The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

Nelson, Jessica Kristine; Sorrentino, Vincenzo; Avagliano Trezza, Rossella; Heride, Claire; Urbe, Sylvie; Distel, Ben; Zelcer, Noam

doi:10.1161/circresaha.115.307298

Cited by 51Ubiquitin and proteasome pathwaysCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index; none of the 51 sources its claims cite is checked for support yet.

The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

Open access

Nelson, Jessica Kristine, Sorrentino, Vincenzo, Avagliano Trezza, Rossella, Heride, Claire, Urbe, Sylvie, Distel, Ben, Zelcer, Noam·2016·Circulation Research

DOI 10.1161/circresaha.115.307298

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Abstract

Rationale: The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholesterol in humans. Acting as an E3-ubiquitin ligase, IDOL promotes ubiquitylation and subsequent lysosomal degradation of the LDLR. Consequently, inhibition of IDOL-mediated degradation of the LDLR represents a potential strategy to increase hepatic LDL-cholesterol clearance. Objective: To establish whether deubiquitylases counteract IDOL-mediated ubiquitylation and degradation of the LDLR. Methods and Results: Using a genetic screening approach, we identify the ubiquitin-specific protease 2 (USP2) as a post-transcriptional regulator of IDOL-mediated LDLR degradation. We demonstrate that both USP2 isoforms, USP2-69 and USP2-45, interact with IDOL and promote its deubiquitylation. IDOL deubiquitylation requires USP2 enzymatic activity and leads to a marked stabilization of IDOL protein. Paradoxically, this also markedly attenuates IDOL-mediated degradation of the LDLR and the ability of IDOL to limit LDL uptake into cells. Conversely, loss of USP2 reduces LDLR protein in an IDOL-dependent manner and limits LDL uptake. We identify a tri-partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation. Conclusions: Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.

AI snapshot

Written from the paper’s full text.

TL;DR

The deubiquitylase USP2 interacts with IDOL, deubiquitylates and stabilizes IDOL, yet paradoxically prevents IDOL-mediated ubiquitylation and degradation of the LDLR. USP2 loss reduces LDLR protein and LDL uptake in an IDOL-dependent manner, identifying USP2 as a regulator of the IDOL–LDLR axis.

Key findings

A yeast-2-hybrid screen of 61 deubiquitylases (77% of known active mammalian deubiquitylases) identified USP2-69 as an IDOL-binding partner; USP2-45 also interacted with IDOL, and the interaction mapped to IDOL’s F3/linker region and was maintained with catalytically inactive USP2 C276A.
USP2 overexpression stabilized IDOL protein, extended IDOL half-life, and reduced ubiquitylated IDOL species; this required USP2 catalytic activity, as USP2 C276A did not stabilize IDOL.
Despite stabilizing IDOL, USP2 prevented IDOL-mediated degradation of the LDLR and VLDLR and counteracted LXR-induced LDLR degradation; USP2 also blocked the IDOL-dependent decrease in LDL uptake.
Silencing USP2 reduced LDLR protein without changing LDLR mRNA, reduced cell-surface LDLR (100±2.6 in control versus 30.4±4.9 in siUSP2, n=8, P<0.0001), and attenuated LDL uptake; in Idol−/− MEFs, LDLR was elevated and insensitive to Usp2 silencing. USP2 silencing efficiency was 55±6% reduction in HepG2/Huh7 cells.

Methods

Yeast-2-hybrid interaction screen using a prey library of 61 deubiquitylases against full-length IDOL or the LDLR intracellular tail (residues 780–860), followed by spot assays and mapping of IDOL domains.
Cell-based assays in HEK293T, HeLa, Huh7, HepG2, A431, DU145, and wild-type or Idol−/− MEFs, with transfections of IDOL, LDLR, VLDLR, USP2-69, USP2-45, USP2 C276A, USP8, ubiquitin, and Epsin1; siRNA knockdown of USP2; immunoblotting, immunoprecipitation, qPCR, cycloheximide chase, MG132 treatment, FACS for surface LDLR, and DyLight 488-labeled LDL uptake.
Data presented as mean±SD; one-way ANOVA with Bonferroni correction for >2 groups, Student’s t test for 2 groups, P<0.05 considered significant.

Limitations

The paper states that endogenous IDOL and endogenous USP2 could not be detected with available antibodies, so several experiments relied on transfected proteins.
The paper states species-dependent differences in hepatic IDOL activity: the IDOL pathway is highly active in human and nonhuman primate hepatocytes but not rodent hepatocytes, and Idol−/− mice do not show a marked cholesterol phenotype or changes in hepatic LDLR content; thus in vivo physiological testing of the USP2–IDOL nexus is limited.
The paper states that it cannot formally rule out an alternative model in which ubiquitylation of IDOL itself regulates both its stability and activity, rather than USP2 acting directly on the LDLR; it also notes that the yeast-2-hybrid assay may miss interactions requiring membrane context or ubiquitylated LDLR tail.

