{"gene":"MYLIP","run_date":"2026-06-10T05:19:52","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 and thereby limiting LDL uptake. Knockdown of Idol in hepatocytes increases LDLR protein levels and LDL uptake; adenoviral overexpression in mouse liver promotes LDLR degradation and elevates plasma LDL levels.","method":"siRNA knockdown, adenoviral overexpression in mouse liver, ubiquitination assays, LXR knockout mice","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, OE, KO mice), replicated across in vitro and in vivo systems, founding mechanistic paper","pmids":["19520913"],"is_preprint":false},{"year":2010,"finding":"IDOL also targets VLDLR and ApoER2 (closely related LDLR family members) for ubiquitination on their cytoplasmic tails, leading to their lysosomal degradation. LXR activation in mice increases Idol expression and decreases Vldlr levels in vivo. IDOL-mediated VLDLR degradation reduces Reelin binding to VLDLR and decreases Dab1 phosphorylation.","method":"Ubiquitination assays, pharmacological LXR activation in mice, siRNA knockdown, Reelin binding assay, Dab1 phosphorylation measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods in a single study establishing substrate expansion and functional downstream consequence","pmids":["20427281"],"is_preprint":false},{"year":2011,"finding":"IDOL requires both its FERM and RING domains for LDLR degradation. The RING domain promotes ubiquitination in vitro and K63-specific ubiquitination of LDLR in vivo. The FERM domain interacts with 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 motif are required for LDLR degradation.","method":"In vitro ubiquitination assay, domain mutagenesis, homology modeling, co-localization imaging, cell-based LDLR degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination reconstitution combined with mutagenesis and cellular imaging; multiple orthogonal methods in one study","pmids":["21734303"],"is_preprint":false},{"year":2011,"finding":"The UBE2D family (UBE2D1-4) are the cognate E2 ubiquitin-conjugating enzymes for IDOL, supporting both IDOL autoubiquitination and IDOL-dependent ubiquitination of LDLR in a cell-free reconstitution system. Crystal structure of the IDOL RING domain–UBE2D1 complex at 2.1 Å revealed key interactions for E2 selectivity. Structure-based mutations that inhibit IDOL dimerization or IDOL–UBE2D interaction block LDLR ubiquitination and degradation; dominant-negative UBE2D inhibits IDOL-mediated LDLR degradation in cells.","method":"Cell-free reconstitution ubiquitination assay, 2.1 Å crystal structure, NMR chemical shift mapping, structure-based mutagenesis, dominant-negative expression in cells","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, in vitro reconstitution, mutagenesis, and cellular validation in one study","pmids":["21685362"],"is_preprint":false},{"year":2011,"finding":"Idol-null cells show markedly elevated LDLR protein and increased LDL uptake. Oxysterols and lipoprotein-containing serum fail to suppress LDLR levels in Idol-null cells. LXR ligands have no effect on LDLR levels in Idol-null cells, demonstrating that Idol is required for LXR-dependent inhibition of the LDLR pathway. The LDLR half-life is prolonged in the absence of Idol. PCSK9- and statin-mediated regulation of LDLR is independent of and additive with the LXR-Idol pathway.","method":"Gene-targeted Idol-null mouse embryonic stem cells, LDL uptake assay, cycloheximide chase (LDLR half-life), pharmacological treatment with oxysterols, LXR agonists, statins, PCSK9","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple pharmacological and biochemical readouts in one study","pmids":["21343340"],"is_preprint":false},{"year":2011,"finding":"The N342S amino acid substitution (rs9370867) in MYLIP is associated with increased LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 does not affect intrinsic MYLIP E3 ligase activity but is critical for LDLR targeting.","method":"Functional mutagenesis, LDL uptake assay, LDLR degradation assay in cells","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus cellular functional assays, single lab","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 upregulates Canopy2 (Cnpy2/Msap), which interacts with MYLIP/Idol. Overexpression of Cnpy2/Msap increases LDLR levels; knockdown of Cnpy2/Msap abrogates the FGF21 effect on LDLR.","method":"siRNA knockdown, overexpression, DiI-LDL uptake assay, Western blotting in human hepatocyte cells and mouse macrophages","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown and overexpression with functional readout, single lab, two complementary approaches","pmids":["22378787"],"is_preprint":false},{"year":2013,"finding":"IDOL stimulates a clathrin-independent, caveolae-independent pathway for LDLR internalization. IDOL is recruited to the plasma membrane by LDLR, promotes LDLR internalization, and shuttles LDLR into the multivesicular body (MVB) pathway via ESCRT complexes (ESCRT-0/HGS and ESCRT-I/TSG101). Knockdown of HGS or TSG101 prevents IDOL-mediated LDLR degradation. USP8 acts downstream of IDOL to deubiquitinate LDLR and is required for LDLR entry into the MVB pathway.","method":"Real-time single-particle tracking, electron microscopy, siRNA knockdown of ESCRT components and USP8, live-cell imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (single-particle tracking, EM, genetic knockdowns) establishing mechanism of IDOL-dependent trafficking in one study","pmids":["23382078"],"is_preprint":false},{"year":2013,"finding":"The LXR-IDOL axis targets an LDLR pool present in lipid rafts for internalization independent of clathrin, caveolin, macroautophagy, and dynamin, but dependent on the endocytic protein epsin. LDLR ubiquitylation by IDOL acts as a sorting signal; degradation can be blocked by perturbing ESCRT or by USP8.","method":"Pharmacological and genetic inhibition of endocytic pathways, functional LDL uptake assay, lipid raft fractionation","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological epistasis with multiple pathway components, replicated endocytic mechanism finding across two independent groups","pmids":["23733886"],"is_preprint":false},{"year":2013,"finding":"Reelin decreases VLDLR levels in hippocampal neurons through an increase in MYLIP/Idol levels; shRNA-mediated knockdown of Mylip/Idol abrogates the Reelin-induced decrease in VLDLRs. BDNF increases VLDLR levels by increasing gene expression, acting through a distinct transcriptional mechanism.","method":"shRNA knockdown of Mylip/Idol in hippocampal neurons, Western blotting, pharmacological treatment with BDNF and Reelin","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — shRNA knockdown with defined functional readout in neurons, single lab","pmids":["23990472"],"is_preprint":false},{"year":2014,"finding":"In cynomolgus monkeys but not mice, LXR activation induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Antisense oligonucleotide knockdown of IDOL in monkeys blunts the effect of LXR agonist on LDL levels, establishing a species- and tissue-specific function of the LXR-IDOL axis in primate lipoprotein metabolism.","method":"LXR agonist treatment in cynomolgus monkeys, antisense oligonucleotide (ASO) knockdown, plasma LDL measurement, liver LDLR protein analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo primate model with ASO knockdown and pharmacological activation, multiple orthogonal readouts","pmids":["25440061"],"is_preprint":false},{"year":2014,"finding":"Hepatic IDOL overexpression increases plasma PCSK9 levels through two mechanisms: LDLR loss activates SREBP2, which transcriptionally upregulates PCSK9; and reduced hepatic LDLR delays clearance of circulating PCSK9.","method":"Adenoviral overexpression of Idol in mouse and hamster liver, LDLR-deficient mice as control, 125I-labeled PCSK9 kinetic study, SREBP2 activation assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse and hamster models, isotopic kinetic study, genetic (LDLR-KO) controls, multiple orthogonal approaches","pmids":["24675665"],"is_preprint":false},{"year":2015,"finding":"USP2 (both isoforms USP2-69 and USP2-45) interacts with IDOL and promotes its deubiquitylation in a USP2 enzymatic activity-dependent manner, markedly stabilizing IDOL protein. Paradoxically, USP2 also forms a tripartite complex with IDOL and LDLR, promotes LDLR deubiquitylation in this context, and thereby prevents LDLR degradation. Loss of USP2 reduces LDLR protein in an IDOL-dependent manner.","method":"Genetic screening, reciprocal Co-immunoprecipitation, USP2 catalytic mutants, siRNA knockdown, LDL uptake assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, enzymatic