Affinage

MYLIP

E3 ubiquitin-protein ligase MYLIP · UniProt Q8WY64

Length
445 aa
Mass
49.9 kDa
Annotated
2026-06-10
69 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2009 High

    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

    PMID:19520913

    Open questions at the time
    • Did not define the domains or E2 enzyme mediating ubiquitination
    • Ubiquitin linkage type and degradation route not yet resolved
  2. 2010 High

    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

    PMID:20427281

    Open questions at the time
    • Neuronal consequences of receptor loss not yet tested in vivo
    • Selectivity rules for which family members are targeted unaddressed
  3. 2011 High

    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

    PMID:21343340 PMID:21685362 PMID:21734303 PMID:21765216

    Open questions at the time
    • Full-length activated FERM–substrate complex structure not determined
    • How dimerization is regulated in cells unknown
  4. 2013 High

    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

    PMID:23382078 PMID:23733886

    Open questions at the time
    • Order and stoichiometry of ESCRT engagement not fully resolved
    • Whether VLDLR/ApoER2 use the identical route untested
  5. 2013 Medium

    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

    PMID:23990472

    Open questions at the time
    • Single-lab knockdown without genetic confirmation
    • Synaptic functional consequences not assessed here
  6. 2014 High

    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

    PMID:24675665 PMID:25440061

    Open questions at the time
    • Molecular basis of mouse vs primate hepatic difference unresolved
    • Human in vivo confirmation absent from these studies
  7. 2015 High

    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

    PMID:26527619 PMID:26666640 PMID:26719329

    Open questions at the time
    • Structural basis of the tripartite IDOL–USP2–LDLR complex unknown
    • Physiological triggers of the sterol-independent promoter element undefined
  8. 2015 High

    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

    PMID:26582899

    Open questions at the time
    • Cell-type specific contributions (neuron vs glia) not dissected
    • Therapeutic targetability in human Alzheimer's untested
  9. 2017 High

    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

    PMID:28891791

    Open questions at the time
    • Signaling pathway downstream of ApoER2 stabilization not fully mapped
    • Whether ubiquitin linkage type matters for neuronal substrates untested
  10. 2018 Medium

    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

    PMID:29707137

    Open questions at the time
    • AR ubiquitination sites and linkage type not defined
    • In vivo prostate cancer relevance not established here
  11. 2018 Medium

    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

    PMID:30079210

    Open questions at the time
    • Dimerization interface inferred from inhibitor, not directly structurally resolved
    • In vivo efficacy of the peptide not tested
  12. 2019 High

    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

    PMID:31597442

    Open questions at the time
    • Population-level cardiovascular impact of the variant not quantified
    • Structural mechanism of how G51S impairs dimerization unresolved
  13. 2020 High

    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

    PMID:32072135 PMID:33154164 PMID:33190106

    Open questions at the time
    • Upstream signals controlling K293 SUMO/ubiquitin switch in vivo unknown
    • Neuronal circuits mediating VLDLR-dependent energy balance not fully mapped
  14. 2020 High

    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

    PMID:32727844

    Open questions at the time
    • The activating trigger that opens the FERM domain not identified
    • Structure of the FERM–LDLR tail complex not solved
  15. 2023 Medium

    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

    PMID:37338407

    Open questions at the time
    • UL136p33 ubiquitination sites and linkage type undefined
    • Single-lab study without genetic IDOL knockout confirmation
  16. 2024 Medium

    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

    PMID:39661280

    Open questions at the time
    • NKRF ubiquitination sites and linkage type not defined
    • Single-lab study lacking endogenous loss-of-function confirmation
  17. 2025 High

