The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index; 10 of the 30 sources its claims cite were checked for support.
The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
Open accessAbstract
Low density lipoprotein (LDL) cholesterol is taken up into cells via clathrin-mediated endocytosis of the LDL receptor (LDLR). Following dissociation of the LDLR-LDL complex, LDL is directed to lysosomes whereas the LDLR recycles to the plasma membrane. Activation of the sterol-sensing nuclear receptors liver X receptors (LXRs) enhances degradation of the LDLR. This depends on the LXR target gene inducible degrader of the LDLR (IDOL), an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR. How ubiquitylation of the LDLR by IDOL controls its endocytic trafficking is currently unknown. Using genetic- and pharmacological-based approaches coupled to functional assessment of LDL uptake, we show that the LXR-IDOL axis targets a LDLR pool present in lipid rafts. IDOL-dependent internalization of the LDLR is independent of clathrin, caveolin, macroautophagy, and dynamin. Rather, it depends on the endocytic protein epsin. Consistent with LDLR ubiquitylation acting as a sorting signal, degradation of the receptor can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT) or by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies. In summary, we provide evidence for the existence of an LXR-IDOL-mediated internalization pathway for the LDLR that is distinct from that used for lipoprotein uptake.
Overview
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Written from the paper’s full text.
TL;DR
The LXR-IDOL axis promotes internalization and lysosomal degradation of a lipid-raft LDLR pool through a route independent of clathrin, caveolae, dynamin, and macroautophagy, but dependent on epsin/ubiquitin adaptors and ESCRT-mediated sorting. This IDOL route is distinct from the clathrin-dependent LDLR pathway used for LDL uptake.
Key findings
- LXR activation with GW3965 reduces total and cell-surface LDLR; lysosomotropic agents bafilomycin A1 or NH4Cl block total LDLR degradation but do not rescue surface LDLR, suggesting IDOL targets plasma membrane LDLR and impedes recycling (surface LDLR set to 100% in sterol-depletion medium; n = 6; P < 0.01).
- IDOL-mediated LDLR degradation persists despite >90% clathrin heavy chain knockdown, in Cav1−/− and Atg5−/− fibroblasts, with dynasore, and with DNM1/DNM2 siRNA, while LDL uptake is severely diminished under clathrin knockdown or dynasore. ARH silencing reduced ARH mRNA by 90 ± 4% and LDL uptake to 57 ± 8% of control (n = 3, P < 0.01) but did not prevent LXR-stimulated LDLR degradation; LDLR Y828C was also degraded.
- IDOL targets a lipid-raft LDLR pool: in HepG2 cells most LDLR was in low-density fractions enriched in Flotillin1 and Caveolin1 and largely devoid of clathrin; MβCD and filipin blocked IDOL-mediated degradation, though MβCD also inhibited LDL uptake by 27 ± 5% (n = 3, P < 0.05).
- Epsin1 overexpression blocked IDOL-mediated degradation of LDLR and VLDLR and led to accumulation of ubiquitylated receptor; TSG101 silencing, dominant-negative VPS4 E228Q, and USP8 blocked LDLR degradation, whereas AMSH did not.
Methods
- Cell-based genetic and pharmacological study using HEK293T, HeLa, HepG2, A431, human fibroblasts reconstituted with WT or Y828C LDLR, Cav1−/− and Atg5−/− mouse embryonic fibroblasts, and doxycycline-inducible CHC-knockdown HeLa cells; cells were sterol-depleted and treated with GW3965, bafilomycin A1, NH4Cl, dynasore, MβCD, or filipin as indicated.
- Main assays included FACS measurement of cell-surface LDLR, DyLight 488-labeled LDL uptake, immunoblotting and immunoprecipitation, immunofluorescence for transferrin/clathrin, sucrose-gradient membrane fractionation, and quantitative PCR; statistical differences were assessed by one-way ANOVA with P < 0.05 considered significant.
- Perturbations included siRNA against ARH, TSG101, DNM1, and DNM2, and expression of IDOL, LDLR, Epsin1, VPS4 WT/E228Q, AMSH, and USP8 constructs.
Limitations
- Stated: current IDOL antibodies, including those developed by the authors and commercial ones, cannot detect endogenous IDOL protein, preventing critical testing of whether lipid rafts recruit IDOL for LDLR downregulation.