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

Integrity signals

Registry

Crossref · 10.1161/circresaha.115.307298

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 51 cited sources checked · 0 supported · 0 flagged

Findingown data
Silencing USP2 attenuated LDL uptake in different cell types.
“and as a consequence attenuated LDL uptake in different cell types (Figure 4D).”
Quote in the paperSubstantial claim
Findingown data
Both USP2 isoforms reduced the degree of ubiquitylated IDOL under proteasomal blocking.
“Under this condition, both USP2 isoforms reduced the degree of ubiquitylated IDOL (Figure 2D and 2E).”
Quote in the paperSubstantial claim
Findingown data
In HepG2 cells, PCSK9 expression was not sensitive to the level of USP2.
“However, this does not seem to be the case because in HepG2 cells, PCSK9 expression was not sensitive to the level of USP2 (Figure 4B).”
Quote in the paperSubstantial claim
Findingown data
IDOL's F3 and linker subdomains are the minimal regions required for interacting with USP2.
“Using the yeast-2-hybrid assay, we mapped IDOL's F3 and linker subdomains as the minimal regions required for interacting with USP2 (Figure 1A and 1B; Online Figure IB).”
Quote in the paperNot a substantial claim
Findingown data
Only the active form of USP2 could increase IDOL levels.
“Thus, in spite of the preserved interaction of IDOL with both wild-type USP2 and USP2 C276A only the active form of USP2 could increase IDOL levels.”
Quote in the paperSubstantial claim