mutants, genetic knockdown with functional readout, single lab multiple orthogonal methods","pmids":["26666640"],"is_preprint":false},{"year":2015,"finding":"DUB inhibition induces LXR-independent transcriptional upregulation of IDOL, driving lysosomal LDLR degradation. A 70-bp region in the IDOL proximal promoter, distinct from the LXR-responsive element, mediates this response. This identifies a sterol-independent mechanism to regulate IDOL expression.","method":"Pharmacological DUB inhibition, Lxrαβ−/− MEFs, reporter assay with IDOL promoter deletion constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic LXR-null cells plus promoter reporter assays in single lab","pmids":["26719329"],"is_preprint":false},{"year":2015,"finding":"MARCH6 is an endogenous inhibitor of the SREBP transcriptional program; loss of MARCH6 unexpectedly decreases cellular lipoprotein uptake despite upregulating LDLR mRNA, because it induces IDOL expression leading to lysosomal LDLR degradation. IDOL induction is the molecular mechanism by which MARCH6 uncouples cholesterol synthesis from lipoprotein uptake in hepatocytes.","method":"Genetic knockdown of MARCH6, IDOL expression analysis, LDL uptake assay, SREBP target gene expression","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic knockdown with functional assay, pathway epistasis placing IDOL downstream of MARCH6, single lab","pmids":["26527619"],"is_preprint":false},{"year":2015,"finding":"IDOL is a primary physiological regulator of LDLR protein in the brain (unlike in mouse liver where its contribution is minimal). Idol deficiency increases brain LDLR, decreases ApoE, decreases soluble and insoluble Aβ, reduces amyloid plaque burden, and ameliorates neuroinflammation in a transgenic Aβ amyloidosis mouse model.","method":"Idol-deficient mice crossed with APP/PS1 amyloidosis model, brain LDLR/ApoE/Aβ quantification, plaque burden histology, neuroinflammation markers","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO in disease model with multiple biochemical and histological readouts","pmids":["26582899"],"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 causes constitutive ApoER2 overexpression, impairs activity-dependent structural remodeling of spines, and causes defective LTP in hippocampal slices. IDOL-deficient mice show impaired experience-dependent cortical circuit reorganization and diminished spatial and associative learning.","method":"Neuronal IDOL loss-of-function (genetic KO), electrophysiology (LTP in hippocampal slices), dendritic spine morphology imaging, barrel cortex plasticity assay, behavioral tests","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal cellular and behavioral readouts across neuronal systems","pmids":["28891791"],"is_preprint":false},{"year":2018,"finding":"CNPY2 inhibits MYLIP-mediated ubiquitination and proteasomal degradation of androgen receptor (AR) in prostate cancer cells by blocking the interaction between MYLIP and its E2 partner UBE2D1. This identifies AR as a substrate of MYLIP E3 ligase activity.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, AR overexpression rescue, in vitro interaction assay between CNPY2-MYLIP-UBE2D1","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay with mechanistic rescue experiments, single lab","pmids":["29707137"],"is_preprint":false},{"year":2018,"finding":"IDOL homodimerization is required for its E3 ligase activity. A cyclic peptide (cyclo-CFFLYT) that disrupts IDOL homodimerization inhibits IDOL activity and produces a dose-dependent increase in LDLR levels in hepatic cells.","method":"SICLOPPS cyclic peptide library screen (3.2 million peptides), cell-based LDLR abundance assay, non-natural amino acid optimization","journal":"Chemical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical genetic screen with cellular functional validation; dimerization requirement inferred from inhibitor mechanism, single lab","pmids":["30079210"],"is_preprint":false},{"year":2019,"finding":"The IDOL G51S variant (rs149696224) stabilizes IDOL protein by inhibiting its dimerization and preventing self-ubiquitination and subsequent proteasomal degradation. IDOL G51S exhibits stronger ability to promote LDLR ubiquitination and degradation. AAV-mediated liver expression of IDOL G51S in mice decreases hepatic LDLR and increases serum LDL-C levels.","method":"Whole-exome sequencing, mutagenesis, dimerization assay, self-ubiquitination assay, LDLR ubiquitination assay, AAV liver expression in mice","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic mutagenesis and biochemical assays validated in vivo with AAV, multiple orthogonal methods","pmids":["31597442"],"is_preprint":false},{"year":2019,"finding":"Loss of IDOL in mice protects against diet-induced obesity not through peripheral metabolic tissues but specifically through controlling lipoprotein receptor abundance in neurons. VLDLR, rather than LDLR, is identified as the primary mediator of IDOL effects on energy balance. IDOL deletion alters hypothalamic gene expression linked to metabolic control, as revealed by single-cell RNA sequencing.","method":"Tissue-specific conditional knockout mice (liver, adipose, endothelium, intestine, skeletal muscle, neuron-specific), single-cell RNA sequencing of hypothalamus, metabolic phenotyping","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic KO panel with defined metabolic phenotype plus transcriptomic pathway analysis","pmids":["32072135"],"is_preprint":false},{"year":2020,"finding":"IDOL can be modified by SUMO-1 at lysine 293, a residue also used for autoubiquitination. SUMOylation of IDOL counteracts its ubiquitination and augments IDOL protein levels. SENP1 (a SUMO-specific peptidase) reverses IDOL SUMOylation in an activity-dependent manner, decreasing IDOL levels, increasing LDLR, and enhancing LDL uptake. Loss of SENP1 lowers LDLR in an IDOL-dependent manner.","method":"SUMOylation assay, ubiquitination assay, mutagenesis at K293, SENP1 overexpression and knockdown, LDL uptake assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific mutagenesis, biochemical SUMOylation and ubiquitination assays, genetic modulation with functional readout in single study","pmids":["33154164"],"is_preprint":false},{"year":2020,"finding":"IDOL-mediated LDLR ubiquitination and degradation is active in intestinal enterocytes. LXR activation in intestinal cell lines decreases LDLR protein abundance, cell surface occupancy, and LDL uptake in an IDOL-dependent manner. Primary enterocytes from Idol-null mice have elevated LDLR. LXR agonist treatment of mice increases Idol expression throughout the intestine with concurrent reduction in LDLR protein.","method":"Idol-KO mouse primary enterocytes, LXR agonist treatment in mice, cell surface LDLR measurement, LDL uptake assay","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with cellular and in vivo functional readouts, single lab","pmids":["33190106"],"is_preprint":false},{"year":2020,"finding":"Crystal structures of the extended FERM domain of IDOL reveal the archetypal F1-F2-F3 trilobed FERM domain structure in which the F3c subdomain orientation obscures the target (LDLR)-binding site. SAXS analysis indicates a compact globular core FERM domain with a flexible, extended C-terminal region, suggesting IDOL may require activation for substrate recognition.","method":"Crystal structure determination of IDOL FERM domain and F3ab subdomain (multiple conformations), small-angle X-ray scattering (SAXS), in vitro ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of multiple FERM domain conformations with SAXS validation and in vitro assay, single lab","pmids":["32727844"],"is_preprint":false},{"year":2023,"finding":"IDOL (the cellular LXR-induced E3 ligase) targets the HCMV UL136p33 protein for proteasomal turnover. IDOL is highly expressed in undifferentiated hematopoietic cells (where HCMV establishes latency) and sharply downregulated upon differentiation. IDOL knockdown affects viral gene expression in wild-type HCMV infection; LXR agonist restricts HCMV reactivation in a UL136p33-dependent manner, establishing IDOL as a host regulator of viral latency.","method":"IDOL knockdown (siRNA), LXR agonist treatment, ubiquitination assay for UL136p33, recombinant stabilized UL136p33 mutant virus, viral gene expression analysis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown and pharmacological activation with viral substrate identification, single lab, mechanistic follow-up with stabilized mutant virus","pmids":["37338407"],"is_preprint":false},{"year":2025,"finding":"MYLIP interacts with HIF-1α and HIF-2α and catalyzes K27-linked polyubiquitination of HIF-1α at K118/K442 and HIF-2α at K117, inducing their proteasomal degradation and attenuating hypoxia signaling. Mylip-deficient zebrafish, bluntsnout bream, and mice show increased hypoxia tolerance.","method":"Co-immunoprecipitation, site-specific K27 ubiquitin linkage assays, K-to-R mutagenesis of HIF-1α/2α, Mylip-KO animals (zebrafish, fish, mouse), hypoxia survival assays","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitin linkage specificity assay, mutagenesis of modification sites, and KO phenotype replicated across three animal species","pmids":["40399570"],"is_preprint":false},{"year":2024,"finding":"MYLIP ubiquitinates and degrades NKRF (a transcriptional repressor) via the proteasomal pathway. MYLIP-mediated NKRF degradation relieves transcriptional repression of SLC25A34 in colorectal cancer cells, suppressing xenograft formation and lung metastases.