP"],"length_aa":445,"mass_kda":49.9,"function":"E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8WY64/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYLIP","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYLIP","total_profiled":1310},"omim":[{"mim_id":"621515","title":"UBIQUITIN-CONJUGATING ENZYME E2 D4; UBE2D4","url":"https://www.omim.org/entry/621515"},{"mim_id":"610082","title":"MYOSIN REGULATORY LIGHT CHAIN-INTERACTING PROTEIN; MYLIP","url":"https://www.omim.org/entry/610082"},{"mim_id":"607017","title":"DEAFNESS, AUTOSOMAL DOMINANT 21; DFNA21","url":"https://www.omim.org/entry/607017"},{"mim_id":"606945","title":"LOW DENSITY LIPOPROTEIN RECEPTOR; LDLR","url":"https://www.omim.org/entry/606945"},{"mim_id":"605861","title":"CANOPY FGF SIGNALING REGULATOR 2; CNPY2","url":"https://www.omim.org/entry/605861"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32528976","citation_count":24,"is_preprint":false},{"pmid":"26990535","id":"PMC_26990535","title":"miR-203 and miR-221 regulate SOCS1 and SOCS3 in essential thrombocythemia.","date":"2016","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/26990535","citation_count":24,"is_preprint":false},{"pmid":"26997445","id":"PMC_26997445","title":"miR-31 and miR-17-5p levels change during transformation of follicular lymphoma.","date":"2015","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26997445","citation_count":22,"is_preprint":false},{"pmid":"33015156","id":"PMC_33015156","title":"miR-9, miR-21, miR-27b, and miR-34a Expression in HPV16/58/52-Infected Cervical Cancer.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/33015156","citation_count":22,"is_preprint":false},{"pmid":"24710937","id":"PMC_24710937","title":"Expressions of miR-22 and miR-135a in acute pancreatitis.","date":"2014","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/24710937","citation_count":21,"is_preprint":false},{"pmid":"26719329","id":"PMC_26719329","title":"Deubiquitylase Inhibition Reveals Liver X Receptor-independent Transcriptional Regulation of the E3 Ubiquitin Ligase IDOL and Lipoprotein Uptake.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26719329","citation_count":21,"is_preprint":false},{"pmid":"24014303","id":"PMC_24014303","title":"miR deregulation in CLL.","date":"2013","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/24014303","citation_count":21,"is_preprint":false},{"pmid":"35876890","id":"PMC_35876890","title":"APE1 controls DICER1 expression in NSCLC through miR-33a and miR-130b.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35876890","citation_count":21,"is_preprint":false},{"pmid":"32072135","id":"PMC_32072135","title":"IDOL regulates systemic energy balance through control of neuronal VLDLR expression.","date":"2019","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32072135","citation_count":20,"is_preprint":false},{"pmid":"33990872","id":"PMC_33990872","title":"Upregulation of miR-3195, miR-3687 and miR-4417 is associated with castration-resistant prostate cancer.","date":"2021","source":"World journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/33990872","citation_count":20,"is_preprint":false},{"pmid":"33154164","id":"PMC_33154164","title":"SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33154164","citation_count":19,"is_preprint":false},{"pmid":"23990472","id":"PMC_23990472","title":"Reciprocal regulation of very low density lipoprotein receptors (VLDLRs) in neurons by brain-derived neurotrophic factor (BDNF) and Reelin: involvement of the E3 ligase Mylip/Idol.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23990472","citation_count":19,"is_preprint":false},{"pmid":"35252180","id":"PMC_35252180","title":"miR-1269a and miR-1269b: Emerging Carcinogenic Genes of the miR-1269 Family.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35252180","citation_count":19,"is_preprint":false},{"pmid":"27630665","id":"PMC_27630665","title":"Post-transcriptional Regulation of BRCA2 through Interactions with miR-19a and miR-19b.","date":"2016","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27630665","citation_count":19,"is_preprint":false},{"pmid":"30234146","id":"PMC_30234146","title":"Biological role of miR-204 and miR-211 in melanoma.","date":"2018","source":"Oncoscience","url":"https://pubmed.ncbi.nlm.nih.gov/30234146","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51555,"output_tokens":5964,"usd":0.122063},"stage2":{"model":"claude-opus-4-6","input_tokens":9566,"output_tokens":3227,"usd":0.192757},"total_usd":0.31482,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"IDOL (MYLIP) is an E3 ubiquitin ligase transcriptionally induced by LXR that triggers ubiquitination of the LDLR on its cytoplasmic domain, targeting it for degradation, thereby suppressing LDL uptake. LXR ligand reduces LDLR protein levels in vivo; Idol knockdown increases LDLR protein and promotes LDL uptake; adenoviral Idol expression in mouse liver promotes LDLR degradation and elevates plasma LDL levels.