    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

    PMID:40399570

    Open questions at the time
    • Whether the FERM domain mediates HIF recognition unknown
    • Crosstalk between HIF degradation and lipoprotein receptor regulation unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-112316 Neuronal System 2 R-HSA-382551 Transport of small molecules 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-8953897 Cellular responses to stimuli 1
Partners
APOER2CNPY2HIF1AHIF2ALDLRUBE2D1USP2VLDLR
Complex memberships
IDOL homodimerIDOL–UBE2D1 (RING–E2) complexIDOL–USP2–LDLR tripartite complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. siRNA knockdown, adenoviral overexpression in mouse liver, ubiquitination assays, LXR knockout mice Science High 19520913
2010 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. Ubiquitination assays, pharmacological LXR activation in mice, siRNA knockdown, Reelin binding assay, Dab1 phosphorylation measurement The Journal of biological chemistry High 20427281
2011 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. In vitro ubiquitination assay, domain mutagenesis, homology modeling, co-localization imaging, cell-based LDLR degradation assay The Journal of biological chemistry High 21734303
2011 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. Cell-free reconstitution ubiquitination assay, 2.1 Å crystal structure, NMR chemical shift mapping, structure-based mutagenesis, dominant-negative expression in cells Genes & development High 21685362
2011 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. Gene-targeted Idol-null mouse embryonic stem cells, LDL uptake assay, cycloheximide chase (LDLR half-life), pharmacological treatment with oxysterols, LXR agonists, statins, PCSK9 Molecular and cellular biology High 21343340
2011 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. Functional mutagenesis, LDL uptake assay, LDLR degradation assay in cells The Journal of clinical investigation Medium 21765216
2012 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. siRNA knockdown, overexpression, DiI-LDL uptake assay, Western blotting in human hepatocyte cells and mouse macrophages The Journal of biological chemistry Medium 22378787
2013 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. Real-time single-particle tracking, electron microscopy, siRNA knockdown of ESCRT components and USP8, live-cell imaging Molecular and cellular biology High 23382078
2013 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. Pharmacological and genetic inhibition of endocytic pathways, functional LDL uptake assay, lipid raft fractionation Journal of lipid research High 23733886
2013 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. shRNA knockdown of Mylip/Idol in hippocampal neurons, Western blotting, pharmacological treatment with BDNF and Reelin The Journal of biological chemistry Medium 23990472
2014 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. LXR agonist treatment in cynomolgus monkeys, antisense oligonucleotide (ASO) knockdown, plasma LDL measurement, liver LDLR protein analysis Cell metabolism High 25440061
2014 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. Adenoviral overexpression of Idol in mouse and hamster liver, LDLR-deficient mice as control, 125I-labeled PCSK9 kinetic study, SREBP2 activation assays Arteriosclerosis, thrombosis, and vascular biology High 24675665
2015 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. Genetic screening, reciprocal Co-immunoprecipitation, USP2 catalytic mutants, siRNA knockdown, LDL uptake assay Circulation research High 26666640
2015 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. Pharmacological DUB inhibition, Lxrαβ−/− MEFs, reporter assay with IDOL promoter deletion constructs The Journal of biological chemistry Medium 26719329
2015 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. Genetic knockdown of MARCH6, IDOL expression analysis, LDL uptake assay, SREBP target gene expression Molecular and cellular biology Medium 26527619
2015 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. Idol-deficient mice crossed with APP/PS1 amyloidosis model, brain LDLR/ApoE/Aβ quantification, plaque burden histology, neuroinflammation markers Science translational medicine High 26582899
2017 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. Neuronal IDOL loss-of-function (genetic KO), electrophysiology (LTP in hippocampal slices), dendritic spine morphology imaging, barrel cortex plasticity assay, behavioral tests eLife High 28891791
2018 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. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, AR overexpression rescue, in vitro interaction assay between CNPY2-MYLIP-UBE2D1 Oncotarget Medium 29707137
2018 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. SICLOPPS cyclic peptide library screen (3.2 million peptides), cell-based LDLR abundance assay, non-natural amino acid optimization Chemical science Medium 30079210
2019 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. Whole-exome sequencing, mutagenesis, dimerization assay, self-ubiquitination assay, LDLR ubiquitination assay, AAV liver expression in mice Arteriosclerosis, thrombosis, and vascular biology High 31597442
2019 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. Tissue-specific conditional knockout mice (liver, adipose, endothelium, intestine, skeletal muscle, neuron-specific), single-cell RNA sequencing of hypothalamus, metabolic phenotyping Nature metabolism High 32072135
2020 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. SUMOylation assay, ubiquitination assay, mutagenesis at K293, SENP1 overexpression and knockdown, LDL uptake assay The Journal of biological chemistry High 33154164
2020 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. Idol-KO mouse primary enterocytes, LXR agonist treatment in mice, cell surface LDLR measurement, LDL uptake assay Atherosclerosis Medium 33190106
2020 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. Crystal structure determination of IDOL FERM domain and F3ab subdomain (multiple conformations), small-angle X-ray scattering (SAXS), in vitro ubiquitination assay The Journal of biological chemistry High 32727844
2023 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. IDOL knockdown (siRNA), LXR agonist treatment, ubiquitination assay for UL136p33, recombinant stabilized UL136p33 mutant virus, viral gene expression analysis Journal of virology Medium 37338407
2025 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. 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 Communications biology High 40399570
2024 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. Co-immunoprecipitation, ubiquitination assay, protein stability assay, MYLIP overexpression in CRC cells, in vivo xenograft and metastasis models Digestive diseases and sciences Medium 39661280