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, MYLIP overexpression in CRC cells, in vivo xenograft and metastasis models","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay with in vivo functional validation, single lab","pmids":["39661280"],"is_preprint":false}],"current_model":"MYLIP/IDOL is a dimeric E3 ubiquitin ligase that uses its FERM domain to recognize substrates at the plasma membrane and its RING domain (in complex with UBE2D family E2 enzymes) to catalyze K63-linked ubiquitination of the LDLR cytoplasmic tail (and related receptors VLDLR, ApoER2), triggering clathrin-independent, epsin/ESCRT-dependent lysosomal degradation; IDOL is transcriptionally induced by LXR in response to elevated sterols, and its activity is post-translationally tuned by autoubiquitination, SUMOylation at K293 (reversed by SENP1), and deubiquitylation by USP2, which paradoxically stabilizes IDOL yet prevents LDLR degradation by deubiquitinating LDLR in a tripartite IDOL–USP2–LDLR complex; beyond lipoprotein receptor regulation, MYLIP ubiquitinates the androgen receptor, HIF-1α/HIF-2α (via K27-linked chains), and the viral protein UL136p33, and controls synaptic plasticity and energy balance through neuronal regulation of ApoER2 and VLDLR abundance."},"narrative":{"mechanistic_narrative":"MYLIP, also known as IDOL, is a sterol-responsive E3 ubiquitin ligase that controls the cellular abundance of LDL receptor family proteins and thereby governs lipoprotein uptake and cholesterol homeostasis [PMID:19520913]. Transcriptionally induced by LXR in response to elevated sterols, IDOL ubiquitinates the cytoplasmic tails of the LDLR, VLDLR, and ApoER2 and targets them for lysosomal degradation, limiting receptor-mediated lipoprotein uptake [PMID:19520913, PMID:20427281]. Catalysis requires two modules acting in concert: a FERM domain that binds the receptor tail near its NPxY motif and recruits IDOL to the plasma membrane, and a RING domain that, partnered with UBE2D-family E2 enzymes, builds K63-linked ubiquitin chains; productive ligase activity additionally depends on IDOL homodimerization, as defined by the IDOL RING–UBE2D1 crystal structure and dimerization-disrupting perturbations [PMID:21734303, PMID:21685362, PMID:30079210]. Ubiquitinated receptor is internalized through a clathrin- and caveolin-independent, epsin- and ESCRT-dependent route into the multivesicular body for lysosomal degradation, with USP8 acting downstream to deubiquitinate the receptor during MVB sorting [PMID:23382078, PMID:23733886]. IDOL is itself tightly regulated post-translationally—by autoubiquitination, by SUMOylation at K293 (reversed by SENP1) that competes with that same ubiquitination site, and by USP2, which stabilizes IDOL yet paradoxically protects LDLR within a tripartite IDOL–USP2–LDLR complex [PMID:26666640, PMID:33154164]. Genetically, the LXR–IDOL axis sets LDLR levels and plasma LDL in primates and is the dominant regulator of LDLR in brain, where IDOL loss reduces amyloid burden; coding variants such as G51S that stabilize IDOL enhance LDLR degradation and raise serum LDL-C [PMID:25440061, PMID:26582899, PMID:31597442]. In the nervous system IDOL tunes synaptic ApoER2 and VLDLR to control dendritic spine plasticity, learning, and—via neuronal VLDLR—energy balance and resistance to diet-induced obesity [PMID:28891791, PMID:32072135]. Beyond lipoprotein receptors, IDOL ubiquitinates HIF-1α/HIF-2α through K27-linked chains to attenuate hypoxia signaling [PMID:40399570] and degrades the HCMV protein UL136p33 to restrict viral reactivation [PMID:37338407].","teleology":[{"year":2009,"claim":"Established the founding mechanism: how do sterols feed back to limit LDL uptake beyond transcription of the receptor itself, by identifying IDOL as an LXR-induced E3 ligase that degrades the LDLR.","evidence":"siRNA knockdown and adenoviral overexpression in mouse liver, ubiquitination assays, LXR-KO mice","pmids":["19520913"],"confidence":"High","gaps":["Did not define the domains or E2 enzyme mediating ubiquitination","Ubiquitin linkage type and degradation route not yet resolved"]},{"year":2010,"claim":"Expanded substrate scope to the related receptors VLDLR and ApoER2, showing IDOL controls a receptor family and feeds into Reelin–Dab1 signaling.","evidence":"Ubiquitination assays, pharmacological LXR activation in mice, Reelin binding and Dab1 phosphorylation readouts","pmids":["20427281"],"confidence":"High","gaps":["Neuronal consequences of receptor loss not yet tested in vivo","Selectivity rules for which family members are targeted unaddressed"]},{"year":2011,"claim":"Resolved the bipartite catalytic logic—FERM for substrate recognition, RING for K63 ubiquitination—and defined UBE2D enzymes and dimerization as required for activity, providing a structural mechanism.","evidence":"Domain mutagenesis with co-localization imaging; cell-free reconstitution plus 2.1 Å RING–UBE2D1 crystal structure; Idol-null ES cells with half-life and pharmacological epistasis; N342S variant functional analysis","pmids":["21734303","21685362","21343340","21765216"],"confidence":"High","gaps":["Full-length activated FERM–substrate complex structure not determined","How dimerization is regulated in cells unknown"]},{"year":2013,"claim":"Defined the trafficking fate of ubiquitinated receptor, showing a clathrin/caveolin-independent, epsin- and ESCRT-dependent MVB route with USP8 acting downstream.","evidence":"Single-particle tracking, EM, siRNA knockdown of ESCRT components, USP8 and epsin; lipid raft fractionation across two groups","pmids":["23382078","23733886"],"confidence":"High","gaps":["Order and stoichiometry of ESCRT engagement not fully resolved","Whether VLDLR/ApoER2 use the identical route untested"]},{"year":2013,"claim":"Linked IDOL to neuronal signaling, showing Reelin lowers VLDLR via IDOL induction in hippocampal neurons.","evidence":"shRNA knockdown in hippocampal neurons with Reelin and BDNF treatment","pmids":["23990472"],"confidence":"Medium","gaps":["Single-lab knockdown without genetic confirmation","Synaptic functional consequences not assessed here"]},{"year":2014,"claim":"Demonstrated species- and tissue-specificity of the axis and its systemic consequences, validating IDOL as a primate LDL determinant and linking it to PCSK9 kinetics.","evidence":"LXR agonist and ASO knockdown in cynomolgus monkeys; adenoviral Idol overexpression in mouse/hamster liver with 125I-PCSK9 kinetics and SREBP2 assays","pmids":["25440061","24675665"],"confidence":"High","gaps":["Molecular basis of mouse vs primate hepatic difference unresolved","Human in vivo confirmation absent from these studies"]},{"year":2015,"claim":"Mapped post-translational and transcriptional control of IDOL itself, including USP2-mediated stabilization with paradoxical LDLR protection, a DUB-driven LXR-independent promoter response, and MARCH6-dependent induction.","evidence":"Reciprocal Co-IP and catalytic mutants for USP2; promoter reporter deletions in LXR-null MEFs; MARCH6 knockdown with LDL uptake assays","pmids":["26666640","26719329","26527619"],"confidence":"High","gaps":["Structural basis of the tripartite IDOL–USP2–LDLR complex unknown","Physiological triggers of the sterol-independent promoter element undefined"]},{"year":2015,"claim":"Identified IDOL as the dominant LDLR regulator in brain and a driver of amyloid pathology, distinguishing CNS from hepatic roles.","evidence":"Idol-deficient mice crossed to APP/PS1 amyloidosis model with brain LDLR/ApoE/Aβ quantification and plaque histology","pmids":["26582899"],"confidence":"High","gaps":["Cell-type specific contributions (neuron vs glia) not dissected","Therapeutic targetability in human Alzheimer's untested"]},{"year":2017,"claim":"Established IDOL as an activity-dependent regulator of synaptic plasticity by