\",\n      \"method\": \"Co-IP/ubiquitination assay, siRNA knockdown, adenoviral overexpression in vivo, LXR knockout mice\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (ubiquitination assays, KD, KO, in vivo overexpression) in a single highly-cited foundational paper\",\n      \"pmids\": [\"19520913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IDOL also targets VLDLR and ApoER2 (in addition to LDLR), triggering ubiquitination of their cytoplasmic tails and lysosomal degradation. LXR activation in mice increases Idol expression and decreases Vldlr levels in vivo. IDOL-dependent reduction of VLDLR decreases Reelin binding and Dab1 phosphorylation, linking LXR-IDOL to Reelin signaling.\",\n      \"method\": \"Ubiquitination assays, siRNA knockdown, LXR agonist treatment in vivo, Dab1 phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro ubiquitination, in vivo pharmacological activation, functional signaling readout; strong mechanistic follow-up paper\",\n      \"pmids\": [\"20427281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IDOL contains conserved FERM and RING domains both required for LDLR degradation. The RING domain promotes ubiquitination in vitro and Lys-63-specific LDLR ubiquitination in vivo. The FERM domain binds the LDLR and co-localizes with it at the plasma membrane; a phosphotyrosine-binding element in the FERM domain and residues in the LDLR preceding the NPVY endocytosis motif are critical for degradation.\",\n      \"method\": \"In vitro ubiquitination assay, domain mutagenesis, fluorescence co-localization, homology modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis plus cellular imaging; multiple orthogonal methods\",\n      \"pmids\": [\"21734303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IDOL forms a complex with the E2 ubiquitin-conjugating enzyme UBE2D family (UBE2D1-4). NMR chemical shift mapping and a 2.1 Å crystal structure of the IDOL RING domain–UBE2D1 complex revealed the structural basis for E2 selectivity. Mutations disrupting IDOL dimerization or IDOL–UBE2D interaction block IDOL-dependent LDLR ubiquitination and degradation; dominant-negative UBE2D inhibits IDOL-mediated LDLR degradation in cells.\",\n      \"method\": \"Cell-free ubiquitination assay, NMR chemical shift mapping, X-ray crystallography (2.1 Å), structure-guided mutagenesis, dominant-negative expression\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + NMR + mutagenesis + in vitro reconstitution in a single study\",\n      \"pmids\": [\"21685362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The MYLIP N342S polymorphism (rs9370867) is associated with high total cholesterol in a Mexican population. Functional characterization showed that the Asn-encoding allele supports more potent LDLR degradation and decreased LDL uptake; mutagenesis of residue 342 does not affect intrinsic E3 ligase activity but is critical for LDLR targeting.\",\n      \"method\": \"Population genetics fine-mapping, cell-based LDLR degradation assay, site-directed mutagenesis, LDL uptake assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetics combined with functional mutagenesis and cellular assays\",\n      \"pmids\": [\"21765216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FGF21 reduces MYLIP/IDOL at the RNA and protein level and increases LDLR levels and stability. FGF21 also enhances expression of Canopy2/Msap, which interacts with MYLIP/IDOL. Cnpy2/Msap knockdown abolishes the FGF21 effect on LDLR levels, and FGF21 increases LDL particle uptake additively with statins.\",\n      \"method\": \"siRNA knockdown, Western blot, DiI-LDL uptake assay, overexpression in hepatocyte and macrophage cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in single lab study; identifies novel regulatory input to MYLIP/IDOL\",\n      \"pmids\": [\"22378787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IDOL stimulates clathrin-independent, caveolae-independent endocytosis of the LDLR. IDOL is recruited to the plasma membrane by LDLR and facilitates LDLR entry into the multivesicular body (MVB)/ESCRT pathway for lysosomal degradation. siRNA knockdown of ESCRT-0 (HGS) or ESCRT-I (TSG101) prevents IDOL-mediated LDLR degradation. USP8 deubiquitinates LDLR downstream of IDOL and is required for LDLR entry into the MVB pathway.