Findingown data
Stabilization of IDOL by USP2 required USP2 catalytic activity, as it was not seen with USP2 C276A.
“The stabilization of wild-type IDOL was equivalent to that observed with the proteasome inhibitor MG132, and required USP2 catalytic activity, as it was not seen with USP2 C276A (Figure 2B).”
Quote in the paperSubstantial claim
Findingown data
USP2-45 interacted with IDOL.
“Like the USP2-69 isoform, the lowermolecular weight isoform, USP2-45 interacted with IDOL as well (Figure 1D).”
Quote in the paperSubstantial claim
Findingown data
Stabilization of wild-type IDOL by USP2 was equivalent to that observed with the proteasome inhibitor MG132.
“The stabilization of wild-type IDOL was equivalent to that observed with the proteasome inhibitor MG132, and required USP2 catalytic activity, as it was not seen with USP2 C276A (Figure 2B).”
Quote in the paperSubstantial claim
Findingown data
The yeast-2-hybrid screen failed to identify any LDLR-tail-interacting deubiquitylases.
“This screen failed to identify any LDLR-tail-interacting deubiquitylases (Online Figure IA).”
Quote in the paperNot a substantial claim
Findingown data
Antagonism of IDOL activity by USP2 counteracted the decrease in cellular LDL uptake imposed by IDOL.
“Functionally, antagonism of IDOL activity by USP2 counteracted the decrease in cellular LDL uptake imposed by IDOL (Figure 3D), positioning this deubiquitylase as a potential regulator of lipoprotein uptake.”
Quote in the paperSubstantial claim
Findingown data
The interaction with USP2 is maintained with a severe IDOL RING mutant, IDOL C387A.
“Importantly, the interaction with USP2 was also maintained with a severe IDOL RING mutant, IDOL C387A .”
Quote in the paperSubstantial claim
Findingown data
Stabilization of IDOL by USP2 was a result of the extension of IDOL's half-life.
“Accordingly, using cycloheximide to prevent protein synthesis we could determine that stabilization of IDOL by USP2 was a result of the extension of IDOL's half-life (Figure 2C; Online Figure III).”
Quote in the paperSubstantial claim
Findingown data
Overexpression of USP2 markedly stabilized IDOL protein.
“Remarkably, we found that overexpression of USP2 markedly stabilized IDOL protein (Figure 2A).”
Quote in the paperSubstantial claim
Findingown data
USP8 failed to stabilize IDOL protein.
“USP8 however failed to do so, supporting the notion that the antagonizing effects of USP8 on the LXR-IDOL-LDLR axis occur primarily at the level of the ubiquitylated receptor.”
Quote in the paperSubstantial claim
Findingown data
Effective silencing of USP2 in HepG2 and Huh7 cells (55±6% reduction) reduced immunodetectable IDOL protein.
“We observed that effective silencing of USP2 in these cells (55±6% reduction) reduced immunodetectable IDOL protein (Online Figure IVA and IVB), consistent with the notion that USP2 removes ubiquitin from IDOL to prevent its degradation.”
Quote in the paperSubstantial claim
Findingown data
The USP2-IDOL interaction takes place in mammalian cells (HEK293T).
“We next confirmed that this interaction also takes place in mammalian cells (HEK293T).”
Quote in the paperSubstantial claim
Findingown data
Effective silencing of Usp2 in wild-type MEFs decreased the LDLR.
“Effective silencing of Usp2 in wildtype cells decreased the LDLR.”
Quote in the paperSubstantial claim
Findingown data
The yeast-2-hybrid assay identified the USP2-69 isoform as an interacting partner of full-length IDOL protein.
“However, the assay identified the deubiquitylase USP2-69 isoform (referred to further as USP2), as an interacting partner of the full-length IDOL protein (Online Table I).”
Quote in the paperSubstantial claim
Findingown data
Silencing USP2 resulted in prominent removal of LDLR from the cell surface (100±2.6 in control versus 30.4±4.9 in siUSP2, n=8, P<0.0001).
“we found that silencing USP2 resulted in prominent removal of LDLR from the cell surface (100±2.6 in control versus 30.4±4.9 in siUSP2, n=8, P<0.0001; Figure 4C)”
Quote in the paperSubstantial claim
Findingown data
Immunoprecipitation of transfected USP2 or IDOL resulted in copurification of the corresponding binding partner.
“Immunoprecipitation of transfected USP2 or IDOL (1:1 ratio) resulted in copurification of the corresponding binding partner (Figure 1C; Online Figure IIA).”
Quote in the paperSubstantial claim
Findingown data
The interaction with IDOL is independent of USP2's catalytic activity because it is maintained in the USP2 C276A catalytic mutant.
“Furthermore, the interaction with IDOL was independent of USP2s catalytic activity because it was maintained in the USP2 C276A catalytic mutant (Online Figure IIB).”
Quote in the paperNot a substantial claim
Findingreasoning
The phenotype is IDOL dependent.
“This would be consistent with the fact that the phenotype is IDOL dependent, and that USP2 is able to process diverse ubiquitin linkages.35,36”
Quote in the paperSubstantial claim
Findingown data
USP2 stabilizes IDOL by promoting its deubiquitylation.
“whereas USP2 dramatically stabilizes IDOL by promoting its deubiquitylation”
- Also stated in: § Additional information · plain
  “We found that USP2 deubiquitylates IDOL resulting in increased IDOL stability.”
Quote in the paperSubstantial claim
Findingown data
USP2 interacts with the LDLR in mammalian cells, albeit weakly.
“we tested whether USP2 interacts with the LDLR in mammalian cells, and found that USP2 could be pulled down with the LDLR, albeit weakly (Figure 5B, lane 4).”
Quote in the paperSubstantial claim
Findingown data
USP2 can control LDLR protein abundance in an IDOL-dependent manner.
“Our results demonstrate that USP2 can control LDLR protein abundance in an IDOL-dependent manner.”
Quote in the paperSubstantial claim
Findingreasoning
Dominant negative Epsin1 increases ubiquitylated LDLR species.
“The use of dominant negative Epsin1 also increased ubiquitylated LDLR species, as expected.”
Quote in the paperNot a substantial claim
Findingown data
USP2 can reverse IDOL-mediated degradation of the LDLR.
“because USP2 can reverse IDOL-mediated degradation of the LDLR”
Quote in the paperSubstantial claim
Findingown data
The screen with the LDLR intracellular tail failed to identify any LDLR-interacting deubiquitylases.
“The screen with the LDLR intracellular tail failed to identify any LDLRinteracting deubiquitylases.”
Quote in the paperSubstantial claim
Findingown data
Using a genetic approach, we identified the deubiquitylase USP2 as an IDOL-interacting partner.
“Using a genetic approach, we identified the deubiquitylase USP2 as an IDOL-interacting partner.”
Quote in the paperSubstantial claim
Findingown data
USP2 is a new regulator of LDL metabolism owing to its ability to counteract IDOL-mediated degradation of the LDLR.
“As such, our study identifies USP2 as a new regulator of LDL metabolism owing to its ability to counteract IDOL-mediated degradation of the LDLR.”
Quote in the paperSubstantial claim
Findingown data
No interaction between USP2 and the intracellular tail of the LDLR was detected in the yeast-2-hybrid screen.
“In the yeast-2-hybrid screen, no interaction between USP2 and the intracellular tail of the LDLR was detected (Online Figure IA).”
Quote in the paperSubstantial claim
Findingown data
The FERM domain interacted with the LDLR.
“As expected, the FERM domain interacted with the LDLR (Figure 5B, lane 7).”
Quote in the paperNot a substantial claim
Findingown data
USP2 inhibits IDOL-stimulated degradation of the LDLR.
“it also inhibits IDOL-stimulated degradation of the LDLR.”
- Also stated in: § Additional information · plain
  “However, despite elevated levels of IDOL degradation of the LDLR is paradoxically attenuated.”
Quote in the paperSubstantial claim
Findingown data
When all three (IDOL, USP2, LDLR) were introduced into cells, both USP2 and IDOL were readily coimmunoprecipitated with the LDLR.
“Yet when all the 3 were introduced into cells, we found that both USP2 and IDOL were readily coimmunoprecipitated with the LDLR (Figure 5B, lane 8).”
Quote in the paperSubstantial claim
Findingown data
When USP2 is also present, the level of ubiquitylated LDLR is markedly reduced.
“Yet when the deubiquitylase USP2 was also present, the level of ubiquitylated LDLR was markedly reduced (Figure 5C, lane 5).”
Quote in the paperSubstantial claim
Findingown data
Introducing USP2 at increasing dose has no effect on LDLR protein in the absence of IDOL.
“We introduced USP2 into cells at an increasing dose but found that this had no effect on LDLR protein, unlike what we observed in the presence of IDOL (Figure 3).”
Quote in the paperSubstantial claim
Findingown data
By screening the deubiquitylase library against IDOL, we identified USP2 as a novel IDOL-binding protein.
“However, by screening the deubiquitylase library against IDOL, we identified USP2 as a novel IDOL-binding protein.”
Quote in the paperSubstantial claim
Interpretationown data