controlling ApoER2 abundance, linking lipoprotein receptor turnover to learning.","evidence":"Neuronal genetic KO with LTP electrophysiology, dendritic spine imaging, barrel cortex plasticity and behavioral tests","pmids":["28891791"],"confidence":"High","gaps":["Signaling pathway downstream of ApoER2 stabilization not fully mapped","Whether ubiquitin linkage type matters for neuronal substrates untested"]},{"year":2018,"claim":"Broadened substrate range to the androgen receptor and confirmed the UBE2D1-dependent catalytic mechanism in a cancer context via CNPY2 inhibition.","evidence":"Co-IP, ubiquitination assay, siRNA and AR rescue, in vitro CNPY2–MYLIP–UBE2D1 interaction","pmids":["29707137"],"confidence":"Medium","gaps":["AR ubiquitination sites and linkage type not defined","In vivo prostate cancer relevance not established here"]},{"year":2018,"claim":"Provided chemical-genetic proof that homodimerization is essential and druggable, using a cyclic peptide to raise LDLR.","evidence":"SICLOPPS cyclic peptide screen with cell-based LDLR abundance assay","pmids":["30079210"],"confidence":"Medium","gaps":["Dimerization interface inferred from inhibitor, not directly structurally resolved","In vivo efficacy of the peptide not tested"]},{"year":2019,"claim":"Connected IDOL protein stability to human LDL genetics, showing the G51S variant blocks self-ubiquitination to stabilize IDOL and enhance LDLR degradation.","evidence":"Whole-exome sequencing, dimerization and self-ubiquitination assays, AAV liver expression in mice","pmids":["31597442"],"confidence":"High","gaps":["Population-level cardiovascular impact of the variant not quantified","Structural mechanism of how G51S impairs dimerization unresolved"]},{"year":2020,"claim":"Defined a neuron-VLDLR axis for energy balance and an enterocyte LDLR role, plus SUMO/ubiquitin crosstalk at K293, extending IDOL physiology and regulation.","evidence":"Tissue-specific conditional KO panel with hypothalamic scRNA-seq; Idol-null enterocytes with LXR agonist in mice; SUMOylation/ubiquitination assays with K293 mutagenesis and SENP1 modulation","pmids":["32072135","33190106","33154164"],"confidence":"High","gaps":["Upstream signals controlling K293 SUMO/ubiquitin switch in vivo unknown","Neuronal circuits mediating VLDLR-dependent energy balance not fully mapped"]},{"year":2020,"claim":"Provided structural insight into FERM-domain autoinhibition, showing the F3c subdomain occludes the LDLR-binding site, implying an activation step for substrate capture.","evidence":"Crystal structures of multiple FERM domain conformations with SAXS and in vitro ubiquitination","pmids":["32727844"],"confidence":"High","gaps":["The activating trigger that opens the FERM domain not identified","Structure of the FERM–LDLR tail complex not solved"]},{"year":2023,"claim":"Identified IDOL as a host antiviral regulator that degrades HCMV UL136p33 to restrict latent virus reactivation.","evidence":"siRNA knockdown, LXR agonist, ubiquitination assay and stabilized UL136p33 mutant virus","pmids":["37338407"],"confidence":"Medium","gaps":["UL136p33 ubiquitination sites and linkage type undefined","Single-lab study without genetic IDOL knockout confirmation"]},{"year":2024,"claim":"Extended IDOL substrate range to the transcriptional repressor NKRF in colorectal cancer, linking its ligase activity to tumor suppression via SLC25A34 derepression.","evidence":"Co-IP, ubiquitination and stability assays, MYLIP overexpression with xenograft and metastasis models","pmids":["39661280"],"confidence":"Medium","gaps":["NKRF ubiquitination sites and linkage type not defined","Single-lab study lacking endogenous loss-of-function confirmation"]},{"year":2025,"claim":"Demonstrated a hypoxia-signaling role by showing IDOL builds K27-linked chains on HIF-1α/2α to degrade them, conserved across vertebrates.","evidence":"Co-IP, K27 linkage-specific ubiquitination assays, K-to-R mutagenesis and Mylip-KO zebrafish, bream and mice with hypoxia survival assays","pmids":["40399570"],"confidence":"High","gaps":["Whether the FERM domain mediates HIF recognition unknown","Crosstalk between HIF degradation and lipoprotein receptor regulation unexplored"]},{"year":null,"claim":"How IDOL's catalytic activity is selectively directed among its diverse substrates (lipoprotein receptors, AR, HIF-α, NKRF, viral proteins) and which signals switch its activation, linkage specificity, and substrate preference in different tissues remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model of substrate selection across substrate classes","Determinants of K63 vs K27 linkage choice unresolved","Activated full-length FERM–substrate structure not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,3,25]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,25,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,12,21]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[16,20]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[25]}],"complexes":["IDOL homodimer","IDOL–UBE2D1 (RING–E2) complex","IDOL–USP2–LDLR tripartite complex"],"partners":["LDLR","VLDLR","APOER2","UBE2D1","USP2","CNPY2","HIF1A","HIF2A"],"other_free_text":[]}},"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. 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axis.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38312562","citation_count":4,"is_preprint":false},{"pmid":"36830035","id":"PMC_36830035","title":"Di-(2-ethylhexyl) Phthalate Limits the Lipid-Lowering Effects of Simvastatin by Promoting Protein Degradation of Low-Density Lipoprotein Receptor: Role of PPARγ-PCSK9 and LXRα-IDOL Signaling Pathways.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36830035","citation_count":4,"is_preprint":false},{"pmid":"25394495","id":"PMC_25394495","title":"Docosahexanoic acid modifies low-density lipoprotein receptor abundance in HepG2 cells via suppression of the LXRα-Idol pathway.","date":"2014","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/25394495","citation_count":4,"is_preprint":false},{"pmid":"33450693","id":"PMC_33450693","title":"Novel associations of SNPs MYLIP rs3757354 and ABCA1 2230806 gene with early-onset-preeclampsia: A case-control candidate genetic study.","date":"2020","source":"Pregnancy hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/33450693","citation_count":3,"is_preprint":false},{"pmid":"39661280","id":"PMC_39661280","title":"E3 Ubiquitination Ligase MYLIP Mediates the NKRF/SLC25A34 Axis to Suppress Malignant Progression in Colorectal Cancer.","date":"2024","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39661280","citation_count":3,"is_preprint":false},{"pmid":"38314097","id":"PMC_38314097","title":"Engineering lentivirus envelope VSV-G for liver targeted delivery of IDOL-shRNA to ameliorate hypercholesterolemia and atherosclerosis.","date":"2024","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/38314097","citation_count":3,"is_preprint":false},{"pmid":"39885913","id":"PMC_39885913","title":"Dendrobium nobile Lindl. alkaloids improve lipid metabolism by increasing LDL uptake through regulation of the LXRα/IDOL/LDLR pathway and inhibition of PCSK9 expression in HepG2 cells.","date":"2025","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39885913","citation_count":3,"is_preprint":false},{"pmid":"38290567","id":"PMC_38290567","title":"Curcumin nicotinate increases LDL cholesterol uptake in hepatocytes through IDOL/LDL-R pathway regulation.","date":"2024","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38290567","citation_count":2,"is_preprint":false},{"pmid":"33845890","id":"PMC_33845890","title":"Genetic polymorphism of IDOL gene was associated with the susceptibility of coronary artery disease in Han population in Xinjiang, China.","date":"2021","source":"Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/33845890","citation_count":2,"is_preprint":false},{"pmid":"19783832","id":"PMC_19783832","title":"Cholesterol worships a new idol.","date":"2009","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19783832","citation_count":2,"is_preprint":false},{"pmid":"40399570","id":"PMC_40399570","title":"MYLIP attenuates hypoxia tolerance by inducing K27-linked polyubiquitination and subsequent proteasomal degradation of HIF-α.