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Cited by 142Cholesterol and Lipid MetabolismUbiquitin and proteasome pathwaysLipoproteins and Cardiovascular Health

The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2

Open access
Hong, Cynthia, Duit, Sarah, Jalonen, Pilvi, Out, Ruud, Scheer, Lilith, Sorrentino, Vincenzo, Boyadjian, Rima, Rodenburg, Kees W. +7 more·2010·Journal of Biological Chemistry
DOI 10.1074/jbc.m110.123729PMC PMC2888382
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Abstract

We have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor (LDLR) (Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism.

AI snapshot

Written from the paper’s full text.

TL;DR

IDOL, an LXR-inducible E3 ubiquitin ligase, targets VLDLR and ApoER2 for ubiquitination and lysosomal degradation, extending its role beyond LDLR. This reduces Reelin binding and Dab1 phosphorylation, suggesting LXR-IDOL cross-talk with neuronal Reelin signaling.

Key findings

  • IDOL degrades VLDLR and ApoER2 in co-transfection assays; an inactivating RING-domain mutation (C387A) abrogates this, and mutation of the conserved lysine immediately after the NPVY motif in VLDLR abolishes degradation. IDOL promotes VLDLR polyubiquitination, and lysosomal inhibitors largely block LXR-mediated Vldlr reduction.
  • LXR activation reduces endogenous VLDLR/ApoER2 protein without changing mRNA. In SNB19 cells, GW3965 or T0901317 reduced VLDLR to 26 ± 4% or 22 ± 8% of control, respectively; in mice, GW3965 at 20 mg/kg/day for 3 days induced Idol and Abca1 and decreased Vldlr in skeletal muscle.
  • In primary rat hippocampal neurons, LXR activation increased Abca1 and Idol mRNA/protein and decreased a Vldlr isoform. In SNB19 cells, LXR activation decreased Reelin binding; in 3T3 cells reconstituted with VLDLR or ApoER2 plus Dab1, LXR activation largely blocked Reelin-stimulated Dab1 phosphorylation without affecting total Dab1.
  • IDOL degraded the locust LDLR-family receptor LpR, and Drosophila Dnr1 degraded human LDLR and VLDLR in a RING-dependent manner. IDOL did not degrade LRP1b or EGFR.

Methods

  • Cell culture and transfections used HEK 293T, SNB19 glioblastoma, 3T3 fibroblasts stably producing VLDLR/ApoER2 and Dab1, and primary rat hippocampal neurons; adenoviral infection was at MOI 80, and LXR ligands GW3965 or T0901317 were typically used at 1 μM for 24 h.
  • Main assays included immunoblotting, immunoprecipitation, quantitative PCR normalized to 36B4, [35S]methionine/cysteine pulse-chase metabolic labeling, Reelin binding, Dab1 phosphorylation, and site-directed mutagenesis.
  • C57BL/6 mice were orally gavaged with 20 mg/kg/day LXR ligand for 3 days; tissues were collected for RNA and protein analysis. Statistics used means ± S.D. and two-tailed Student’s t test with p < 0.05 considered significant.

Limitations

  • Stated: whether IDOL modulates the Reelin pathway in vivo is unknown; whether IDOL and PCSK9 functionally cooperate remains to be seen; and whether Idol contributes to the neuronal migration defect in LXR-null mice remains to be seen.
  • Evident: many mechanistic conclusions rely on overexpression/co-transfection in immortalized cell lines, and the in vivo evidence for VLDLR degradation is in skeletal muscle, whereas the Reelin/Dab1 functional link is shown only in cell culture.
  • Evident: endogenous Idol detection is described as difficult, some supporting data are supplemental, and no human data are presented.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1074/jbc.m110.123729

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

24 of 44 cited sources checked · 19 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Idol is not regulated by SREBPs.

    “Unlike the LDLR and PCSK9 genes, Idol is not regulated by SREBPs.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Zelcer, 2009, Science source
  • Interpretationown data

    These observations are consistent with Idol-dependent lysosomal degradation of the VLDLR.

    “These observations are consistent with Idol-dependent lysosomal degradation of the VLDR as we recently proposed for the LDLR (13).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Zelcer, 2009, Science source
  • Premisecitation

    LXR null mice have substantially reduced Idol expression.

    “Because the formation of vertical processes emanating from these cells requires proper Reelin signaling (39) and the LXR null mice have substantially reduced Idol expression (13), it remains to be seen whether Idol contributes to the observed migratory defect.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Zelcer, 2009, Science source
  • Premisecitation

    A mutant LDLR lacking the intracellular domain is resistant to IDOL-mediated degradation.