The deubiquitylase activity of USP2, rather than steric hindrance, is required for IDOL stabilization.
“This finding implies that the deubiquitylase activity of USP2, rather than steric hindrance is required for IDOL stabilization.”
Quote in the paperSubstantial claim
Premisecitation
The LXR-IDOL-LDLR axis is a potent ubiquitylation-dependent mechanism to acutely limit lipoprotein-derived cholesterol uptake.
“Thus, the LXR-IDOL-LDLR axis is a potent ubiquitylation-dependent mechanism to acutely limit lipoprotein-derived cholesterol uptake.13,14”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [13]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Premisecitation
Ubiquitylation of the LDLR plays an important role in controlling the intracellular trafficking of the receptor.
“ubiquitylation of the LDLR plays an important role in controlling the intracellular trafficking of the receptor, 6,7 similar to the role this process plays for other membrane receptors.”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [6]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationown data
USP2 removes ubiquitin from IDOL to prevent its degradation.
“consistent with the notion that USP2 removes ubiquitin from IDOL to prevent its degradation.”
Quote in the paperSubstantial claim
Premisecitation
IDOL is an E3-ubiquitin ligase that specifically promotes ubiquitylation of the LDLR.
“We have recently identified inducible degrader of the LDLR (IDOL) as an E3-ubiquitin ligase (E3) that specifically promotes ubiquitylation of the LDLR.8”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [8]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationown data
Both gain and loss of USP2 function modulate the level of IDOL protein.
“Thus, our experiments demonstrate that both gain and loss of USP2 function modulate the level of IDOL protein.”
Quote in the paperSubstantial claim
Premisecitation
Genome-wide association studies identify an association between genetic variation in the IDOL locus and circulating levels of LDL-cholesterol.
“The role of IDOL in human lipoprotein metabolism is supported by genome-wide association studies that identify an association between genetic variation in the IDOL locus and circulating levels of LDL-cholesterol.9,10”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [9]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationown data
USP2 is a negative regulator of IDOL-dependent degradation of the LDLR.
“Herein, we identify USP2 as a negative regulator of IDOL-dependent degradation of the LDLR, thereby implicating this deubiquitylase as a regulator of lipoprotein metabolism.”
Quote in the paperSubstantial claim
- Rests on an assumption: Whether deubiquitylases play a role in cholesterol metabolism is largely unknown.
- Rests on an assumption: Post-transcriptional mechanisms are important determinants of LDLR abundance.
Interpretationown data
USP2 is a potential regulator of lipoprotein uptake.
“positioning this deubiquitylase as a potential regulator of lipoprotein uptake.”
Quote in the paperSubstantial claim
Interpretationown data
USP2 is a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.
“Our findings identify USP2 as a novel regulator of lipoprotein clearance owing to its ability to control ubiquitylation-dependent degradation of the LDLR by IDOL.”
Quote in the paperSubstantial claim
- Rests on an assumption: Whether deubiquitylases play a role in cholesterol metabolism is largely unknown.
- Rests on an assumption: Post-transcriptional mechanisms are important determinants of LDLR abundance.
Interpretationown data
The antagonizing effects of USP8 on the LXR-IDOL-LDLR axis occur primarily at the level of the ubiquitylated receptor.
“supporting the notion that the antagonizing effects of USP8 on the LXR-IDOL-LDLR axis occur primarily at the level of the ubiquitylated receptor.”
Quote in the paperNot a substantial claim
Premisecitation
IDOL is a highly unstable protein, likely because of its high autoubiquitylation activity.
“We have previously reported that IDOL is a highly unstable protein, likely because of its high autoubiquitylation activity.8”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [8]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationown data
The USP2-IDOL nexus is functionally important in physiological control of LDLR levels.
“Collectively, these results demonstrate the functional importance of the USP2-IDOL nexus in physiological control of LDLR levels.”
Quote in the paperSubstantial claim
Premisecitation
Ubiquitylation of the LDLR marks the receptor for internalization and subsequent lysosomal degradation.
“In turn, ubiquitylation of the LDLR serves to mark the receptor for internalization and subsequent lysosomal degradation.8”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [8]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Premisecitation
The FERM domain binds USP2.
“the FERM domain binds USP2, and it is recruited to, and binds the LDLR at the plasma membrane, 22 but does not stimulate degradation of the receptor because of the lack of the RING domain.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [22]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationreasoning
IDOL activity represents an acute mechanism to shut down uptake of LDL-derived cholesterol into cells.
“As such, IDOL activity represents an acute mechanism to shut down uptake of LDL-derived cholesterol into cells.”
Quote in the paperNot a substantial claim
Interpretationown data
For USP2 to modulate LDLR levels, ubiquitylation of the receptor is required.
“This suggests that for USP2 to modulate LDLR levels, ubiquitylation of the receptor is required.”
Quote in the paperSubstantial claim
Interpretationreasoning
A functional USP2-IDOL interaction will be predominantly active in human hepatocytes.
“We therefore anticipate that a functional USP2-IDOL interaction will be predominantly active in human hepatocytes.”
Quote in the paperSubstantial claim
Premisecitation
The FERM domain does not stimulate degradation of the LDLR because it lacks the RING domain.
“the FERM domain binds USP2, and it is recruited to, and binds the LDLR at the plasma membrane, 22 but does not stimulate degradation of the receptor because of the lack of the RING domain.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [22]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationown data
A tri-partite complex containing IDOL, USP2, and the LDLR is formed at the plasma membrane.
“This result supports the idea that a tri-partite complex, containing IDOL, USP2, and the LDLR is formed at the plasma membrane.”
Quote in the paperSubstantial claim
Premisenone given
The E3 ubiquitin ligase IDOL promotes ubiquitylation and subsequent degradation of the LDLR.
“The E3 ubiquitin ligase IDOL promotes ubiquitylation and subsequent degradation of the LDLR.”
Quote in the paperSubstantial claim
Interpretationreasoning
Expression of USP2 is sensitive to nutritional and circadian input.
“The above-mentioned regulation suggests that expression of USP2 is sensitive to nutritional and circadian input.”
Quote in the paperNot a substantial claim
Premisecitation
Dominant negative Epsin1 blocks IDOL-stimulated degradation of the LDLR.
“We have previously used this approach to demonstrate that it effectively blocks IDOL-stimulated degradation of the LDLR.6”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [6]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationreasoning
The increased stabilization of IDOL is a result of its USP2-dependent deubiquitylation.
“The increased stabilization of IDOL is a result of its USP2-dependent deubiquitylation, similar to what has been described for the USP2-MDM2 and USP2-MDMX complexes.28,32”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [28]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [32]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Interpretationreasoning
Epsin1 blocks internalization of the LDLR following IDOL-mediated ubiquitylation, resulting in accumulation of ubiquitylated LDLR at the plasma membrane.
“This is because of Epsin1 blocking internalization of the LDLR following IDOL-mediated ubiquitylation, thus resulting in accumulation of ubiquitylated LDLR at the plasma membrane.”
Quote in the paperSubstantial claim
Interpretationreasoning
IDOL-mediated ubiquitylation of the LDLR is counteracted by subsequent removal of ubiquitin chains from the LDLR by USP2.
“The most plausible scenario to explain this outcome is that IDOL-mediated ubiquitylation of the LDLR is counteracted by subsequent removal of ubiquitin chains from the LDLR by USP2.”
Quote in the paperSubstantial claim
Premisecitation
Genetic variation in IDOL is a modifier of LDL cholesterol in humans.
“the growing body of evidence pointing toward genetic variation in IDOL as a modifier of LDL cholesterol in humans, [9][10][11]”
Quote in the paperNot a substantial claim0 of 3 sources checked
- cites [9]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