\",\n      \"method\": \"Real-time single-particle tracking, electron microscopy, siRNA knockdown of ESCRT components, live-cell imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — single-particle tracking + EM + genetic knockdown of pathway components; multiple orthogonal methods\",\n      \"pmids\": [\"23382078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IDOL-dependent LDLR internalization is clathrin-, caveolin-, macroautophagy-, and dynamin-independent, targeting a LDLR pool in lipid rafts. It depends on the endocytic protein epsin, and degradation can be blocked by perturbation of ESCRT or by USP8.\",\n      \"method\": \"Pharmacological and genetic inhibition of endocytic pathways, lipid raft fractionation, LDL uptake assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological dissection of endocytic pathway; replicated findings from companion paper\",\n      \"pmids\": [\"23733886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Reelin decreases VLDLR levels in hippocampal neurons via upregulation of the E3 ligase Mylip/IDOL; shRNA knockdown of Mylip/IDOL abrogates the Reelin-induced decrease in VLDLRs. BDNF increases VLDLR levels by increasing gene expression, acting through a transcriptional mechanism.\",\n      \"method\": \"shRNA knockdown, Western blot, primary hippocampal neuron culture\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific cellular readout in primary neurons, single lab\",\n      \"pmids\": [\"23990472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The LXR-IDOL axis is tissue- and species-specific. In mice, LXR agonist induces Idol in peripheral tissues but not liver, and does not raise plasma LDL; Idol-deficient mice have elevated LDLR in peripheral but not hepatic tissues. In cynomolgus monkeys, LXR activation induces hepatic IDOL, reduces hepatic LDLR protein, and raises plasma LDL; antisense oligonucleotide knockdown of IDOL in monkeys blunts LXR-induced LDL elevation.\",\n      \"method\": \"Idol knockout mice, antisense oligonucleotide knockdown in nonhuman primates, plasma lipid measurement, tissue LDLR protein quantification\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse + primate ASO knockdown with in vivo lipid readout; replicated across two species\",\n      \"pmids\": [\"25440061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Liver-specific expression of a degradation-resistant, dominant-active IDOL (sIDOL) in mice dramatically reduces hepatic LDLR protein, elevates plasma LDL cholesterol on chow and Western diet, and causes marked atherosclerotic lesion formation, demonstrating that increased hepatic IDOL activity is sufficient to cause hypercholesterolemia and atherosclerosis.\",\n      \"method\": \"Albumin-promoter transgenic mice, Western diet feeding, atherosclerosis lesion quantification, plasma lipid measurement\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo transgenic model with quantitative disease endpoints\",\n      \"pmids\": [\"24935961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP2 (both isoforms USP2-69 and USP2-45) interacts with IDOL, promotes its deubiquitylation in an activity-dependent manner, and paradoxically stabilizes IDOL while attenuating IDOL-mediated LDLR degradation. A tripartite IDOL–USP2–LDLR complex was identified in which USP2 deubiquitylates LDLR and prevents its degradation. Loss of USP2 reduces LDLR in an IDOL-dependent manner.\",\n      \"method\": \"Genetic screen, reciprocal Co-IP, deubiquitylation assay, siRNA knockdown, LDL uptake assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — enzymatic activity assay + reciprocal Co-IP + genetic KD with functional readout; identification of tripartite complex\",\n      \"pmids\": [\"26666640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MARCH6 indirectly regulates LDLR levels by inducing IDOL expression. Loss of MARCH6 increases SREBP-regulated gene expression but decreases cellular lipoprotein uptake due to enhanced lysosomal LDLR degradation driven by IDOL induction.\",\n      \"method\": \"Genetic knockdown/knockout, SREBP reporter, LDLR protein measurement, LDL uptake assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic approach with mechanistic follow-up identifying IDOL as mediator, single lab\",\n      \"pmids\": [\"26527619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DUB inhibition transcriptionally induces IDOL expression through an LXR-independent mechanism mediated by a 70-bp proximal promoter region distinct from the LXR-responsive element, leading to LDLR ubiquitylation and lysosomal degradation.