- Stated: Epsin1 silencing alone did not block IDOL-mediated LDLR degradation, likely due to functional redundancy with related ubiquitin adaptors such as Eps15/Eps15R; the authors note preliminary EPS15/EPS15R knockdown data and that the study was not specifically geared toward addressing Epsin1’s role in LDL uptake.
- Stated/evident: the authors report a discrepancy with Scotti et al. regarding lipid rafts, with filipin used at 10 μg/ml versus 1 μg/ml; many mechanistic conclusions rely on overexpression or dominant-negative constructs and pharmacological inhibitors, some immunoblots are representative of only two independent experiments, and no in vivo model is presented.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
10 of 30 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
- Findingcitation§ RESULTS
Epsin1 over-expression blocks IDOL-mediated degradation of the VLDL receptor (VLDLR).
“Similarly, Epsin1 over-expression also blocked degradation of another IDOL target, the VLDL receptor (VLDLR ) (supplementary Fig. V) ( 30 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Hong, 2010, The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2, J. Biol. Chem. source
The Results (page unavailable) show that IDOL reduces VLDLR protein levels, supporting the description of VLDLR as an IDOL target. The cited paper does not report Epsin1 over-expression blocking that degradation; a search for Epsin1 found no relevant passage. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
This LXR-dependent degradation of LDLR depends on IDOL, an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR.
“This depends on the LXR target gene inducible degrader of the LDLR (IDOL), an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [21] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science. source
- cites [22] Sorrentino, 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), J. Biol. Chem. source
- Premisecitation§ DISCUSSION
IDOL stimulates poly-K63 ubiquitylation of the LDLR.
“This fi nding is consistent with our earlier report that IDOL stimulates poly-K63 ubiquitylation of the LDLR, a known lysosomal targeting tag for membrane receptors ( 22 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [22] Sorrentino, 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), J. Biol. Chem. source
- Premisecitation§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
Activation of LXRs enhances degradation of the LDLR.
“Activation of the sterol-sensing nuclear receptors liver X receptors (LXRs) enhances degradation of the LDLR .”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [19] Zelcer, 2006, Liver X receptors as integrators of metabolic and inflammatory signaling, J. Clin. Invest. source
The sections on whole-body cholesterol homeostasis and macrophage cholesterol metabolism describe LXR-driven cholesterol transport and efflux, but not LDLR degradation. A search for LDLR and LDL-receptor degradation found only references to LDLR-deficient mice in the atherosclerosis section, not evidence that LXR activation enhances degradation of the receptor. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [20] Janowski, 1996, An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha, Nature. source
- cites [21] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science. source
- Findingown data§ DISCUSSION
The ESCRT system is required for sorting of ubiquitylated LDLR.
“Fig. 8. The ESCRT system is required for sorting of ubiquitylated LDLR.”
- Also stated in: § DISCUSSION · boosted
“Our study also illustrates the role of the ESCRT system in sorting ubiquitylated LDLR toward MVBs.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · boosted
- Findingown data§ RESULTS
IDOL-mediated degradation of the LDLR is dynamin-independent.
“Fig. 5. IDOL-mediated LDLR degradation is dynamin independent.”
- Also stated in: § DISCUSSION · plain
“In fact, this pathway is not only clathrin-independent, but does not require caveolin or dynamin activity either.”
- Also stated in: § DISCUSSION · boosted
“Both studies, using different methodologies, demonstrate that IDOL-stimulated internalization of the LDLR is clathrin-, caveolae-, and dynamin-independent, and identify the ESCRT system and associated DUB USP8 as important determinants for sorting ubiquitylated LDLR to MVBs.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data§ RESULTS
Epsin1 was distributed along the membrane gradient in HepG2 cells.
“Consistent with its use by multiple endocytic pathways Epsin1 was distributed along the membrane gradient in HepG2 cells (supplementary. Fig. IVA, B).”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
Functional inhibition of the ESCRT system at the level of VPS4, TSG101, or USP8 attenuates IDOL-stimulated degradation of the LDLR.
“Functional inhibition of the ESCRT system at the level of VPS4, TSG101, or USP8 attenuated IDOL-stimulated degradation of the LDLR.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
In HepG2 cells, the bulk of the LDLR is located in lipid rafts.