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40399570","citation_count":1,"is_preprint":false},{"pmid":"33399227","id":"PMC_33399227","title":"MiR-455-5p monitors myotube morphogenesis by targeting mylip.","date":"2021","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33399227","citation_count":1,"is_preprint":false},{"pmid":"32063587","id":"PMC_32063587","title":"Billy Idol.","date":"2020","source":"Perspectives in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32063587","citation_count":0,"is_preprint":false},{"pmid":"41384508","id":"PMC_41384508","title":"Deletion of neuronal Idol ameliorates Alzheimer's disease-related pathologies via APOE receptors.","date":"2025","source":"Alzheimer's & dementia : the journal of the Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/41384508","citation_count":0,"is_preprint":false},{"pmid":"42235836","id":"PMC_42235836","title":"MYLIP-dependent ubiquitination and degradation of LDLR in acute myeloid leukemia and MAPK signaling.","date":"2026","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/42235836","citation_count":0,"is_preprint":false},{"pmid":"39748219","id":"PMC_39748219","title":"IDOL alleviates the body weight by upregulating UCP-1 in mice.","date":"2025","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39748219","citation_count":0,"is_preprint":false},{"pmid":"40176834","id":"PMC_40176834","title":"Influence of the IDOL Gene Variants on Low-Density Lipoprotein Cholesterol Levels in Turkish Patients with Familial Hypercholesterolemia.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/40176834","citation_count":0,"is_preprint":false},{"pmid":"36368255","id":"PMC_36368255","title":"Fused-ring α-pyrones from intramolecular C-H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation.","date":"2022","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36368255","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36105,"output_tokens":7138,"usd":0.107692,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16381,"output_tokens":5608,"usd":0.111052,"stage2_stop_reason":"end_turn"},"total_usd":0.218744,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","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 and thereby limiting LDL uptake. Knockdown of Idol in hepatocytes increases LDLR protein levels and LDL uptake; adenoviral overexpression in mouse liver promotes LDLR degradation and elevates plasma LDL levels.\",\n      \"method\": \"siRNA knockdown, adenoviral overexpression in mouse liver, ubiquitination assays, LXR knockout mice\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, OE, KO mice), replicated across in vitro and in vivo systems, founding mechanistic paper\",\n      \"pmids\": [\"19520913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IDOL also targets VLDLR and ApoER2 (closely related LDLR family members) for ubiquitination on their cytoplasmic tails, leading to their lysosomal degradation. LXR activation in mice increases Idol expression and decreases Vldlr levels in vivo. IDOL-mediated VLDLR degradation reduces Reelin binding to VLDLR and decreases Dab1 phosphorylation.\",\n      \"method\": \"Ubiquitination assays, pharmacological LXR activation in mice, siRNA knockdown, Reelin binding assay, Dab1 phosphorylation measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo methods in a single study establishing substrate expansion and functional downstream consequence\",\n      \"pmids\": [\"20427281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IDOL requires both its FERM and RING domains for LDLR degradation. The RING domain promotes ubiquitination in vitro and K63-specific ubiquitination of LDLR in vivo. The FERM domain interacts with 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 motif are required for LDLR degradation.\",\n      \"method\": \"In vitro ubiquitination assay, domain mutagenesis, homology modeling, co-localization imaging, cell-based LDLR degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination reconstitution combined with mutagenesis and cellular imaging; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21734303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The UBE2D family (UBE2D1-4) are the cognate E2 ubiquitin-conjugating enzymes for IDOL, supporting both IDOL autoubiquitination and IDOL-dependent ubiquitination of LDLR in a cell-free reconstitution system. Crystal structure of the IDOL RING domain–UBE2D1 complex at 2.1 Å revealed key interactions for E2 selectivity. Structure-based mutations that inhibit IDOL dimerization or IDOL–UBE2D interaction block LDLR ubiquitination and degradation; dominant-negative UBE2D inhibits IDOL-mediated LDLR degradation in cells.\",\n      \"method\": \"Cell-free reconstitution ubiquitination assay, 2.1 Å crystal structure, NMR chemical shift mapping, structure-based mutagenesis, dominant-negative expression in cells\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, in vitro reconstitution, mutagenesis, and cellular validation in one study\",\n      \"pmids\": [\"21685362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Idol-null cells show markedly elevated LDLR protein and increased LDL uptake. Oxysterols and lipoprotein-containing serum fail to suppress LDLR levels in Idol-null cells. LXR ligands have no effect on LDLR levels in Idol-null cells, demonstrating that Idol is required for LXR-dependent inhibition of the LDLR pathway. The LDLR half-life is prolonged in the absence of Idol. PCSK9- and statin-mediated regulation of LDLR is independent of and additive with the LXR-Idol pathway.\",\n      \"method\": \"Gene-targeted Idol-null mouse embryonic stem cells, LDL uptake assay, cycloheximide chase (LDLR half-life), pharmacological treatment with oxysterols, LXR agonists, statins, PCSK9\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple pharmacological and biochemical readouts in one study\",\n      \"pmids\": [\"21343340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The N342S amino acid substitution (rs9370867) in MYLIP is associated with increased LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 does not affect intrinsic MYLIP E3 ligase activity but is critical for LDLR targeting.\",\n      \"method\": \"Functional mutagenesis, LDL uptake assay, LDLR degradation assay in cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus cellular functional assays, single lab\",\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 upregulates Canopy2 (Cnpy2/Msap), which interacts with MYLIP/Idol. Overexpression of Cnpy2/Msap increases LDLR levels; knockdown of Cnpy2/Msap abrogates the FGF21 effect on LDLR.\",\n      \"method\": \"siRNA knockdown, overexpression, DiI-LDL uptake assay, Western blotting in human hepatocyte cells and mouse macrophages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown and overexpression with functional readout, single lab, two complementary approaches\",\n      \"pmids\": [\"22378787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IDOL stimulates a clathrin-independent, caveolae-independent pathway for LDLR internalization. IDOL is recruited to the plasma membrane by LDLR, promotes LDLR internalization, and shuttles LDLR into the multivesicular body (MVB) pathway via ESCRT complexes (ESCRT-0/HGS and ESCRT-I/TSG101). Knockdown of HGS or TSG101 prevents IDOL-mediated LDLR degradation. USP8 acts downstream of IDOL to deubiquitinate LDLR and is required for LDLR entry into the MVB pathway.\",\n      \"method\": \"Real-time single-particle tracking, electron microscopy, siRNA knockdown of ESCRT components and USP8, live-cell imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (single-particle tracking, EM, genetic knockdowns) establishing mechanism of IDOL-dependent trafficking in one study\",\n      \"pmids\": [\"23382078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The LXR-IDOL axis targets an LDLR pool present in lipid rafts for internalization independent of clathrin, caveolin, macroautophagy, and dynamin, but dependent on the endocytic protein epsin. LDLR ubiquitylation by IDOL acts as a sorting signal; degradation can be blocked by perturbing ESCRT or by USP8.\",\n      \"method\": \"Pharmacological and genetic inhibition of endocytic pathways, functional LDL uptake assay, lipid raft fractionation\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological epistasis with multiple pathway components, replicated endocytic mechanism finding across two independent groups\",\n      \"pmids\": [\"23733886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Reelin decreases VLDLR levels in hippocampal neurons through an increase in MYLIP/Idol levels; shRNA-mediated knockdown of Mylip/Idol abrogates the Reelin-induced decrease in VLDLRs. BDNF increases VLDLR levels by increasing gene expression, acting through a distinct transcriptional mechanism.