\",\n      \"method\": \"Pharmacological DUB inhibition, promoter deletion analysis, Lxrαβ−/− MEFs, LDLR protein/mRNA measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter mapping + genetic (Lxrαβ KO) validation; identifies novel regulatory mechanism\",\n      \"pmids\": [\"26719329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IDOL determines synaptic ApoER2 protein levels in response to neuronal activation and regulates dendritic spine morphogenesis and plasticity. Loss of IDOL in neurons causes constitutive ApoER2 overexpression, impairs activity-dependent structural remodeling of spines, and produces defective LTP. IDOL-deficient mice show impaired experience-dependent reorganization of barrel cortex synaptic circuits and diminished spatial and associative learning.\",\n      \"method\": \"Neuronal IDOL knockout, LTP recording in hippocampal slices, dendritic spine imaging, barrel cortex mapping, behavioral learning assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with electrophysiological, structural, and behavioral readouts; multiple orthogonal methods\",\n      \"pmids\": [\"28891791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Deletion of Idol in mice protects from diet-induced obesity and metabolic dysfunction, reducing circulating cholesterol, triglycerides, glucose, and insulin. Idol-KO mice show protection from weight gain, reduced hepatosteatosis, increased UCP1/TH in brown adipose tissue, and increased locomotion and lipoprotein particle clearance.\",\n      \"method\": \"Idol knockout mice, Western diet feeding, indirect calorimetry, tissue gene expression, in vivo lipoprotein clearance\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO model with multiple metabolic readouts; identifies broader metabolic role\",\n      \"pmids\": [\"29903737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IDOL controls systemic energy balance through regulation of VLDLR (not LDLR) abundance in neurons, not in peripheral metabolic tissues. Tissue-specific knockout analysis showed that neuronal IDOL deletion alters hypothalamic gene expression linked to metabolic control. VLDLR is identified as the primary mediator of IDOL effects on food intake, thermogenesis, and diet-induced obesity.\",\n      \"method\": \"Tissue-specific (neuron, liver, adipose, endothelium, intestine, skeletal muscle) conditional KO mice, single-cell RNA sequencing of hypothalamus, metabolic phenotyping\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic tissue-specific KO combined with scRNA-seq; identifies neuronal VLDLR as key substrate\",\n      \"pmids\": [\"32072135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IDOL is SUMOylated at least at K293 by SUMO1. SUMOylation counteracts IDOL autoubiquitination at K293, stabilizing IDOL protein and increasing its levels. SENP1 reverses SUMOylation of IDOL in an activity-dependent manner, thereby decreasing IDOL levels, increasing LDLR protein, and enhancing LDL uptake. Loss of SENP1 lowers LDLR in an IDOL-dependent manner.\",\n      \"method\": \"SUMOylation assay, site-directed mutagenesis (K293), SENP1 overexpression and siRNA knockdown, LDLR protein measurement, LDL endocytosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical SUMOylation assay + mutagenesis + genetic KD with functional readout; identifies novel PTM\",\n      \"pmids\": [\"33154164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Statin treatment rapidly and dose-dependently decreases Idol mRNA in human hepatoma cells and primary hepatocytes, in contrast to its induction of PCSK9. Idol siRNA transfection increases basal LDLR protein by ~60% in HepG2 cells, and the statin-induced increase in LDLR is partially dependent on Idol suppression.\",\n      \"method\": \"siRNA knockdown, qRT-PCR, Western blot in hepatocyte cell lines and primary hepatocytes\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA epistasis with pharmacological treatment; single lab, two orthogonal readouts\",\n      \"pmids\": [\"21069265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LXR agonist treatment of HCV-infected Huh7.5.1 cells inhibits HCV infection in a dose-dependent manner; exogenous expression of Idol confers resistance to HCV infection. This defines an LXR-IDOL-LDLR pathway relevant to HCV entry, as LDLR is required for HCV particle entry.