“Our experiments demonstrate that in HepG2 cells the bulk of the LDLR is located in lipid rafts and that this pool is particularly sensitive to IDOL-mediated degradation.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Inhibition of LDLR and VLDLR degradation by IDOL is accompanied by accumulation of ubiquitylated receptors.
“Inhibition of LDLR and VLDLR degradation by IDOL was also accompanied by accumulation of lower mobility receptors, clearly visible with the VLDLR and requiring longer exposures with LDLR, which we identifi ed as ubiquitylated receptors ( Fig. 7B , supplementary Fig. V).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
The lipid raft LDLR pool is particularly sensitive to IDOL-mediated degradation.
“Our experiments demonstrate that in HepG2 cells the bulk of the LDLR is located in lipid rafts and that this pool is particularly sensitive to IDOL-mediated degradation.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Coexpression of AMSH is unable to prevent LDLR degradation by IDOL.
“Coexpression of AMSH was unable to prevent LDLR degradation by IDOL.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The LXR-IDOL degradation pathway targets a lipid-raft resident LDLR pool.
“Fig. 6. The LXR-IDOL degradation pathway targets a lipid-raft resident LDLR pool.”
Quote in the paperSubstantial claim - Findingown data§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
IDOL-dependent internalization of the LDLR depends on the endocytic protein epsin.
“Rather, it depends on the endocytic protein epsin.”
Quote in the paperSubstantial claim- Rests on an assumption: Epsin1 silencing failure to block IDOL degradation is due to functional redundancy with other related ubiquitin adaptors like Eps15 and Eps15R.
- Findingown data§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
The LXR-IDOL axis targets a LDLR pool present in lipid rafts.
“Using genetic- and pharmacological-based approaches coupled to functional assessment of LDL uptake, we show that the LXR-IDOL axis targets a LDLR pool present in lipid rafts.”
- Also stated in: § RESULTS · hedged
“Collectively, these results support the idea that IDOL targets a LDLR pool located in lipid rafts.”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · hedged
- Findingown data§ RESULTS
USP8 is a potent inhibitor of IDOL-dependent degradation of the LDLR.
“However, in this setting USP8 was a potent inhibitor of IDOL-dependent degradation of the LDLR, further supporting the role of the ESCRT system in LDLR degradation ( Fig. 8C ).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Silencing of TSG101 in A431 cells attenuates LDLR degradation upon LXR activation without affecting LDLR and IDOL mRNA levels.
“Silencing of TSG101 in A431 cells attenuated LDLR degradation upon LXR activation without affecting LDLR and IDOL mRNA levels ( Fig. 8A and not shown), in line with the critical role of TSG101 in sorting ubiquitinated cargo in endosomes.”
Quote in the paperSubstantial claim - Findingown data§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
Degradation of the LDLR can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT).
“degradation of the receptor can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT) or by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
IDOL-mediated degradation of the LDLR does not require ARH.
“Collectively, this series of experiments indicates that degradation of the LDLR by the LXR-IDOL axis does not require clathrin-mediated internalization and the adaptor protein ARH.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
IDOL preferentially targets LDLR in membrane fractions typically associated with lipid rafts.
“Unlike Scotti et al . ( 56 ) who observed no effect of fi lipin (1 𝛍 g/ml), we found that perturbing lipid raft integrity with fi lipin (10 𝛍 g/ml) or M 𝛃 CD attenuated degradation of the LDLR by IDOL, and that IDOL preferentially targeted LDLR in membrane fractions typically associated with lipid rafts.”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
IDOL-mediated internalization and degradation of the LDLR is clathrin-independent.
“In this respect, the main fi nding of our study is that IDOL-mediated internalization and degradation of the LDLR is clathrin-independent, thus distinguishing it from the route that is used for lipoprotein uptake via the LDLR pathway.”
- Also stated in: § RESULTS · plain
“This cellular itinerary is clathrin-independent and distinct from that used for LDL internalization.”
- Also stated in: § DISCUSSION · boosted
“Both studies, using different methodologies, demonstrate that IDOL-stimulated internalization of the LDLR is clathrin-, caveolae-, and dynamin-independent, and identify the ESCRT system and associated DUB USP8 as important determinants for sorting ubiquitylated LDLR to MVBs.”