It may state two separate claims as one. 41
Probably not a substantial claim. 26

It may state two separate claims as one.
Findingown data
All three individual USP2 siRNAs effectively knocked down expression of USP2 in HepG2 cells and decreased the protein levels of the LDLR.
“All the 3 effectively knocked down expression of USP2 in HepG2 cells and decreased the protein levels of the LDLR (Online Figure VIIA and VIIB).”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
Neither LXR activation nor variation of cellular sterol content altered USP2 expression.
“However, we found that neither LXR activation nor variation of the cellular sterol content altered USP2 expression (Online Figure VD).”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Findingown data
In Idol (-/-) cells, LDLR protein was elevated, as previously reported, yet was insensitive to loss of Usp2.
“In Idol (-/-) cells LDLR protein was elevated, as previously reported, 30 yet was insensitive to loss of Usp2.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [30]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Findingown data
USP2 can counteract LXR-induced LDLR degradation, even though IDOL expression was induced.
“In agreement with our findings, USP2 was also able to counteract LXR-induced LDLR degradation, even though expression of IDOL was induced (Online Figure VB and VC).”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown data
EGFR remained either unchanged or slightly increased after knockdown of USP2.
“unchanged or even slightly increased after knockdown of USP2 in these cells (Figure 4A; Online Figure VIB).”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Findingown data
Silencing of USP2 in hepatic and nonhepatic cell lines led to a marked reduction in LDLR protein without changing the level of LDLR mRNA.
“Silencing of USP2 in these cells led to a marked reduction in LDLR protein without changing the level of LDLR mRNA (Figure 4A and 4B; Online Figure VIB-VID).”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
USP2 C276A and USP8 did not change the degree of IDOL ubiquitylation.
“Furthermore, consistent with the lack of IDOL stabilization by the catalytic mutant USP2 C276A or by USP8, we observed no changes in the degree of IDOL ubiquitylation by these deubiquitylases.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
USP2 interacts with IDOL and significantly increases its lifespan.
“Our biochemical and molecular-based findings collectively indicate that USP2 interacts with IDOL and significantly increases its lifespan.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
This study reports the identification of the deubiquitylase USP2 as an endogenous inhibitor of IDOL and a novel modulator of lipoprotein uptake owing to its ability to counteract IDOL-stimulated degradation of the LDLR.
“In summary, this study reports the identification of the deubiquitylase USP2 as an endogenous inhibitor of IDOL and a novel modulator of lipoprotein uptake owing to its ability to counteract IDOL-stimulated degradation of the LDLR (graphically summarized in Online Figure VIII).”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
The role of USP2 in regulating the IDOL-LDLR pathway seems to be exclusively dependent on post-transcriptional events because USP2 expression is unaffected by perturbing the cellular sterol content or by pharmacologically activating LXR in different cell types.
“The role of USP2 in regulating the IDOL-LDLR pathway seems to be exclusively dependent on post-transcriptional events because USP2 expression is unaffected by perturbing the cellular sterol content or by pharmacologically activating LXR in different cell types.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
Both Epsin1 and USP2 can block IDOL-dependent degradation of the receptor.
“As shown, both Epsin1 and USP2 could block IDOL-dependent degradation of the receptor (Figure 5C, lanes 1-4).”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
IDOL, USP2, and the LDLR can form a tri-partite complex in which USP2 can deubiquitylate the LDLR.
“Underlying these observations, we demonstrate that IDOL, USP2, and the LDLR can form a tri-partite complex in which USP2 can deubiquitylate the LDLR.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingreasoning
Silencing of USP2 accelerates LDLR degradation and decreases LDL uptake in an IDOL-dependent manner in a variety of cell types.
“In line with this, silencing of USP2 accelerates LDLR degradation and decreases LDL uptake in an IDOL-dependent manner in a variety of cell types.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingnone given
The main finding of this study is the identification of USP2 as a deubiquitylase counteracting IDOL activity, and as a consequence abundance of the LDLR.
“The main finding of this study is the identification of USP2 as a deubiquitylase counteracting IDOL activity, and as a consequence abundance of the LDLR.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingnone given
The 2 major USP2 isoforms, USP2-69 and USP2-45, promote IDOL deubiquitylation and rescue LDLR degradation.
“The 2 major USP2 isoforms, USP2-69 and USP2-45, promote IDOL deubiquitylation and rescue LDLR degradation.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown data
USP2 can remove ubiquitin chains from an IDOL mutant lacking autoubiquitylation activity.
“we have observed that USP2 can remove ubiquitin chains from an IDOL mutant lacking autoubiquitylation activity (data not shown).”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Findingown data
Deubiquitylation of IDOL by USP2 leads to increased levels of the E3 ligase mirrored by decreased degradation of its targets (LDLR and VLDLR) and enhanced cellular LDL uptake.
“In contrast to this model, deubiquitylation of IDOL by USP2 leads to a paradoxical outcome in which increased levels of the E3 ligase are mirrored by decreased degradation of its targets (ie, the LDLR and very low-density lipoprotein receptor) and functionally leads to enhanced cellular LDL uptake.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Findingown data
Silencing of USP2 decreases IDOL protein yet enhances degradation of the LDLR.
“silencing of USP2 decreases IDOL protein yet enhances degradation of the LDLR.”
- Also stated in: § Additional information · plain
  “Conversely, silencing of USP2 expression enhances IDOL-dependent degradation of the LDLR.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
The efficiency of USP2 silencing was assessed by quantitative polymerase chain reaction.
“The efficiency of USP2 silencing was assessed by quantitative polymerase chain reaction.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
Transcription of the LDLR is controlled by sterol regulatory element-binding proteins and is increased when cellular cholesterol levels decline to allow increased endocytosis of cholesterol-rich LDL particles.
“Transcription of the LDLR is controlled by the sterol regulatory element-binding proteins, and it is increased when cellular cholesterol levels decline to allow increased endocytosis of cholesterol-rich LDL particles.”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [4]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [5]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