    “We have previously found that a mutant LDLR lacking the intracellular domain is resistant to IDOL-mediated degradation (13).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Zelcer, 2009, Science source
  • Findingcitation

    Ligand-activated LXR decreases VLDLR and APOER2 protein levels in 3T3 fibroblasts stably expressing these receptors.

    “In similar studies, we also found that ligand-activated LXR decreased the level of VLDLR and APOER2 in 3T3 fibroblasts stably expressing these receptors (Fig. 1C) (22).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [22] Mayer, 2006, Mol. Cell. Biol. source
  • May combine two claims. 25
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Premisecitation

    Knockdown of Idol expression increases LDLR protein and LDL uptake.

    “Conversely, knockdown of Idol expression leads to an increase in LDLR protein and LDL uptake.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Zelcer, 2009, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several isoforms of the VLDLR have been observed in neurons.

    “Several isoforms of the VLDLR have been observed in neurons (26, 29).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [26] Poirier, 2008, J. Biol. Chem. source
    • cites [29] Sakai, 2009, Brain Res. source

  • May combine two claims.

    Premisecitation

    Overexpression of Idol reduces LDLR protein levels in vitro and in vivo and inhibits LDL uptake.

    “Overexpression of Idol potently reduces LDLR protein levels in vitro and in vivo and inhibits LDL uptake.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Zelcer, 2009, Science source

  • Classified as probably not a substantial claim.

    Premisecitation

    Reelin interaction with the VLDLR and ApoER2 is critical during development because it properly directs the positioning of neurons.

    “Reelin interaction with the VLDLR and ApoER2 is critical during development because it properly directs the positioning of neurons (16, 20, 21).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [16] Trommsdorff, 1999, Cell source
    • cites [20] Hiesberger, 1999, Neuron source
    • cites [21] D'Arcangelo, 1999, Neuron source

  • May combine two claims.

    Premisecitation

    Idol triggers ubiquitination of the LDLR on conserved residues in its intracellular tail, leading to degradation of the receptor.

    “Idol triggers ubiquitination of the LDLR on conserved residues in its intracellular tail, leading to degradation of the receptor.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Zelcer, 2009, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The intracellular domain of the LDLR forms a scaffold for protein-protein interactions essential for proper function and trafficking of the receptor.

    “The intracellular domain of the LDLR forms a scaffold for protein-protein interactions essential for proper function and trafficking of the receptor (42).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] Gotthardt, 2000, J. Biol. Chem. source

      The Discussion reports adaptor and scaffold proteins interacting with LDL receptor family cytoplasmic tails, and the Results show that DAB1 binding to the LDL receptor tail affects its endocytosis. But the Results explicitly say there is no indication that DAB1 binding to the LDL receptor tail has a critical physiological function in vivo. The claim’s assertion that these interactions are essential for proper LDLR function and trafficking is therefore stronger than the evidence. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Idol is a transcriptional target of LXRs and a post-transcriptional regulator of the LDLR pathway.

    “We have recently identified the E3 ubiquitin ligase Idol (inducible degrader of the LDLR) as a transcriptional target of LXRs and a post-transcriptional regulator of the LDLR pathway (13).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Zelcer, 2009, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    VLDLR and ApoER2 interact with Reelin, leading to phosphorylation of Dab1.

    “A body of evidence demonstrates that the VLDLR and ApoER2 interact with an extracellular ligand, Reelin, leading, as a first event, to phosphorylation of the adaptor molecule Dab1 (20, 21).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [20] Hiesberger, 1999, Neuron source
    • cites [21] D'Arcangelo, 1999, Neuron source

  • Classified as probably not a substantial claim.

    Premisecitation

    The formation of vertical processes emanating from radial glia cells requires proper Reelin signaling.

    “Because the formation of vertical processes emanating from these cells requires proper Reelin signaling (39) and the LXR null mice have substantially reduced Idol expression (13), it remains to be seen whether Idol contributes to the observed migratory defect.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [39] Hartfuss, 2003, Development source

      The Discussion says Reelin is a necessary factor for radial process elongation or maintenance in the reeler mutant cortex. But it also says some radial glia extend long processes without Reelin and that radial glia in other CNS regions do not require its signaling. The claim omits this regional and cellular qualification. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dnr1 is an inhibitor of the inflammatory IMD pathway in flies.