Quote in the paperSubstantial claim - Also stated in: § RESULTS · plain
- Findingown data§ DISCUSSION
IDOL-mediated internalization and degradation of the LDLR does not require caveolin/caveolae activity.
“In fact, this pathway is not only clathrin-independent, but does not require caveolin or dynamin activity either.”
- Also stated in: § DISCUSSION · boosted
“Both studies, using different methodologies, demonstrate that IDOL-stimulated internalization of the LDLR is clathrin-, caveolae-, and dynamin-independent, and identify the ESCRT system and associated DUB USP8 as important determinants for sorting ubiquitylated LDLR to MVBs.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · boosted
- Findingown data§ RESULTS
Treating cells for a short (4 h) period with a synthetic LXR ligand to induce IDOL expression reduces the level of total LDLR.
“treating the cells for a short (4 h) period with a synthetic LXR ligand to induce IDOL expression reduces the level of total LDLR.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Effective silencing of EPN1 in both HeLa and A431 cells does not abrogate the ubiquitylation-coupled internalization of the LDLR by IDOL.
“Our study was not specifi cally geared toward addressing the role of Epsin1 in LDL uptake, yet our results demonstrate that effective silencing of EPN1 in both HeLa and A431 cells does not abrogate the ubiquitylation-coupled internalization of the LDLR by IDOL.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Over-expressed USP8 stabilizes transfected IDOL.
“Intriguingly, over-expressed USP8 also stabilizes transfected IDOL, similar to what we observe by over-expression of Epsin1 or mutant VPS4 E228Q , which have no deubiquitylase activity.”
Quote in the paperNot a substantial claim - Findingown data§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
Degradation of the LDLR can be blocked by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies.
“degradation of the receptor can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT) or by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Perturbing lipid raft integrity with filipin (10 μg/ml) or MβCD attenuates degradation of the LDLR by IDOL.
“Unlike Scotti et al . ( 56 ) who observed no effect of fi lipin (1 𝛍 g/ml), we found that perturbing lipid raft integrity with fi lipin (10 𝛍 g/ml) or M 𝛃 CD attenuated degradation of the LDLR by IDOL, and that IDOL preferentially targeted LDLR in membrane fractions typically associated with lipid rafts.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Epsin1 over-expression inhibits IDOL-mediated degradation of the LDLR in a dose-dependent manner.
“Coexpression of Epsin1 together with LDLR and IDOL inhibited degradation of the receptor in a dose-dependent manner ( Fig. 7A ), which paradoxically, was also accompanied by stabilization of IDOL protein.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
IDOL targets a plasma membrane-resident LDLR pool.
“Because epsins control cargo internalization at the plasma membrane, this result further strengthens our conclusion that IDOL targets a plasma membrane-resident LDLR pool.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
The study establishes an intracellular trafficking sequence for the LDLR that emanates from lipid rafts at the plasma membrane and culminates in sorting to MVBs and receptor degradation.
“Thus, our study establishes an intracellular traffi cking sequence for the LDLR that emanates from lipid rafts at the plasma membrane and culminates in sorting to MVBs and receptor degradation.”
Quote in the paperSubstantial claim - Interpretationcitation§ DISCUSSION
USP8 likely acts on ubiquitylated LDLR directly and shunts it away from degradation.
“Likely, USP8 acts on ubiquitylated LDLR directly and shunts it away from degradation, as has been shown in the case of the EGFR ( 52 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Mizuno, 2005, Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes, Mol. Biol. Cell. source
- Interpretationown data§ RESULTS
Epsin-dependent processes act downstream of IDOL-mediated ubiquitylation of the LDLR to sort the receptor toward lysosomal degradation.
“Thus, our results indicate that epsin-dependent processes act downstream of IDOL-mediated ubiquitylation of the LDLR to sort the receptor toward lysosomal degradation.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
Over-expression of Epsin1 is known to act in a dominant fashion and pan-inhibit epsin-dependent processes.
“Over-expression of Epsin1, which is known to act in a dominant fashion and pan-inhibit epsindependent processes ( 41 ), effectively blocked IDOL-mediated degradation of the LDLR and the VLDLR.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Ford, 2002, Curvature of clathrin-coated pits driven by epsin, Nature. source
- Interpretationown data§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation
The LXR-IDOL axis defines an endocytic route for LDLR internalization and lysosomal degradation that is distinct from that used for lipoprotein uptake.