Mutations in the LDLR are the leading cause of autosomal-dominant hypercholesterolemia, characterized by reduced hepatic LDL clearance, elevated plasma cholesterol, and accelerated atherosclerosis.
“mutations in this receptor are the leading cause for development of autosomal-dominant hypercholesterolemia, a disease characterized by reduced hepatic LDL clearance, elevated plasma cholesterol levels, and accelerated atherosclerosis.”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [2]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [3]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
Interpretationcitation
The USP8-mediated deubiquitylation most likely represents a nonselective step used to salvage ubiquitin from ubiquitylated cargo before it enters multivesicular bodies.
“However, this most likely represents a nonselective deubiquitylation step used to salvage ubiquitin from ubiquitylated cargo before it entering multivesicular bodies.”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [6]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationreasoning
IDOL is subject to USP2-mediated deubiquitylation, which prevents its degradation.
“The most parsimonious explanation for this observation is that IDOL is subject to USP2-mediated deubiquitylation, which prevents its degradation.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Interpretationcitation
USP2 does not compete with binding of the E2-ligase to IDOL, an interaction that depends on an intact RING domain.
“Furthermore, this result also indicates that USP2 does not compete with binding of the E2-ligase to IDOL, an interaction that depends on an intact RING domain.22,26”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [22]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [26]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation
The IDOL C387A mutation disrupts the conserved RING structure and results in inability to promote LDLR degradation and support IDOL autoubiquitylation.
“This mutation disrupts the conserved RING structure and as a result this mutant is unable to promote LDLR degradation and to support IDOL autoubiquitylation, 8”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [8]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. It may state two separate claims as one.
Premisecitation
Ubiquitylation is reversible, a process dependent on deubiquitylases.
“Similar to other post-translational modifications, ubiquitylation is reversible; a process dependent on the activity of deubiquitylases.15”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [15]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisereasoning
The level of the LDLR is subject to tight homeostatic regulation.
“the level of the LDLR is subject to tight homeostatic regulation.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
All immunoblots are representative of at least 3 independent experiments.
“All immunoblots are representative of at least 3 independent experiments.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
Recent studies indicate that deubiquitylases may act directly on E3s, modifying the stability and activity of the latter.
“recent studies indicate that in addition to removing or remodeling ubiquitin (chains) from ubiquitylated substrates, deubiquitylases may also act directly on E3s, thereby modifying the stability and activity of the latter.19,20”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [19]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [20]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
The human genome encodes approximately 100 deubiquitylases, 79 of which are predicted to be active.
“The human genome encodes ≈100 deubiquitylases, 79 of which are predicted to be active.16,17”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [16]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationcitation
The catalytic C-terminal region of USP2 is the IDOL interacting region, which is the same region implicated in the interaction of USP2 with the E3 MDM2.
“This points to the catalytic C-terminal region of USP2 as the IDOL interacting region, which is the same region implicated in the interaction of USP2 with the E3 MDM2.28”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [28]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
PCSK9 promotes degradation of the LDLR and is expressed by HepG2 cells.
“The secreted protein PCSK9 promotes degradation of the LDLR, and it is expressed by HepG2 cells.31”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [31]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation
Silencing of IDOL in nonhuman primates using RNAi resulted in a reduction of circulating LDL-cholesterol, associated with increased hepatic LDLR protein.
“silencing of IDOL in nonhuman primates using an RNAi-based approach resulted in a reduction of circulating levels of LDLcholesterol, which was associated with increased levels of hepatic LDLR protein.12”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [12]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data
Both LDLR degradation and IDOL autoubiquitylation functions are not essential for the physical interaction of USP2 and IDOL.
“suggesting that both functions are not essential for the physical interaction of USP2 and IDOL.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
Activity of ESCRT-associated USP8 is required for IDOL-dependent degradation of ubiquitylated LDLR.
“Our work and that of Scotti et al 7 have recently shown that activity of the endosomal-sorting complex required for transport-associated USP8 is required for IDOL-dependent degradation of ubiquitylated LDLR.6”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [6]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone given
All plasmids used in this study were isolated by CsCl2 gradient centrifugation and their correctness verified by sequencing.
“All plasmids used in this study experiments were isolated by CsCl 2 gradient centrifugation and their correctness verified by sequencing.”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Premisecitation
Activation of LXR when cellular sterol levels increase leads to induction of IDOL expression and activity, and subsequent ubiquitylation of conserved residues in the LDLR intracellular tail.
“Activation of LXR when cellular sterol levels increase leads to induction of IDOL expression and activity, and subsequent ubiquitylation of conserved residues in the short intracellular tail of the LDLR.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [8]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given
Transfection efficiency was monitored by cotransfection of a GFP expression plasmid.
“transfection efficiency was monitored by cotransfection of a GFP expression plasmid.”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Premisecitation
The plasma membrane pool of LDLR is highly sensitive to IDOL activity, and ubiquitylation leads to rapid removal of this receptor pool via an epsin-dependent but clathrin-independent endocytic route.
“In particular, the plasma membrane pool of LDLR is highly sensitive to IDOL activity, and ubiquitylation leads to rapid removal of this receptor pool via an epsin-dependent but clathrin-independent endocytic route.6”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [6]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
IDOL is subject to direct transcriptional regulation by liver X receptors (LXR).