\",\n      \"method\": \"Adenoviral IDOL overexpression, LXR agonist treatment, HCV infection assay in Huh7.5.1 cells\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with viral infection readout; single lab, mechanistic link to LDLR\",\n      \"pmids\": [\"22713431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-224 and miR-520d directly repress IDOL (as well as PCSK9 and HMGCR) through their 3'-UTR response elements. Overexpression of miR-224 or miR-520d in hepatocytes reduces IDOL mRNA and protein, leading to increased LDLR protein and cell-surface expression and enhanced LDL binding. In vivo delivery of miR-224 to Ldlr+/- mice decreases plasma LDL cholesterol by 15%.\",\n      \"method\": \"3'-UTR luciferase reporter assays with response element mutagenesis, gain/loss-of-function in hepatocytes, in vivo lipid nanoparticle delivery in mice\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay with mutagenesis + in vivo delivery; identifies miRNA-mediated post-transcriptional regulation of IDOL\",\n      \"pmids\": [\"32528976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Platycodin D reduces IDOL mRNA, decreasing IDOL-mediated LDLR ubiquitination, increasing LDLR protein half-life (cycloheximide chase), and enhancing LDL-C uptake in HepG2 cells; effects are synergistic with simvastatin.\",\n      \"method\": \"Cycloheximide chase assay, in vivo ubiquitination assay, LDL-C uptake assay, qRT-PCR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays demonstrating IDOL-mediated mechanism; single lab\",\n      \"pmids\": [\"33199761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-19b directly downregulates MYLIP through its 3'-UTR, promoting breast cancer cell migration and metastasis. Overexpression of miR-19b or inhibition of MYLIP facilitates migration/invasion; MYLIP suppression by miR-19b alters cell adhesion molecule expression (E-Cadherin down, ICAM-1 and Integrin β1 up) and activates Ras-MAPK and PI3K-AKT pathways in vitro and in vivo.\",\n      \"method\": \"3'-UTR luciferase reporter assay, wound healing and transwell invasion assay, mouse tumor growth model, Western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reporter assay confirms direct targeting; in vivo tumor model; links MYLIP to cytoskeletal/adhesion function; single lab\",\n      \"pmids\": [\"28969074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LncRNA TUSC8 functions as a competing endogenous RNA (ceRNA) sponging miR-190b-5p, thereby preventing miR-190b-5p from suppressing MYLIP expression. TUSC8 knockdown promotes breast cancer proliferation, migration, and invasion in vitro and in vivo, at least partly through reducing MYLIP levels and modulating EMT markers.\",\n      \"method\": \"Luciferase reporter assay, RIP assay, RNA pull-down, siRNA knockdown, mouse xenograft model\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple RNA interaction methods; in vivo model; single lab\",\n      \"pmids\": [\"32039833\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYLIP (IDOL) is an LXR-transcriptionally regulated E3 ubiquitin ligase that, together with its obligate E2 partner UBE2D, ubiquitinates the cytoplasmic tails of LDLR, VLDLR, and ApoER2 via its FERM (receptor-binding) and RING (catalytic) domains, routing these receptors through a clathrin-independent, epsin/ESCRT-dependent pathway for lysosomal degradation; IDOL activity is modulated post-translationally by SUMOylation (stabilizing) and deubiquitylation by USP2 (paradoxically reducing LDLR degradation), and in neurons it governs ApoER2/VLDLR abundance to control synaptic plasticity and, via hypothalamic VLDLR, systemic energy balance.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MYLIP (also called IDOL) is an E3 ubiquitin ligase that controls the abundance of LDL receptor family members at the plasma membrane, thereby regulating cholesterol uptake, Reelin signaling, and systemic energy balance. Transcriptionally induced by LXR, MYLIP binds LDLR, VLDLR, and ApoER2 through its FERM domain and catalyzes Lys-63-linked ubiquitination of their cytoplasmic tails via its RING domain in partnership with the E2 enzyme UBE2D, routing these receptors through an epsin- and ESCRT-dependent, clathrin-independent pathway to lysosomes for degradation [PMID:19520913, PMID:20427281, PMID:21734303, PMID:21685362, PMID:23382078]. MYLIP protein stability is enhanced by SUMO1 conjugation at K293, which antagonizes autoubiquitination, while the deubiquitinase USP2 forms a tripartite complex with MYLIP and LDLR to deubiquitinate LDLR and restrain its degradation [PMID:33154164, PMID:26666640]. In neurons, MYLIP-dependent turnover of ApoER2 and VLDLR governs dendritic spine plasticity, long-term potentiation, and experience-dependent circuit remodeling, and hypothalamic MYLIP control of VLDLR abundance regulates food intake, thermogenesis, and susceptibility to diet-induced obesity [PMID:28891791, PMID:32072135].