“In summary, we provide evidence for the existence of an LXR-IDOL-mediated internalization pathway for the LDLR that is distinct from that used for lipoprotein uptake.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Lipid rafts can serve as a platform for recruiting IDOL for LDLR downregulation.
“Thus, we propose that lipid rafts can serve as a platform for recruiting IDOL for LDLR downregulation.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
IDOL-mediated internalization and degradation of the LDLR is distinct from the route used for lipoprotein uptake via the LDLR pathway.
“In this respect, the main fi nding of our study is that IDOL-mediated internalization and degradation of the LDLR is clathrin-independent, thus distinguishing it from the route that is used for lipoprotein uptake via the LDLR pathway.”
- Also stated in: § DISCUSSION · boosted
“In summary, IDOL establishes a previously unrecognized pathway for LDLR internalization that is distinct from that used for lipoprotein uptake.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · boosted
- Interpretationown data§ DISCUSSION
Accumulation of ubiquitylated receptor positions epsins downstream of receptor ubiquitylation by IDOL.
“This was also accompanied by accumulation of ubiquitylated receptor, positioning epsins downstream of receptor ubiquitylation by IDOL.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Our study implicates epsins or related ubiquitin-interacting proteins in the initial steps of IDOL-mediated internalization of ubiquitylated LDLR.
“Additionally, our study implicates epsins or related ubiquitin-interacting proteins in the initial steps of IDOL-mediated internalization of ubiquitylated LDLR.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
A common feature of these perturbations is their ability to inhibit degradation of the LDLR by IDOL.
“A common feature of these perturbations is their ability to inhibit degradation of the LDLR by IDOL.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
Knockdown of EPN1 in HeLa cells does not block internalization of LDL.
“Similarly, knockdown of EPN1 in HeLa cells did not block internalization of LDL ( 4 ), supporting the idea that Epsin1 is not required for LDL or LDLR internalization.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Keyel, 2006, A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors, Mol. Biol. Cell. source
- Premisecitation§ DISCUSSION
Epsin1 is not required for LDL or LDLR internalization.
“Similarly, knockdown of EPN1 in HeLa cells did not block internalization of LDL ( 4 ), supporting the idea that Epsin1 is not required for LDL or LDLR internalization.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Keyel, 2006, A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors, Mol. Biol. Cell. source
- Interpretationreasoning§ DISCUSSION
IDOL establishes a previously unrecognized pathway for LDLR internalization that is distinct from that used for lipoprotein uptake.
“In summary, IDOL establishes a previously unrecognized pathway for LDLR internalization that is distinct from that used for lipoprotein uptake.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 12
- Probably not a substantial claim. 14
- The quote only partly states this claim. 2
It may state two separate claims as one.
Premisecitation§ DISCUSSIONWhereas the LDLR is degraded in the lysosome, IDOL is subject to proteasomal breakdown.
“We think that this is unlikely, as we previously reported that whereas the LDLR is degraded in the lysosome, IDOL is subject to proteasomal breakdown ( 21 ).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [21] Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science. source
It may state two separate claims as one.
Premisecitation§ DISCUSSIONThe PCSK9 route does not require ESCRT-mediated sorting and is a clathrin-dependent process that capitalizes on the same cellular machinery used for LDL endocytosis.
“In contrast to IDOL-stimulated degradation of the LDLR, the PCSK9 route does not require ESCRT-mediated sorting and is a clathrin-dependent process that capitalizes on the same cellular machinery used for LDL endocytosis ( 55 ).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [55] Wang, 2012, Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR, J. Lipid Res. source
The Results section ('PCSK9-mediated LDLR degradation requires clathrin-mediated endocytosis') says the PCSK9–LDLR complex uses the same endocytic machinery that imports LDL. The ESCRT Results section says degradation does not require the first ESCRT components tested, but explicitly allows that the complex may enter the pathway downstream. The claim overstates that qualified finding as independence from ESCRT-mediated sorting altogether. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DISCUSSIONSignaling and internalization of receptors largely depends on recruitment of specific adaptor proteins, including ubiquitin-ligases and epsins.