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science (New York, N.Y.) 682 19520913
2016 Improving cell mixture deconvolution by identifying optimal DNA methylation libraries (IDOL). BMC bioinformatics 151 26956433
2010 The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. The Journal of biological chemistry 119 20427281
2012 Feedback regulation of cholesterol uptake by the LXR-IDOL-LDLR axis. Arteriosclerosis, thrombosis, and vascular biology 102 22936343
2014 The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice. Cell metabolism 79 25440061
2011 The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor. Genes & development 74 21685362
2013 IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor. Molecular and cellular biology 72 23382078
2011 Targeted disruption of the idol gene alters cellular regulation of the low-density lipoprotein receptor by sterols and liver x receptor agonists. Molecular and cellular biology 64 21343340
2012 Fibroblast growth factor-21 (FGF21) regulates low-density lipoprotein receptor (LDLR) levels in cells via the E3-ubiquitin ligase Mylip/Idol and the Canopy2 (Cnpy2)/Mylip-interacting saposin-like protein (Msap). The Journal of biological chemistry 62 22378787
2013 The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation. Journal of lipid research 60 23733886
2018 Bergapten inhibits liver carcinogenesis by modulating LXR/PI3K/Akt and IDOL/LDLR pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 30227322
2011 The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans. The Journal of clinical investigation 54 21765216
2013 Role of PCSK9 and IDOL in the pathogenesis of acquired LDL receptor deficiency and hypercholesterolemia in nephrotic syndrome. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 53 24166456
2011 Distinct functional domains contribute to degradation of the low density lipoprotein receptor (LDLR) by the E3 ubiquitin ligase inducible Degrader of the LDLR (IDOL). The Journal of biological chemistry 48 21734303
2015 The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL. Circulation research 46 26666640
2017 miR-19b promotes breast cancer metastasis through targeting MYLIP and its related cell adhesion molecules. Oncotarget 42 28969074
2015 The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis. Science translational medicine 42 26582899
2015 A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes. Molecular and cellular biology 38 26527619
2010 Suppression of Idol expression is an additional mechanism underlying statin-induced up-regulation of hepatic LDL receptor expression. International journal of molecular medicine 34 21069265
2020 Long non-coding RNA TUSC8 inhibits breast cancer growth and metastasis via miR-190b-5p/MYLIP axis. Aging 33 32039833
2020 Platycodin D enhances LDLR expression and LDL uptake via down-regulation of IDOL mRNA in hepatic cells. Scientific reports 30 33199761
2012 Liver X receptors agonists impede hepatitis C virus infection in an Idol-dependent manner. Antiviral research 29 22713431
2014 Hepatic overexpression of idol increases circulating protein convertase subtilisin/kexin type 9 in mice and hamsters via dual mechanisms: sterol regulatory element-binding protein 2 and low-density lipoprotein receptor-dependent pathways. Arteriosclerosis, thrombosis, and vascular biology 28 24675665
2018 Inactivation of the E3 Ubiquitin Ligase IDOL Attenuates Diet-Induced Obesity and Metabolic Dysfunction in Mice. Arteriosclerosis, thrombosis, and vascular biology 25 29903737
2017 The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning. eLife 25 28891791
2015 IDOL, inducible degrader of low-density lipoprotein receptor, serves as a potential therapeutic target for dyslipidemia. Medical hypotheses 25 26601593
2014 Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis in mice. Circulation research 25 24935961
2019 IDOL regulates systemic energy balance through control of neuronal VLDLR expression. Nature metabolism 21 32072135
2015 Deubiquitylase Inhibition Reveals Liver X Receptor-independent Transcriptional Regulation of the E3 Ubiquitin Ligase IDOL and Lipoprotein Uptake. The Journal of biological chemistry 21 26719329
2020 SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1. The Journal of biological chemistry 20 33154164
2018 CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells. Oncotarget 19 29707137
2013 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. The Journal of biological chemistry 19 23990472
2021 Identification of MYLIP gene and miRNA-802 involved in the growth and metastasis of cervical cancer cells. Cancer biomarkers : section A of Disease markers 18 33185588
2019 IDOL G51S Variant Is Associated With High Blood Cholesterol and Increases Low-Density Lipoprotein Receptor Degradation. Arteriosclerosis, thrombosis, and vascular biology 18 31597442
2020 Regulation of intestinal LDLR by the LXR-IDOL axis. Atherosclerosis 17 33190106