\",\n      \"method\": \"shRNA knockdown of Mylip/Idol in hippocampal neurons, Western blotting, pharmacological treatment with BDNF and Reelin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — shRNA knockdown with defined functional readout in neurons, single lab\",\n      \"pmids\": [\"23990472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In cynomolgus monkeys but not mice, LXR activation induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Antisense oligonucleotide knockdown of IDOL in monkeys blunts the effect of LXR agonist on LDL levels, establishing a species- and tissue-specific function of the LXR-IDOL axis in primate lipoprotein metabolism.\",\n      \"method\": \"LXR agonist treatment in cynomolgus monkeys, antisense oligonucleotide (ASO) knockdown, plasma LDL measurement, liver LDLR protein analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo primate model with ASO knockdown and pharmacological activation, multiple orthogonal readouts\",\n      \"pmids\": [\"25440061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Hepatic IDOL overexpression increases plasma PCSK9 levels through two mechanisms: LDLR loss activates SREBP2, which transcriptionally upregulates PCSK9; and reduced hepatic LDLR delays clearance of circulating PCSK9.\",\n      \"method\": \"Adenoviral overexpression of Idol in mouse and hamster liver, LDLR-deficient mice as control, 125I-labeled PCSK9 kinetic study, SREBP2 activation assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse and hamster models, isotopic kinetic study, genetic (LDLR-KO) controls, multiple orthogonal approaches\",\n      \"pmids\": [\"24675665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP2 (both isoforms USP2-69 and USP2-45) interacts with IDOL and promotes its deubiquitylation in a USP2 enzymatic activity-dependent manner, markedly stabilizing IDOL protein. Paradoxically, USP2 also forms a tripartite complex with IDOL and LDLR, promotes LDLR deubiquitylation in this context, and thereby prevents LDLR degradation. Loss of USP2 reduces LDLR protein in an IDOL-dependent manner.\",\n      \"method\": \"Genetic screening, reciprocal Co-immunoprecipitation, USP2 catalytic mutants, siRNA knockdown, LDL uptake assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, enzymatic mutants, genetic knockdown with functional readout, single lab multiple orthogonal methods\",\n      \"pmids\": [\"26666640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DUB inhibition induces LXR-independent transcriptional upregulation of IDOL, driving lysosomal LDLR degradation. A 70-bp region in the IDOL proximal promoter, distinct from the LXR-responsive element, mediates this response. This identifies a sterol-independent mechanism to regulate IDOL expression.\",\n      \"method\": \"Pharmacological DUB inhibition, Lxrαβ−/− MEFs, reporter assay with IDOL promoter deletion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic LXR-null cells plus promoter reporter assays in single lab\",\n      \"pmids\": [\"26719329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MARCH6 is an endogenous inhibitor of the SREBP transcriptional program; loss of MARCH6 unexpectedly decreases cellular lipoprotein uptake despite upregulating LDLR mRNA, because it induces IDOL expression leading to lysosomal LDLR degradation. IDOL induction is the molecular mechanism by which MARCH6 uncouples cholesterol synthesis from lipoprotein uptake in hepatocytes.\",\n      \"method\": \"Genetic knockdown of MARCH6, IDOL expression analysis, LDL uptake assay, SREBP target gene expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic knockdown with functional assay, pathway epistasis placing IDOL downstream of MARCH6, single lab\",\n      \"pmids\": [\"26527619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IDOL is a primary physiological regulator of LDLR protein in the brain (unlike in mouse liver where its contribution is minimal). Idol deficiency increases brain LDLR, decreases ApoE, decreases soluble and insoluble Aβ, reduces amyloid plaque burden, and ameliorates neuroinflammation in a transgenic Aβ amyloidosis mouse model.\",\n      \"method\": \"Idol-deficient mice crossed with APP/PS1 amyloidosis model, brain LDLR/ApoE/Aβ quantification, plaque burden histology, neuroinflammation markers\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO in disease model with multiple biochemical and histological readouts\",\n      \"pmids\": [\"26582899\"],\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 causes constitutive ApoER2 overexpression, impairs activity-dependent structural remodeling of spines, and causes defective LTP in hippocampal slices. IDOL-deficient mice show impaired experience-dependent cortical circuit reorganization and diminished spatial and associative learning.\",\n      \"method\": \"Neuronal IDOL loss-of-function (genetic KO), electrophysiology (LTP in hippocampal slices), dendritic spine morphology imaging, barrel cortex plasticity assay, behavioral tests\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal cellular and behavioral readouts across neuronal systems\",\n      \"pmids\": [\"28891791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CNPY2 inhibits MYLIP-mediated ubiquitination and proteasomal degradation of androgen receptor (AR) in prostate cancer cells by blocking the interaction between MYLIP and its E2 partner UBE2D1. This identifies AR as a substrate of MYLIP E3 ligase activity.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, AR overexpression rescue, in vitro interaction assay between CNPY2-MYLIP-UBE2D1\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay with mechanistic rescue experiments, single lab\",\n      \"pmids\": [\"29707137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IDOL homodimerization is required for its E3 ligase activity. A cyclic peptide (cyclo-CFFLYT) that disrupts IDOL homodimerization inhibits IDOL activity and produces a dose-dependent increase in LDLR levels in hepatic cells.\",\n      \"method\": \"SICLOPPS cyclic peptide library screen (3.2 million peptides), cell-based LDLR abundance assay, non-natural amino acid optimization\",\n      \"journal\": \"Chemical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical genetic screen with cellular functional validation; dimerization requirement inferred from inhibitor mechanism, single lab\",\n      \"pmids\": [\"30079210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The IDOL G51S variant (rs149696224) stabilizes IDOL protein by inhibiting its dimerization and preventing self-ubiquitination and subsequent proteasomal degradation. IDOL G51S exhibits stronger ability to promote LDLR ubiquitination and degradation. AAV-mediated liver expression of IDOL G51S in mice decreases hepatic LDLR and increases serum LDL-C levels.\",\n      \"method\": \"Whole-exome sequencing, mutagenesis, dimerization assay, self-ubiquitination assay, LDLR ubiquitination assay, AAV liver expression in mice\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic mutagenesis and biochemical assays validated in vivo with AAV, multiple orthogonal methods\",\n      \"pmids\": [\"31597442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of IDOL in mice protects against diet-induced obesity not through peripheral metabolic tissues but specifically through controlling lipoprotein receptor abundance in neurons. VLDLR, rather than LDLR, is identified as the primary mediator of IDOL effects on energy balance. IDOL deletion alters hypothalamic gene expression linked to metabolic control, as revealed by single-cell RNA sequencing.\",\n      \"method\": \"Tissue-specific conditional knockout mice (liver, adipose, endothelium, intestine, skeletal muscle, neuron-specific), single-cell RNA sequencing of hypothalamus, metabolic phenotyping\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic KO panel with defined metabolic phenotype plus transcriptomic pathway analysis\",\n      \"pmids\": [\"32072135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IDOL can be modified by SUMO-1 at lysine 293, a residue also used for autoubiquitination. SUMOylation of IDOL counteracts its ubiquitination and augments IDOL protein levels. SENP1 (a SUMO-specific peptidase) reverses IDOL SUMOylation in an activity-dependent manner, decreasing IDOL levels, increasing LDLR, and enhancing LDL uptake. Loss of SENP1 lowers LDLR in an IDOL-dependent manner.\",\n      \"method\": \"SUMOylation assay, ubiquitination assay, mutagenesis at K293, SENP1 overexpression and knockdown, LDL uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific mutagenesis, biochemical SUMOylation and ubiquitination assays, genetic modulation with functional readout in single study\",\n      \"pmids\": [\"33154164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IDOL-mediated LDLR ubiquitination and degradation is active in intestinal enterocytes. LXR activation in intestinal cell lines decreases LDLR protein abundance, cell surface occupancy, and LDL uptake in an IDOL-dependent manner. Primary enterocytes from Idol-null mice have elevated LDLR. LXR agonist treatment of mice increases Idol expression throughout the intestine with concurrent reduction in LDLR protein.