“Signaling and internalization of receptors largely depends on recruitment of specifi c adaptor proteins, including ubiquitin-ligases and epsins ( 13, 14, 46 ).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [13] Sigismund, 2012, Endocytosis and signaling: cell logistics shape the eukaryotic cell plan, Physiol. Rev. source
In “Ligand-Induced Ubiquitination of Adaptors” (page unavailable), the review says endocytic adaptors play a critical role in receptor internalization and identifies epsin-1 as an endocytic protein involved in adaptor ubiquitination. “Ligand-Induced Ubiquitination of Cargo” describes adaptors recruiting E3 ubiquitin ligases to receptors, rather than identifying the ligases themselves as adaptor proteins. The review supports the importance of these proteins in the pathways discussed, but not the claim’s classification of ubiquitin ligases as adaptors. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [14] MacGurn, 2012, Ubiquitin and membrane protein turnover: from cradle to grave, Annu. Rev. Biochem. source
- cites [46] Lafont, 2001, Raft-partitioning of the ubiquitin ligases Cbl and Nedd4 upon IgE-triggered cell signaling, Proc. Natl. Acad. Sci. USA. source
It may state two separate claims as one.
Premisecitation§ DISCUSSIONIDOL and PCSK9 represent major posttranscriptional pathways that promote LDLR degradation, and these pathways represent distinct routes for LDLR degradation.
“IDOL and PCSK9 represent the major posttranscriptional pathways that promote LDLR degradation, and as previously suggested these pathways represent distinct routes for LDLR degradation ( 23, 54 ).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [23] Sorrentino, 2012, Post-transcriptional regulation of lipoprotein receptors by the E3-ubiquitin ligase inducible degrader of the low-density lipoprotein receptor, Curr. Opin. Lipidol. source
- cites [54] Scotti, 2011, Targeted disruption of the idol gene alters cellular regulation of the low-density lipoprotein receptor by sterols and liver x receptor agonists, Mol. Cell. Biol. source
The quote only partly states this claim.
Findingown data§ RESULTSIDOL-dependent internalization of the LDLR is independent of clathrin.
“IDOL-mediated degradation of the LDLR is clathrin independent.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ DISCUSSIONBafilomycin A1 attenuates IDOL-mediated degradation of the LDLR but does not lead to parallel stabilization of IDOL.
“Furthermore, the lysosomotropic agent bafi lomycin A1, which attenuates IDOL-mediated degradation of the LDLR, does not lead to parallel stabilization of IDOL (not shown).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown data§ RESULTSIDOL-dependent internalization of the LDLR is independent of caveolin.
“Degradation of the LDLR by IDOL is independent of caveolin and macroautophagy.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ RESULTSExpression of a mutant VPS4 E228Q form in HEK293T cells abolishes degradation of the LDLR by IDOL, while WT VPS4 has no effect.
“Accordingly, expression of a mutant VPS4 E228Q form in HEK293T cells abolished degradation of the LDLR by IDOL ( Fig. 8B ), while WT VPS4 had no effect.”
Quote in the paperSubstantial claimProbably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
Findingown data§ DISCUSSIONEPS15 and EPS15R are involved in IDOL-mediated internalization of ubiquitylated LDLR.
“Our preliminary results rather suggest that EPS15 and EPS15R are involved in this process and studies to elucidate the critical role of these ubiquitin-adaptors as downstream effectors of ubiquitylated LDLR sorting are ongoing.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ DISCUSSIONUSP8 can break down both K48- and K63-linked ubiquitin chains and can remove attached ubiquitin from cargo as well as modify the ubiquitylation state of ESCRT components.
“USP8 can break down both K48- and K63-linked ubiquitin chains and can remove attached ubiquitin from cargo as well as modify the ubiquitylation state of ESCRT components ( 45 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Clague, 2006, Endocytosis: the DUB version, Trends Cell Biol. source
Probably not a substantial claim.
Premisecitation§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradationLDL is taken up into cells via clathrin-mediated endocytosis of the LDL receptor (LDLR).
“Low density lipoprotein (LDL) cholesterol is taken up into cells via clathrin-mediated endocytosis of the LDL receptor (LDLR).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ DISCUSSIONSilencing of EPN1 in monkey BSC-1 cells prevents entry of the influenza virus via clathrin-dependent endocytosis, but internalization of LDL or transferrin in these cells via the same pathway remains unchanged.