“IDOL itself is subject to direct transcriptional regulation by the sterol-sensing transcription factors liver X receptors (LXR).”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [8]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data
USP2 is a novel-binding partner of IDOL and a potential regulatory component of the IDOL-LDLR axis.
“Taken together, these results identify USP2 as a novel-binding partner of IDOL and as a potential regulatory component of the IDOL-LDLR axis.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
A rare loss-of-function IDOL variant was described in individuals with LDL-cholesterol.
“we recently described a rare loss-of-function IDOL variant in individuals with LDL-cholesterol.11”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [11]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationreasoning
In the yeast-2-hybrid assay, the LDLR tail is likely not ubiquitylated because yeast do not encode an IDOL homolog and the tail is presented out of its normal membrane-linked context.
“Yet, in this assay it is likely that the tail is not ubiquitylated because yeast do not encode an IDOL homolog, and in this assay the tail is presented out of its normal, membrane-linked context.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation
The USP2-69 isoform is induced by androgens both in human and in rat prostate cells and by the AKT-mTORC1 axis in hepatocellular carcinoma.
“The USP2-69 isoform is induced by androgens both in human and in rat prostate cells 41 and by the AKT-mTORC1 axis in hepatocellular carcinoma.42”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [41]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [42]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisereasoning
IDOL also promotes its own ubiquitylation and degradation and is, therefore, a highly unstable protein.
“Yet IDOL also promotes its own ubiquitylation and degradation and is, therefore, a highly unstable protein.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
The mouse Usp2-45 isoform is regulated by the transcriptional coactivator PGC-1α, which couples the circadian and nutritional control in the liver in response to starvation.
“The mouse Usp2-45 isoform is regulated by the transcriptional coactivator PGC-1α, which couples the circadian and nutritional control in the liver in response to starvation.43”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [43]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation
The FERM domain is recruited to and binds the LDLR at the plasma membrane.
“the FERM domain binds USP2, and it is recruited to, and binds the LDLR at the plasma membrane, 22 but does not stimulate degradation of the receptor because of the lack of the RING domain.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [22]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationreasoning
IDOL, USP2, and the LDLR form a tri-partite complex at the plasma membrane, and in that context ubiquitylation of the receptor is decreased.
“Our results suggest that IDOL, USP2, and the LDLR form a tri-partite complex at the plasma membrane, and in that context ubiquitylation of the receptor is decreased.”
Quote in the paperSubstantial claim
Probably not a substantial claim.
Study design and conductown data
We cannot determine the endogenous level of IDOL in cells, as no commercial or homemade antibodies are able to detect it.
“Unfortunately, we cannot determine the endogenous level of IDOL in cells, as no commercial or homemade antibodies are able to detect it (data not shown).”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown data
We were unable to detect endogenous USP2 with commercially available antibodies in our experimental assays.
“Unfortunately, we were unable to detect endogenous USP2 with commercially available antibodies in our experimental assays (not shown).”
Quote in the paperNot a substantial claim
It may state two separate claims as one.
Interpretationreasoning
Inhibition of IDOL activity would result in increased LDLR abundance and enhance LDL uptake.
“This finding further supports the notion that inhibition of IDOL activity would result in increased LDLR abundance and enhance LDL uptake”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Premisenone given
Idol (-/-) mice do not display a marked cholesterol phenotype or changes in hepatic LDLR content.
“Accordingly, Idol (-/-) mice do not display a marked cholesterol phenotype or changes in hepatic LDLR content.”
Quote in the paperSubstantial claim
- Rests on an assumption: Idol (-/-) mice do not display a marked cholesterol phenotype or changes in hepatic LDLR content.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
USP8 is essential for IDOL-mediated degradation of the LDLR.
“previous studies, ours included, reported that USP8 is essential for IDOL-mediated degradation of the LDLR, 6,7”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [6]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data
USP2 can counteract IDOL-dependent ubiquitylation of the LDLR and prevent the receptor from being directed toward lysosomal degradation.
“Collectively, these experiments support the notion that USP2 can counteract IDOL-dependent ubiquitylation of the LDLR, and prevent the receptor from being directed toward lysosomal degradation.”
Quote in the paperSubstantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
The USP2 gene is alternatively spliced into 3 isoforms, all sharing an identical C-terminal catalytic core.
“The USP2 gene is alternatively spliced into 3 isoforms, 27 all sharing an identical C-terminal catalytic core.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [27]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
Study design and conductown data
To establish specificity of the USP2 siRNA and rule out off-target effects, three individual USP2 siRNAs were tested.
“Therefore, to establish the specificity of our USP2 siRNA and to rule out off target effects, we tested 3 individual USP2 siR-NAs.”
Quote in the paperSubstantial claim
It may state two separate claims as one.
Interpretationreasoning
USP2 is recruited by IDOL and acts directly on the receptor.
“In this sequential scenario, USP2 is recruited by IDOL and acts directly on the receptor, reminiscent of the reported effect of USP2 on EGFR after ligand binding.34”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [34]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Interpretationreasoning
The cytosolic LDLR tail is only recognized by USP8 when ubiquitylated and in the context of a biological membrane, and not in the native form prevalent in the yeast-2-hybrid assay.
“This apparent incongruence is possibly because of the fact that the cytosolic LDLR tail is only recognized by USP8 when ubiquitylated and in the context of a biological membrane, and not in the native form that is likely the one prevalent in the yeast-2-hybrid assay.”
Quote in the paperNot a substantial claim
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation
USP2 is able to process diverse ubiquitin linkages.
“This would be consistent with the fact that the phenotype is IDOL dependent, and that USP2 is able to process diverse ubiquitin linkages.35,36”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [35]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [36]
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