2018 Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase. Chemical science 17 30079210
2014 The MYLIP p.N342S polymorphism is associated with response to lipid-lowering therapy in Brazilian patients with familial hypercholesterolemia. Pharmacogenetics and genomics 17 25171759
2012 MYLIP p.N342S polymorphism is not associated with lipid profile in the Brazilian population. Lipids in health and disease 17 22741812
2009 Mylip makes an Idol turn into regulation of LDL receptor. Cellular and molecular life sciences : CMLS 15 19688294
2020 Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice. Molecular and cellular biology 13 31964754
2020 Structural analysis of the LDL receptor-interacting FERM domain in the E3 ubiquitin ligase IDOL reveals an obscured substrate-binding site. The Journal of biological chemistry 13 32727844
2016 Stable liver-specific expression of human IDOL in humanized mice raises plasma cholesterol. Cardiovascular research 12 26786161
2015 IDOL N342S Variant, Atherosclerosis Progression and Cardiovascular Disorders in the Italian General Population. PloS one 11 25927920
2011 Identification of the source of ivory idol by DNA analysis. Journal of forensic sciences 10 21392005
2010 Reduced VLDL clearance in Apoe(-/-)Npc1(-/-) mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels. Journal of lipid research 10 20562239
2021 The expression of myosin-regulated light chain interacting protein (MYLIP) in lung cancer and its inhibitory effects on lung carcinomas. Translational cancer research 9 35116554
2023 Mouse Spinal Cord Vascular Transcriptome Analysis Identifies CD9 and MYLIP as Injury-Induced Players. International journal of molecular sciences 8 37047406
2020 IDOL gene variant is associated with hyperlipidemia in Han population in Xinjiang, China. Scientific reports 7 32868861
2012 Association of MYLIP rs3757354 SNP and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Lipids in health and disease 7 23107276
2022 Idol Depletion Protects against Spontaneous Atherosclerosis in a Hamster Model of Familial Hypercholesterolemia. Oxidative medicine and cellular longevity 6 35656026
2023 Liver X Receptor-Inducible Host E3 Ligase IDOL Targets a Human Cytomegalovirus Reactivation Determinant. Journal of virology 5 37338407
2024 LncRNA LBX2-AS1 inhibits acute myeloid leukemia progression through miR-455-5p/MYLIP axis. Heliyon 4 38312562
2023 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. Antioxidants (Basel, Switzerland) 4 36830035
2014 Docosahexanoic acid modifies low-density lipoprotein receptor abundance in HepG2 cells via suppression of the LXRα-Idol pathway. Molecular medicine reports 4 25394495
2025 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. Experimental and therapeutic medicine 3 39885913
2024 Engineering lentivirus envelope VSV-G for liver targeted delivery of IDOL-shRNA to ameliorate hypercholesterolemia and atherosclerosis. Molecular therapy. Nucleic acids 3 38314097
2024 E3 Ubiquitination Ligase MYLIP Mediates the NKRF/SLC25A34 Axis to Suppress Malignant Progression in Colorectal Cancer. Digestive diseases and sciences 3 39661280
2020 Novel associations of SNPs MYLIP rs3757354 and ABCA1 2230806 gene with early-onset-preeclampsia: A case-control candidate genetic study. Pregnancy hypertension 3 33450693
2024 Curcumin nicotinate increases LDL cholesterol uptake in hepatocytes through IDOL/LDL-R pathway regulation. European journal of pharmacology 2 38290567
2021 Genetic polymorphism of IDOL gene was associated with the susceptibility of coronary artery disease in Han population in Xinjiang, China. Hereditas 2 33845890
2009 Cholesterol worships a new idol. Journal of molecular cell biology 2 19783832
2025 MYLIP attenuates hypoxia tolerance by inducing K27-linked polyubiquitination and subsequent proteasomal degradation of HIF-α. Communications biology 1 40399570
2021 MiR-455-5p monitors myotube morphogenesis by targeting mylip. Journal of cellular biochemistry 1 33399227
2026 MYLIP-dependent ubiquitination and degradation of LDLR in acute myeloid leukemia and MAPK signaling. Molecular and cellular probes 0 42235836
2025 IDOL alleviates the body weight by upregulating UCP-1 in mice. Diabetes, obesity & metabolism 0 39748219
2025 Deletion of neuronal Idol ameliorates Alzheimer's disease-related pathologies via APOE receptors. Alzheimer's & dementia : the journal of the Alzheimer's Association 0 41384508
2024 Influence of the IDOL Gene Variants on Low-Density Lipoprotein Cholesterol Levels in Turkish Patients with Familial Hypercholesterolemia. Molecular syndromology 0 40176834
2022 Fused-ring α-pyrones from intramolecular C-H activation and their lipids-lowering activity associated with LXR-IDOL-LDLR axis regulation. European journal of medicinal chemistry 0 36368255
2020 Billy Idol. Perspectives in biology and medicine 0 32063587

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