“For example, while silencing of EPN1 (EPSIN1) in monkey BSC-1 cells prevents entry of the infl uenza virus via clathrin-dependent endocytosis, internalization of LDL or transferrin in these cells via the same pathway remains unchanged ( 50 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50] Chen, 2008, Epsin 1 is a cargo-specific adaptor for the clathrin-mediated endocytosis of the influenza virus, Proc. Natl. Acad. Sci. USA. source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DISCUSSIONScotti et al. reported findings similar to those reported here.
“While completing our study, Scotti et al. ( 56 ) reported fi ndings similar to those reported here.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [56] Scotti, 2013, IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor, Mol. Cell. Biol. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given§ MATERIALS AND METHODSUnless otherwise indicated, all immunoblots shown are representative of at least three independent experiments with similar results.
“Unless otherwise indicated, all immunoblots shown are representative of at least three independent experiments with similar results.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DISCUSSIONLipid rafts are dynamic microdomains consisting of cholesterol and sphingolipids in the plasma membrane.
“Lipid rafts are dynamic microdomains consisting of cholesterol and sphingolipids in the plasma membrane ( 36 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Simons, 2000, Lipid rafts and signal transduction, Nat. Rev. Mol. Cell Biol. source
It may state two separate claims as one.
Interpretationown data§ DISCUSSIONIDOL-mediated internalization of the LDLR requires epsins and subsequent sorting by the ESCRT system.
“Instead, we propose that IDOL-mediated internalization of the LDLR requires epsins and subsequent sorting by the ESCRT system.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DISCUSSIONFunctional coupling of target ubiquitylation and degradation to that of the cognate E3-ubiquitin ligase is an emerging concept in the ubiquitin field.
“Functional coupling of target ubiquitylation and degradation to that of the cognate E3-ubiquitin ligase is an emerging concept in the ubiquitin fi eld ( 53 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53] de Bie, 2011, Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms, Cell Death Differ. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DISCUSSIONEpsins are a class of ubiquitin adaptors implicated in internalization and sorting of plasma membrane receptors.
“Epsins are a class of ubiquitin adaptors that are implicated in internalization and sorting of plasma membrane receptors ( 39, 40, 47 ), and are implicated in tuning, among other, EGFR ( 27, 38 ), Notch ( 48 ), and VEFGR2 signaling ( 49 ).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [39] Polo, 2002, A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins, Nature. source
- cites [40] Wendland, 2002, Epsins: adaptors in endocytosis?, Nat. Rev. Mol. Cell Biol. source
- cites [47] Horvath, 2007, Epsin: inducing membrane curvature, Int. J. Biochem. Cell Biol. source
It may state two separate claims as one.
Interpretationown data§ RESULTSIDOL-dependent degradation of the LDLR emanates from lipid rafts and requires ubiquitylation and subsequent initial sorting by epsins that is followed by ESCRT-dependent sorting into MVBs.
“Overall, our experiments propose that IDOL-dependent degradation of the LDLR emanates from lipid rafts and requires ubiquitylation and subsequent initial sorting by epsins that is followed by ESCRT-dependent sorting into MVBs.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DISCUSSIONDisrupting lipid raft integrity, e.g., with MβCD or filipin, perturbs cell-signaling and protein-interaction networks.
“Moreover, disrupting lipid raft integrity, e.g., with M 𝛃 CD or fi lipin, perturbs cell-signaling and protein-interaction networks ( 36 ).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Simons, 2000, Lipid rafts and signal transduction, Nat. Rev. Mol. Cell Biol. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given§ Plasmids and expression constructsDNA sequencing was used to verify the correctness of all constructs used in this study.
“DNA sequencing was used to verify the correctness of all the constructs used in this study.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Premisecitation§ DISCUSSIONBoth studies demonstrate that IDOL-stimulated internalization of the LDLR is clathrin-, caveolae-, and dynamin-independent, and identify the ESCRT system and associated DUB USP8 as important determinants for sorting ubiquitylated LDLR to MVBs.