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of MYLIP/IDOL as an LXR-inducible E3 ligase that ubiquitinates LDLR and promotes its degradation established the first sterol-regulated, post-translational pathway for LDLR turnover independent of PCSK9.\",\n      \"evidence\": \"Co-IP/ubiquitination assays, siRNA, adenoviral overexpression in mouse liver, LXR-knockout mice\",\n      \"pmids\": [\"19520913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic domain requirements and E2 partner not yet defined\", \"Substrate specificity beyond LDLR unknown\", \"Endocytic route not characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extension of IDOL substrate scope to VLDLR and ApoER2 linked the LXR-IDOL axis to Reelin signaling and revealed IDOL as a general regulator of the LDLR family, while statin treatment was shown to suppress IDOL transcription, adding a pharmacological dimension.\",\n      \"evidence\": \"Ubiquitination assays, LXR agonist in vivo, Dab1 phosphorylation readout; qRT-PCR and siRNA in hepatocytes\",\n      \"pmids\": [\"20427281\", \"21069265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain architecture mediating receptor recognition unresolved\", \"Whether Reelin signaling feeds back on IDOL unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Structural and biochemical dissection of IDOL's FERM and RING domains, identification of UBE2D as the obligate E2 partner (crystal structure at 2.1 Å), and demonstration that RING-mediated dimerization is required for activity defined the minimal catalytic mechanism.\",\n      \"evidence\": \"X-ray crystallography, NMR, in vitro ubiquitination, domain mutagenesis, fluorescence co-localization\",\n      \"pmids\": [\"21734303\", \"21685362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length IDOL structure unavailable\", \"Whether other E2s can substitute in vivo untested\", \"Structural basis of FERM–receptor interaction not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The MYLIP N342S coding polymorphism was linked to total cholesterol variation in humans and shown to alter LDLR targeting efficiency without affecting intrinsic E3 activity, providing the first human genetic evidence that IDOL variation affects lipid metabolism.\",\n      \"evidence\": \"Population genetic fine-mapping in Mexican cohort, cell-based LDLR degradation and LDL uptake assays with site-directed mutagenesis\",\n      \"pmids\": [\"21765216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which N342S alters receptor targeting unclear\", \"Replication in diverse populations incomplete at that time\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Elucidation of the IDOL-triggered endocytic itinerary showed that LDLR is internalized via a clathrin-, caveolin-, and dynamin-independent route that depends on epsin and the ESCRT machinery, with USP8 acting as a downstream deubiquitinase required for MVB sorting.\",\n      \"evidence\": \"Single-particle tracking, electron microscopy, siRNA of ESCRT-0/I components and epsin, lipid raft fractionation\",\n      \"pmids\": [\"23382078\", \"23733886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cargo adaptor linking ubiquitinated LDLR to epsin not defined\", \"Whether the same route applies to VLDLR/ApoER2 not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reelin was found to upregulate IDOL in hippocampal neurons to decrease VLDLR, establishing a neuronal activity–IDOL feedback loop that modulates Reelin receptor availability.\",\n      \"evidence\": \"shRNA knockdown of IDOL in primary hippocampal neurons, Western blot for VLDLR\",\n      \"pmids\": [\"23990472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway from Reelin to IDOL transcription not mapped\", \"Whether LXR mediates this induction in neurons unresolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Species- and tissue-specificity of the LXR–IDOL axis was resolved: in mice IDOL operates peripherally but not in liver, whereas in primates hepatic IDOL is LXR-responsive and its knockdown prevents LXR-driven LDL elevation, clarifying why murine models underestimate IDOL's role in cholesterol homeostasis.