    “Dnr1 is an inhibitor of the inflammatory IMD pathway in flies (28).”
    • Also stated in: § DISCUSSION · hedged
      “Dnr1 has been reported to inhibit the IMD pathway in flies.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Foley, 2004, PLoS Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mice lacking LXR display disrupted neuronal migration, which Fan et al. attributed to a reduction in the number of vertical processes emanating from radial glia cells.

    “Intriguingly, despite having a similar Reelin level, mice lacking LXR display disrupted neuronal migration, which Fan et al. (38) attributed to a reduction in the number of vertical processes emanating from the radial glia cells.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Fan, 2008, Proc. Natl. Acad. Sci. U.S.A. source

  • Classified as probably not a substantial claim.

    Premisecitation

    The VLDLR and ApoER2 are critical for neuronal migration during development.

    “In addition to their proposed roles in metabolism, the VLDLR and ApoER2 are critical for neuronal migration during development (16, 20, 21).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [16] Trommsdorff, 1999, Cell source
    • cites [20] Hiesberger, 1999, Neuron source
    • cites [21] D'Arcangelo, 1999, Neuron source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In macrophages, ligation of ApoER2 by activated protein C results in Dab1-dependent signaling events.

    “In macrophages, ligation of ApoER2 by activated protein C results in Dab1-dependent signaling events (40).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Yang, 2009, Proc. Natl. Acad. Sci. U.S.A. source

      The Results report that activated protein C induced Dab1 phosphorylation in U937 cells and that ApoER2 knockdown abolished it. The Discussion describes this as ApoER2-mediated, Dab1-dependent signaling, but the study used a monocytic cell line rather than macrophages, so the claim extends the finding to a different cell population. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    A 70% reduction in Idol expression increases basal VLDLR and largely abrogates the ability of activated LXR to reduce VLDLR in 3T3-VLDLR cells.

    “A 70% reduction in Idol expression resulted in an increased basal level of VLDLR in 3T3-VLDLR cells and largely abrogated the ability of activated LXR to reduce the level of this receptor (supplemental Fig. S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Activation of the LXR pathway leads to decreased levels of VLDLR and ApoER2 protein without an effect on the respective transcript.

    “Activation of the LXR pathway leads to decreased levels of VLDLR and ApoER2 protein without an effect on the respective transcript (Fig. 1, A–C, and not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pharmacological dosing of mice with GW3965 induces the LXR pathway in metabolic tissues without affecting VLDLR expression.

    “Pharmacological dosing of mice with GW3965 led to induction of the LXR pathway in metabolic tissues without affecting VLDLR expression (Fig. 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    IDOL degrades the LpR, an ancient LDLR-related receptor from the migrating locust (Locusta migratoria) that is important for lipoprotein uptake in this species.

    “Accordingly, we find that IDOL degrades the LpR, an ancient LDLR-related receptor from the migrating locust (Locusta migratoria) that is important for lipoprotein uptake in this species (Fig. 3, A and D) (25).”
    • Also stated in: § DISCUSSION · plain
      “Remarkably, IDOL was also able to degrade an ancient LDLR family member important for lipoprotein uptake in the migrating locust.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Van Hoof, 2002, J. Cell Sci. source

  • May combine two claims.

    Findingreasoning

    IDOL degrades the LDLR in cells that do not express PCSK9 (e.g. macrophages) as well as endocytosis mutants of the LDLR, VLDLR, and ApoER2.

    “IDOL degrades the LDLR in cells that do not express PCSK9 (e.g. macrophages) as well as endocytosis mutants of the LDLR, VLDLR, and ApoER2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Depletion of oxysterol LXR agonists by Sult2b1 in SNB19 cells decreases LXR target gene expression and has no effect on VLDLR expression.

    “Depletion of oxysterol LXR agonists by Sult2b1 in SNB19 cells decreased expression of LXR target genes as expected and had no effect on VLDLR expression (Fig. 1D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Pharmacological activation of the LXR pathway in mice increases Idol expression and decreases Vldlr levels in vivo.

    “Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LXR ligand treatment decreases VLDLR protein without decreasing VLDLR mRNA.

    “This reduction was not a result of decreased VLDLR expression. Whereas expression of the LXR target genes ABCA1 and IDOL were increased, that of the VLDLR remained unchanged (Fig. 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IDOL does not reduce LRP1b or EGFR levels.

    “Unexpectedly, IDOL did not reduce the level of LRP1b, as may have been predicted based on sequence homology (Fig. 3, A and B) or the level of another NPVY-containing receptor, the epidermal growth factor receptor (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Endogenous VLDLR level is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway.