\",\n      \"method\": \"Idol-KO mouse primary enterocytes, LXR agonist treatment in mice, cell surface LDLR measurement, LDL uptake assay\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cellular and in vivo functional readouts, single lab\",\n      \"pmids\": [\"33190106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structures of the extended FERM domain of IDOL reveal the archetypal F1-F2-F3 trilobed FERM domain structure in which the F3c subdomain orientation obscures the target (LDLR)-binding site. SAXS analysis indicates a compact globular core FERM domain with a flexible, extended C-terminal region, suggesting IDOL may require activation for substrate recognition.\",\n      \"method\": \"Crystal structure determination of IDOL FERM domain and F3ab subdomain (multiple conformations), small-angle X-ray scattering (SAXS), in vitro ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of multiple FERM domain conformations with SAXS validation and in vitro assay, single lab\",\n      \"pmids\": [\"32727844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IDOL (the cellular LXR-induced E3 ligase) targets the HCMV UL136p33 protein for proteasomal turnover. IDOL is highly expressed in undifferentiated hematopoietic cells (where HCMV establishes latency) and sharply downregulated upon differentiation. IDOL knockdown affects viral gene expression in wild-type HCMV infection; LXR agonist restricts HCMV reactivation in a UL136p33-dependent manner, establishing IDOL as a host regulator of viral latency.\",\n      \"method\": \"IDOL knockdown (siRNA), LXR agonist treatment, ubiquitination assay for UL136p33, recombinant stabilized UL136p33 mutant virus, viral gene expression analysis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown and pharmacological activation with viral substrate identification, single lab, mechanistic follow-up with stabilized mutant virus\",\n      \"pmids\": [\"37338407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYLIP interacts with HIF-1α and HIF-2α and catalyzes K27-linked polyubiquitination of HIF-1α at K118/K442 and HIF-2α at K117, inducing their proteasomal degradation and attenuating hypoxia signaling. Mylip-deficient zebrafish, bluntsnout bream, and mice show increased hypoxia tolerance.\",\n      \"method\": \"Co-immunoprecipitation, site-specific K27 ubiquitin linkage assays, K-to-R mutagenesis of HIF-1α/2α, Mylip-KO animals (zebrafish, fish, mouse), hypoxia survival assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitin linkage specificity assay, mutagenesis of modification sites, and KO phenotype replicated across three animal species\",\n      \"pmids\": [\"40399570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYLIP ubiquitinates and degrades NKRF (a transcriptional repressor) via the proteasomal pathway. MYLIP-mediated NKRF degradation relieves transcriptional repression of SLC25A34 in colorectal cancer cells, suppressing xenograft formation and lung metastases.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, MYLIP overexpression in CRC cells, in vivo xenograft and metastasis models\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay with in vivo functional validation, single lab\",\n      \"pmids\": [\"39661280\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYLIP/IDOL is a dimeric E3 ubiquitin ligase that uses its FERM domain to recognize substrates at the plasma membrane and its RING domain (in complex with UBE2D family E2 enzymes) to catalyze K63-linked ubiquitination of the LDLR cytoplasmic tail (and related receptors VLDLR, ApoER2), triggering clathrin-independent, epsin/ESCRT-dependent lysosomal degradation; IDOL is transcriptionally induced by LXR in response to elevated sterols, and its activity is post-translationally tuned by autoubiquitination, SUMOylation at K293 (reversed by SENP1), and deubiquitylation by USP2, which paradoxically stabilizes IDOL yet prevents LDLR degradation by deubiquitinating LDLR in a tripartite IDOL–USP2–LDLR complex; beyond lipoprotein receptor regulation, MYLIP ubiquitinates the androgen receptor, HIF-1α/HIF-2α (via K27-linked chains), and the viral protein UL136p33, and controls synaptic plasticity and energy balance through neuronal regulation of ApoER2 and VLDLR abundance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYLIP, also known as IDOL, is a sterol-responsive E3 ubiquitin ligase that controls the cellular abundance of LDL receptor family proteins and thereby governs lipoprotein uptake and cholesterol homeostasis [#0]. Transcriptionally induced by LXR in response to elevated sterols, IDOL ubiquitinates the cytoplasmic tails of the LDLR, VLDLR, and ApoER2 and targets them for lysosomal degradation, limiting receptor-mediated lipoprotein uptake [#0, #1]. Catalysis requires two modules acting in concert: a FERM domain that binds the receptor tail near its NPxY motif and recruits IDOL to the plasma membrane, and a RING domain that, partnered with UBE2D-family E2 enzymes, builds K63-linked ubiquitin chains; productive ligase activity additionally depends on IDOL homodimerization, as defined by the IDOL RING–UBE2D1 crystal structure and dimerization-disrupting perturbations [#2, #3, #18]. Ubiquitinated receptor is internalized through a clathrin- and caveolin-independent, epsin- and ESCRT-dependent route into the multivesicular body for lysosomal degradation, with USP8 acting downstream to deubiquitinate the receptor during MVB sorting [#7, #8]. IDOL is itself tightly regulated post-translationally—by autoubiquitination, by SUMOylation at K293 (reversed by SENP1) that competes with that same ubiquitination site, and by USP2, which stabilizes IDOL yet paradoxically protects LDLR within a tripartite IDOL–USP2–LDLR complex [#12, #21]. Genetically, the LXR–IDOL axis sets LDLR levels and plasma LDL in primates and is the dominant regulator of LDLR in brain, where IDOL loss reduces amyloid burden; coding variants such as G51S that stabilize IDOL enhance LDLR degradation and raise serum LDL-C [#10, #15, #19]. In the nervous system IDOL tunes synaptic ApoER2 and VLDLR to control dendritic spine plasticity, learning, and—via neuronal VLDLR—energy balance and resistance to diet-induced obesity [#16, #20]. Beyond lipoprotein receptors, IDOL ubiquitinates HIF-1α/HIF-2α through K27-linked chains to attenuate hypoxia signaling [#25] and degrades the HCMV protein UL136p33 to restrict viral reactivation [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the founding mechanism: how do sterols feed back to limit LDL uptake beyond transcription of the receptor itself, by identifying IDOL as an LXR-induced E3 ligase that degrades the LDLR.\",\n      \"evidence\": \"siRNA knockdown and adenoviral overexpression in mouse liver, ubiquitination assays, LXR-KO mice\",\n      \"pmids\": [\"19520913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the domains or E2 enzyme mediating ubiquitination\", \"Ubiquitin linkage type and degradation route not yet resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Expanded substrate scope to the related receptors VLDLR and ApoER2, showing IDOL controls a receptor family and feeds into Reelin–Dab1 signaling.\",\n      \"evidence\": \"Ubiquitination assays, pharmacological LXR activation in mice, Reelin binding and Dab1 phosphorylation readouts\",\n      \"pmids\": [\"20427281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuronal consequences of receptor loss not yet tested in vivo\", \"Selectivity rules for which family members are targeted unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the bipartite catalytic logic—FERM for substrate recognition, RING for K63 ubiquitination—and defined UBE2D enzymes and dimerization as required for activity, providing a structural mechanism.\",\n      \"evidence\": \"Domain mutagenesis with co-localization imaging; cell-free reconstitution plus 2.1 Å RING–UBE2D1 crystal structure; Idol-null ES cells with half-life and pharmacological epistasis; N342S variant functional analysis\",\n      \"pmids\": [\"21734303\", \"21685362\", \"21343340\", \"21765216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length activated FERM–substrate complex structure not determined\", \"How dimerization is regulated in cells unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the trafficking fate of ubiquitinated receptor, showing a clathrin/caveolin-independent, epsin- and ESCRT-dependent MVB route with USP8 acting downstream.