\",\n      \"evidence\": \"Idol-KO mice, antisense oligonucleotide knockdown in cynomolgus monkeys, plasma lipid profiling\",\n      \"pmids\": [\"25440061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for species-specific hepatic LXR–IDOL regulation unknown\", \"Whether IDOL ASO is therapeutically viable long-term not assessed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Gain-of-function expression of a stabilized IDOL in mouse liver was sufficient to cause hypercholesterolemia and atherosclerosis, establishing IDOL as a causal driver of cardiovascular disease when overactive.\",\n      \"evidence\": \"Albumin-promoter transgenic mice, Western diet, atherosclerotic lesion quantification\",\n      \"pmids\": [\"24935961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous IDOL levels ever reach pathological thresholds in humans unclear\", \"Contribution of non-LDLR substrates to atherosclerosis phenotype not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery of USP2 as a deubiquitinase that forms a tripartite complex with IDOL and LDLR revealed a paradoxical regulatory circuit: USP2 stabilizes IDOL yet attenuates LDLR degradation by deubiquitinating LDLR directly.\",\n      \"evidence\": \"Genetic screen, reciprocal Co-IP, in vitro deubiquitylation, siRNA, LDL uptake assay\",\n      \"pmids\": [\"26666640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance in animal models not demonstrated\", \"Whether USP2 competes with USP8 at the ESCRT step unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"IDOL was shown to be essential for activity-dependent regulation of synaptic ApoER2, dendritic spine remodeling, LTP, and experience-dependent cortical plasticity, establishing a non-metabolic, neuronal function.\",\n      \"evidence\": \"Neuronal conditional KO mice, hippocampal slice LTP, spine imaging, barrel cortex mapping, behavioral learning assays\",\n      \"pmids\": [\"28891791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LDLR or VLDLR also contributes to the synaptic phenotype not fully excluded\", \"Upstream signals regulating neuronal IDOL during plasticity not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Systematic tissue-specific knockout and scRNA-seq identified neuronal VLDLR (not hepatic LDLR) as the primary IDOL substrate governing systemic energy balance, linking hypothalamic IDOL to food intake, thermogenesis, and diet-induced obesity.\",\n      \"evidence\": \"Conditional KO in six tissue compartments, hypothalamic single-cell RNA-seq, metabolic phenotyping\",\n      \"pmids\": [\"32072135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific hypothalamic neuronal subtype(s) mediating the effect not pinpointed\", \"Whether ApoER2 contributes to hypothalamic energy regulation via IDOL untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"SUMOylation at K293 was identified as a stabilizing post-translational modification of IDOL that antagonizes autoubiquitination; SENP1-mediated deSUMOylation destabilizes IDOL and consequently increases LDLR, adding a SUMO-dependent regulatory layer.\",\n      \"evidence\": \"SUMOylation assay, K293 mutagenesis, SENP1 overexpression/knockdown, LDLR and LDL uptake measurement\",\n      \"pmids\": [\"33154164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals controlling IDOL SUMOylation unknown\", \"Whether other SUMO sites exist not exhaustively mapped\", \"Interplay between SUMOylation and USP2-mediated regulation unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full-length atomic structure of IDOL, the structural basis of FERM domain–receptor selectivity, the signaling pathways that regulate neuronal IDOL during synaptic plasticity, and whether therapeutic IDOL inhibition can safely lower LDL cholesterol in primates without perturbing neuronal or metabolic functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length IDOL structure\", \"No selective small-molecule IDOL inhibitor reported\", \"Crosstalk between SUMO, USP2, and epsin/ESCRT pathways not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 11, 17]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7, 11, 17]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 9, 10, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8, 14, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"UBE2D1\",\n      \"USP2\",\n      \"LDLR\",\n      \"VLDLR\",\n      \"LRP8\",\n      \"USP8\",\n      \"SENP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}