59 of 59

The paper relies on this without support.
Whether deubiquitylases play a role in cholesterol metabolism is largely unknown.
“Whether deubiquitylases play a role in cholesterol metabolism is largely unknown.”
The paper relies on this without support.
Post-transcriptional mechanisms are important determinants of LDLR abundance.
“Next to transcriptional regulation, post-transcriptional mechanisms are also emerging as important determinants of LDLR abundance.”
The paper relies on this without support.
Idol (-/-) mice do not display a marked cholesterol phenotype or changes in hepatic LDLR content.
“Accordingly, Idol (-/-) mice do not display a marked cholesterol phenotype or changes in hepatic LDLR content.”

3 of 3

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?

IDOL robustly promotes its own ubiquitination, making it a short-lived protein with a half-life of about 5 minutes.
“Additionally, IDOL robustly promotes its own ubiquitination [62,66,67], making it a short-lived protein (t 1/2 -5 min [69]).”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [69]
In “USP2 Deubiquitylates and Stabilizes IDOL” (page unavailable), the paper describes IDOL as highly unstable, likely because of its high autoubiquitylation activity, and reports that USP2 extends its half-life. It does not give a half-life of about 5 minutes, which is the specific point attached to this source’s citation [69]. (LLM, conf=0.86)
Experimental — accuracy not yet measured
USP2 significantly regulates LDLR protein.
“These results revealed that USP2 could significantly regulate LDLR protein, which was consistent with the outcomes of a previous research.13)”
From USP16 Regulates the Stability and Function of LDL receptor by Deubiquitination (2020) · cites this paper as [13]
USP2 regulates the LDLR pathway by counteracting the E3-ubiquitin ligase IDOL.
“It has been reported that USP2 can regulate the deubiquitination of LDLR.13)”
From USP16 Regulates the Stability and Function of LDL receptor by Deubiquitination (2020) · cites this paper as [13]
USP2 can deubiquitylate IDOL and extend its half-life.
“Intriguingly, IDOL-stimulated auto-degradation itself may be subject to regulation by the deubiquitylase USP2 that can deubiquitylate IDOL and extend its half-life [69].”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [69]
USP2 attenuates LDLR degradation by IDOL despite increasing abundance of IDOL.
“Paradoxically, USP2 attenuates LDLR degradation by IDOL, despite increasing abundance of IDOL.”
From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [69]

A Receptor-Mediated Pathway for Cholesterol Homeostasis
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Self-citation
Increased Lipogenesis, Induced by AKT-mTORC1-RPS6 Signaling, Promotes Development of Human Hepatocellular Carcinoma
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The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer
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The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation
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Ubiquitination of E3 ligases: self-regulation of the ubiquitin system via proteolytic and non-proteolytic mechanisms
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Engineered diubiquitin synthesis reveals Lys29-isopeptide specificity of an OTU deubiquitinase
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The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2
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The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor
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Authors: Nelson, J. K., Sorrentino, V., Avagliano Trezza, R., Heride, C., Urbe, S., Distel, B., & Zelcer, N.
Affiliations: University of Liverpool (GB)
From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands (J.K.N., V.S., R.A.T., B.D., N.Z.); and Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom (C.H., S.U.).
Corresponding author: Nelson, Jessica Kristine
Sorrentino, Vincenzo
ORCID: Sorrentino, Vincenzo
Heride, Claire
Distel, Ben
Zelcer, Noam
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2016-02-05
Volume: 118
Issue: 3
Pages: 410-419
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/circresaha.115.307298
OpenAlex: W2203925846
Cited by: 51
References: 42
Citations by year: 2026: 6 · 2025: 2 · 2024: 7 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 9 · 2019: 8 · 2018: 1 · 2017: 5 · 2016: 3
FWCI: 1.04
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Circulation Research (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (submittedVersion, other-oa)
National University of Singapore (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: Nederlandse Organisatie voor Wetenschappelijk Onderzoek
FP7 Ideas: European Research Council (617376)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Keywords: USP2, idols, LDL receptor, deubiquitination, E3 ubiquitin ligase, LDLR degradation, lipoprotein uptake, protein stability
MeSH terms: Animals, Enzyme Stability, HeLa Cells, Humans, Cholesterol, LDL, Multienzyme Complexes, Endopeptidases, Protein Binding, Receptors, LDL, Transfection, Mice, Knockout, RNA Interference, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Ubiquitination, Hep G2 Cells, HEK293 Cells, Proteolysis

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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.

A language model drew the claims from the paper on 2026-11-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

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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The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

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