    “We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation.

    “We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The presence of the lysine residue following the NPVY motif is not sufficient for IDOL targeting, because LRP1b is not targeted by IDOL.

    “However, its presence is not sufficient, because LRP1b is not targeted by IDOL.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    3T3 cells stably reconstituted with VLDLR or ApoER2 and Dab1 responded to Reelin in a similar fashion to primary neurons, with Reelin binding strongly stimulating Dab1 phosphorylation.

    “Functionally, these cells responded to Reelin in a similar fashion to primary neurons, with Reelin binding strongly stimulating Dab1 phosphorylation (Fig. 5D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of SNB19 glioblastoma cells with GW3965 or T0901317 increases ABCA1 and decreases endogenous VLDLR protein levels.

    “Treatment of these cells with GW3965 or T0901317 increased the level of the LXR-responsive protein ABCA1 and concomitantly decreased the levels of the endogenous VLDLR (Fig. 1A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sult2b1 depletion increases VLDLR protein, and this increase is reversed by a synthetic LXR ligand.

    “Nevertheless, this treatment increased VLDLR protein, and this effect was reversed by a synthetic LXR ligand (Fig. 1E).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Dnr1 inhibits the IMD pathway by blocking the activity of the fly caspases-8 homolog, Dredd.

    “Dnr1 inhibits the IMD pathway by blocking the activity of the fly caspases-8 homolog, Dredd (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Primrose, 2007, J. Cell Sci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The immunoblots shown are representative of at least two independent experiments.

    “The blots are representative of at least two independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    It is highly unlikely that IDOL and PCSK9 directly interact.

    “It is highly unlikely that these two proteins directly interact.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    VLDLR and ApoER2 have a critical role in the neuronal Reelin pathway essential for proper neuronal positioning and brain development.

    “studies in recent years have established a critical role for VLDLR and ApoER2 in the neuronal Reelin pathway that is essential for proper neuronal positioning and brain development (16–19).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [16] Trommsdorff, 1999, Cell source
    • cites [17] Sheldon, 1997, Nature source
    • cites [18] Howell, 1997, Nature source
    • cites [19] Hirotsune, 1995, Nat. Genet. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Statistical analysis was done with a two-tailed Student's t test, and p < 0.05 was considered statistically significant.

    “Statistical analysis was done with a two-tailed Student's t test. A probability value of p < 0.05 was considered statistically significant.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The animal experiments were conducted in accordance with institutional guidelines.

    “The animal experiments were conducted in accordance with institutional guidelines.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PCSK9 is a secreted protein that binds the ecto-domain of the receptors and promotes their endocytosis and lysosomal degradation.

    “PCSK9 is a secreted protein that binds the ecto-domain of the receptors and promotes their endocytosis and lysosomal degradation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Poirier, 2008, J. Biol. Chem. source
    • cites [27] Shan, 2008, Biochem. Biophys. Res. Commun. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Restriction digest analysis and DNA sequencing were used to verify the correctness of all constructs used in this study.

    “Restriction digest analysis and DNA sequencing were used to verify the correctness of all of the constructs used in this study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The ability of the LXR-IDOL pathway to target multiple members of the LDLR superfamily suggests a potential role for this pathway in processes beyond lipid metabolism.

    “The ability of the LXR-IDOL pathway to target multiple members of the LDLR superfamily suggests a potential role for this pathway in processes beyond lipid metabolism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PCSK9 post-translationally modulates the levels of LDLR, VLDLR, and ApoER2.

    “Similar to IDOL, the secreted protein PCSK9 also post-translationally modulates the levels of the LDLR, VLDLR, and ApoER2 (26, 27).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Poirier, 2008, J. Biol. Chem. source
    • cites [27] Shan, 2008, Biochem. Biophys. Res. Commun. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    VLDLR and ApoER2 share the highest overall sequence homology with LDLR among the LDLR family.

    “Among the LDLR family of proteins, the VLDLR (very low density lipoprotein receptor) and ApoER2 (also known as LRP8) share the highest overall sequence homology with the LDLR (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Herz, 2002, Annu. Rev. Biochem. source

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Interpretationreasoning

    The overlapping substrate specificities of IDOL and PCSK9 raise the possibility that they act in a concerted fashion.

    “The overlapping substrate specificities of IDOL and PCSK9 raise the intriguing possibility that they act in a concerted fashion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    In addition to potential roles in metabolism, IDOL may also have a role in neurons during development.