“Both studies, using different methodologies, demonstrate that IDOL-stimulated internalization of the LDLR is clathrin-, caveolae-, and dynamin-independent, and identify the ESCRT system and associated DUB USP8 as important determinants for sorting ubiquitylated LDLR to MVBs.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [56] Scotti, 2013, IDOL stimulates clathrin-independent endocytosis and multivesicular body-mediated lysosomal degradation of the low-density lipoprotein receptor, Mol. Cell. Biol. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ The LXR-IDOL axis defi nes a clathrin-, caveolae -, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradationFollowing dissociation of the LDLR-LDL complex, LDL is directed to lysosomes whereas the LDLR recycles to the plasma membrane.
“Following dissociation of the LDLR-LDL complex, LDL is directed to lysosomes whereas the LDLR recycles to the plasma membrane.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Brown, 1986, A receptor-mediated pathway for cholesterol homeostasis, Science. source
It may state two separate claims as one.
Interpretationreasoning§ RESULTSBy promoting LDLR ubiquitylation, the LXR-IDOL pathway targets the plasma membrane LDLR for lysosomal degradation and impedes receptor recycling.
“Therefore, our observations suggest that by promoting LDLR ubiquitylation, the LXR-IDOL pathway targets the plasma membrane LDLR for lysosomal degradation and impedes receptor recycling.”
Quote in the paperSubstantial claimProbably not a substantial claim.
Study design and conductnone given§ siRNA interference experimentsSilencing of target genes was assessed by quantitative PCR or Western blotting.
“Silencing of target genes was assessed by quantitative PCR or Western blotting.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The chemical dynasore is an inhibitor of dynamin-dependent processes.
“The chemical dynasore is an inhibitor of dynamin-dependent processes”
The paper relies on this without support.
Epsin1 silencing failure to block IDOL degradation is due to functional redundancy with other related ubiquitin adaptors like Eps15 and Eps15R.
“most likely pointing to functional redundancy with other related ubiquitin adaptors like Eps15 and Eps15R”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Contradictory evidence suggests that USP8 may prevent IDOL-mediated LDLR degradation, with co-expression of IDOL and USP8 increasing total cellular LDLR.
“However, there is also contradictory evidence suggesting that the action of USP8 may prevent IDOL-mediated LDLR degradation, with co-expression of IDOL and USP8 resulting in an increase in total cellular LDLR [47].”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [47]
Polyubiquitination targets the LDLR to the lysosome via selective sorting into multivesicular bodies, requiring proteins from the epsin-family and ESCRT complexes.
“This polyubiquitination targets the LDLR to the lysosome via selective sorting into multivesicular bodies that are transported to, and fuse with, the lysosome. This protein sorting and lysosomal targeting requires proteins from the epsin-family and ESCRT complexes [47].”
From Post-translational regulation of the low-density lipoprotein receptor provides new targets for cholesterol regulation (2024) · cites this paper as [47]
IDOL is implicated in lysosomal targeting and degradation of LDLR.
“the E3 ligase IDOL, which has also been implicated in lysosomal targeting and degradation of the LDLR (28,33,34).”
From A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes (2016) · cites this paper as [28]
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Effect of Total SMS Activity on LDL Catabolism in Mice
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Metadata
- Authors
- Sorrentino, V., Nelson, J. K., Maspero, E., Marques, A. R. A., Scheer, L., Polo, S., & Zelcer, N.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- IFOM (IT)
- University of Milan (IT)
- Corresponding author
- Zelcer, Noam
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 54
- Issue
- 8
- Pages
- 2174-2184
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC3708367
- OpenAlex
- W2110245801
- Cited by
- 68
- References
- 57
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 6 · 2016: 4 · 2015: 9 · 2014: 7 · 2013: 1
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- National University of Singapore (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- LDL receptor, liver X receptor, idols, LDL cholesterol uptake, receptor internalization, lysosomal degradation, ubiquitination, epsin, ESCRT, USP8, lipid rafts, endosomal trafficking, caveolae, dynamin-independent endocytosis, macroautophagy
- MeSH terms
- Liver X Receptors, Cells, Cultured, Clathrin, Endocytosis, HeLa Cells, Humans, Lysosomes, Receptors, LDL, Caveolae, Dynamins, Ubiquitin-Protein Ligases, Hep G2 Cells, Orphan Nuclear Receptors, HEK293 Cells
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