\",\n      \"evidence\": \"Single-particle tracking, EM, siRNA knockdown of ESCRT components, USP8 and epsin; lipid raft fractionation across two groups\",\n      \"pmids\": [\"23382078\", \"23733886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order and stoichiometry of ESCRT engagement not fully resolved\", \"Whether VLDLR/ApoER2 use the identical route untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked IDOL to neuronal signaling, showing Reelin lowers VLDLR via IDOL induction in hippocampal neurons.\",\n      \"evidence\": \"shRNA knockdown in hippocampal neurons with Reelin and BDNF treatment\",\n      \"pmids\": [\"23990472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab knockdown without genetic confirmation\", \"Synaptic functional consequences not assessed here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated species- and tissue-specificity of the axis and its systemic consequences, validating IDOL as a primate LDL determinant and linking it to PCSK9 kinetics.\",\n      \"evidence\": \"LXR agonist and ASO knockdown in cynomolgus monkeys; adenoviral Idol overexpression in mouse/hamster liver with 125I-PCSK9 kinetics and SREBP2 assays\",\n      \"pmids\": [\"25440061\", \"24675665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of mouse vs primate hepatic difference unresolved\", \"Human in vivo confirmation absent from these studies\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped post-translational and transcriptional control of IDOL itself, including USP2-mediated stabilization with paradoxical LDLR protection, a DUB-driven LXR-independent promoter response, and MARCH6-dependent induction.\",\n      \"evidence\": \"Reciprocal Co-IP and catalytic mutants for USP2; promoter reporter deletions in LXR-null MEFs; MARCH6 knockdown with LDL uptake assays\",\n      \"pmids\": [\"26666640\", \"26719329\", \"26527619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the tripartite IDOL–USP2–LDLR complex unknown\", \"Physiological triggers of the sterol-independent promoter element undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified IDOL as the dominant LDLR regulator in brain and a driver of amyloid pathology, distinguishing CNS from hepatic roles.\",\n      \"evidence\": \"Idol-deficient mice crossed to APP/PS1 amyloidosis model with brain LDLR/ApoE/Aβ quantification and plaque histology\",\n      \"pmids\": [\"26582899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specific contributions (neuron vs glia) not dissected\", \"Therapeutic targetability in human Alzheimer's untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established IDOL as an activity-dependent regulator of synaptic plasticity by controlling ApoER2 abundance, linking lipoprotein receptor turnover to learning.\",\n      \"evidence\": \"Neuronal genetic KO with LTP electrophysiology, dendritic spine imaging, barrel cortex plasticity and behavioral tests\",\n      \"pmids\": [\"28891791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of ApoER2 stabilization not fully mapped\", \"Whether ubiquitin linkage type matters for neuronal substrates untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Broadened substrate range to the androgen receptor and confirmed the UBE2D1-dependent catalytic mechanism in a cancer context via CNPY2 inhibition.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, siRNA and AR rescue, in vitro CNPY2–MYLIP–UBE2D1 interaction\",\n      \"pmids\": [\"29707137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AR ubiquitination sites and linkage type not defined\", \"In vivo prostate cancer relevance not established here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided chemical-genetic proof that homodimerization is essential and druggable, using a cyclic peptide to raise LDLR.\",\n      \"evidence\": \"SICLOPPS cyclic peptide screen with cell-based LDLR abundance assay\",\n      \"pmids\": [\"30079210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dimerization interface inferred from inhibitor, not directly structurally resolved\", \"In vivo efficacy of the peptide not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected IDOL protein stability to human LDL genetics, showing the G51S variant blocks self-ubiquitination to stabilize IDOL and enhance LDLR degradation.\",\n      \"evidence\": \"Whole-exome sequencing, dimerization and self-ubiquitination assays, AAV liver expression in mice\",\n      \"pmids\": [\"31597442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Population-level cardiovascular impact of the variant not quantified\", \"Structural mechanism of how G51S impairs dimerization unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a neuron-VLDLR axis for energy balance and an enterocyte LDLR role, plus SUMO/ubiquitin crosstalk at K293, extending IDOL physiology and regulation.\",\n      \"evidence\": \"Tissue-specific conditional KO panel with hypothalamic scRNA-seq; Idol-null enterocytes with LXR agonist in mice; SUMOylation/ubiquitination assays with K293 mutagenesis and SENP1 modulation\",\n      \"pmids\": [\"32072135\", \"33190106\", \"33154164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling K293 SUMO/ubiquitin switch in vivo unknown\", \"Neuronal circuits mediating VLDLR-dependent energy balance not fully mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided structural insight into FERM-domain autoinhibition, showing the F3c subdomain occludes the LDLR-binding site, implying an activation step for substrate capture.\",\n      \"evidence\": \"Crystal structures of multiple FERM domain conformations with SAXS and in vitro ubiquitination\",\n      \"pmids\": [\"32727844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The activating trigger that opens the FERM domain not identified\", \"Structure of the FERM–LDLR tail complex not solved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified IDOL as a host antiviral regulator that degrades HCMV UL136p33 to restrict latent virus reactivation.\",\n      \"evidence\": \"siRNA knockdown, LXR agonist, ubiquitination assay and stabilized UL136p33 mutant virus\",\n      \"pmids\": [\"37338407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"UL136p33 ubiquitination sites and linkage type undefined\", \"Single-lab study without genetic IDOL knockout confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended IDOL substrate range to the transcriptional repressor NKRF in colorectal cancer, linking its ligase activity to tumor suppression via SLC25A34 derepression.\",\n      \"evidence\": \"Co-IP, ubiquitination and stability assays, MYLIP overexpression with xenograft and metastasis models\",\n      \"pmids\": [\"39661280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NKRF ubiquitination sites and linkage type not defined\", \"Single-lab study lacking endogenous loss-of-function confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a hypoxia-signaling role by showing IDOL builds K27-linked chains on HIF-1α/2α to degrade them, conserved across vertebrates.\",\n      \"evidence\": \"Co-IP, K27 linkage-specific ubiquitination assays, K-to-R mutagenesis and Mylip-KO zebrafish, bream and mice with hypoxia survival assays\",\n      \"pmids\": [\"40399570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the FERM domain mediates HIF recognition unknown\", \"Crosstalk between HIF degradation and lipoprotein receptor regulation unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IDOL's catalytic activity is selectively directed among its diverse substrates (lipoprotein receptors, AR, HIF-α, NKRF, viral proteins) and which signals switch its activation, linkage specificity, and substrate preference in different tissues remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model of substrate selection across substrate classes\", \"Determinants of K63 vs K27 linkage choice unresolved\", \"Activated full-length FERM–substrate structure not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 3, 25]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 25, 26]},\n      {\"term_id\": \"GO:0061630\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0061630\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 12, 21]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [16, 20]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [\n      \"IDOL homodimer\",\n      \"IDOL–UBE2D1 (RING–E2) complex\",\n      \"IDOL–USP2–LDLR tripartite complex\"\n    ],\n    \"partners\": [\n      \"LDLR\",\n      \"VLDLR\",\n      \"ApoER2\",\n      \"UBE2D1\",\n      \"USP2\",\n      \"CNPY2\",\n      \"HIF1A\",\n      \"HIF2A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}