    “This suggests that in addition to potential roles in metabolism, IDOL may also have a role in neurons during development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The intracellular domain is both necessary and sufficient to direct Idol-dependent degradation of plasma membrane proteins.

    “This result demonstrates that the intracellular domain is both necessary and sufficient to direct Idol-dependent degradation of plasma membrane proteins.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: APP is not targeted by IDOL.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The LXR-IDOL pathway may be involved not only in Reelin signaling in the CNS but also in peripheral Dab1-dependent processes.

    “This raises the possibility that the LXR-IDOL pathway may be involved not only in Reelin signaling in the CNS but also in peripheral Dab1-dependent processes.”
    Quote in the paperNot a substantial claim
43 of 43

  • The paper relies on this without support.

    The two VLDLR bands detected in SNB19 cells represent the precursor and mature (fully glycosylated) receptor.

    “we detect the VLDLR as two bands that likely represent the precursor and mature (fully glycosylated) receptor (Fig. 1A).”

  • The paper relies on this without support.

    APP is not targeted by IDOL.

    “replacing the natural intracellular domain of APP, which is not targeted by IDOL, with that of the LDLR allowed IDOL to target the chimeric receptor for destruction (Fig. 3C).”

  • The paper relies on this without support.

    The conserved lysine residue adjacent to the NPVY motif in VLDLR and ApoER2 is the site of IDOL-mediated ubiquitination.

    “Because this residue is highly conserved in the VLDLR and ApoER2, we tested whether IDOL underlies the LXR-mediated reduction of these receptors.”

  • The paper relies on this without support.

    The function of members of the LDLR family of receptors is evolutionarily conserved.

    “The function of members of the LDLR family of receptors is evolutionarily conserved.”

  • The paper relies on this without support.

    Idol is an E3 ubiquitin-ligase.

    “Because Idol is an E3 ubiquitin-ligase, we tested whether the VLDLR was ubiquitinated by Idol.”

  • The paper relies on this without support.

    The intracellular domain of the LDLR is both required and sufficient for recognition by IDOL.

    “Furthermore, this domain is both required and sufficient for recognition by IDOL.”
6 of 6

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Authors
Hong, C., Duit, S., Jalonen, P., Out, R., Scheer, L., Sorrentino, V., Boyadjian, R., Rodenburg, K. W., Foley, E., Korhonen, L., Lindholm, D., Nimpf, J., van Berkel, T. J. C., Tontonoz, P., & Zelcer, N.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Max Perutz Labs (AT)
  • Minerva Foundation (FI)
  • Leiden University (NL)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Utrecht University (NL)
  • University of Alberta (CA)
  • University of Helsinki (FI)
Corresponding author
Zelcer, Noam
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2010-06
Volume
285
Issue
26
Pages
19720-19726
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m110.123729
PMC
PMC2888382
OpenAlex
W2164276007
Semantic Scholar
0b069956933d85443eeb045d415d6c60b0697071
Cited by
142
References
43
Citations by year
2026: 8 · 2025: 9 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 2 · 2020: 7 · 2019: 8 · 2018: 12 · 2017: 4 · 2016: 7 · 2015: 10 · 2014: 12 · 2013: 10 · 2012: 17
FWCI
14.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Academy of Finland
  • Fondation pour la Recherche Médicale
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • Herzfelder'sche Familienstiftung
  • National Institutes of Health (HL090553)
  • Canadian Institutes of Health Research
  • National Heart, Lung, and Blood Institute (P01HL090553, HL066088, HL090553, R01HL066088)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
idols, E3 ubiquitin ligase, VLDLR, ApoER2, liver X receptor, receptor degradation, ubiquitination, Reelin signaling, neuronal development, lipid metabolism
MeSH terms
Liver X Receptors, Reelin Protein, Benzenesulfonamides, Animals, Benzoates, Benzylamines, Cell Line, Fluorocarbons, Humans, Hydrocarbons, Fluorinated, Mice, Inbred C57BL, Nerve Tissue Proteins, Phosphorylation, Protein Binding, Receptors, LDL, Serine Endopeptidases, Sulfonamides, Transfection, Immunoblotting, Signal Transduction, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Receptors, Lipoprotein, Mice, Knockout, LDL-Receptor Related Proteins, NIH 3T3 Cells, Ubiquitin-Protein Ligases, Cell Line, Tumor, Mice, Ubiquitination, Orphan Nuclear Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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