Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein

Sorrentino, Vincenzo; Fouchier, Sigrid W.; Motazacker, Mohammad Mahdi; Nelson, Jessica K.; Defesche, Joep C.; Dallinga‐Thie, Geesje M.; Kastelein, John J.P.; Hovingh, G. Kees; Zelcer, Noam

doi:10.1093/eurheartj/ehs472

Cited by 50 publications

(36 citation statements)

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“…9,10 Furthermore, we recently described a rare loss-of-function IDOL variant in individuals with LDL-cholesterol. 11 Consistent with this, 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 Thus, the LXR-IDOL-LDLR axis is a potent ubiquitylation-dependent mechanism to acutely limit lipoprotein-derived cholesterol uptake.…”

mentioning

confidence: 54%

“…We therefore anticipate that a functional USP2-IDOL interaction will be predominantly active in human hepatocytes. In that respect, the growing body of evidence pointing toward genetic variation in IDOL as a modifier of LDL cholesterol in humans, [9][10][11] warrants further studies to investigate the basic mechanisms governing IDOL activity and regulation by USP2.…”

Section: Discussionmentioning

confidence: 99%

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

Nelson

Sorrentino

Trezza

et al. 2016

Circulation Research

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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.

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confidence: 54%

Section: Discussionmentioning

confidence: 99%

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

Nelson

Sorrentino

Trezza

et al. 2016

Circulation Research

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“…We therefore anticipate that the functional MARCH6-IDOL network will be predominantly active in human hepatocytes. There is increasing genetic evidence from human studies implicating common and rare genetic variation in the IDOL locus as a modifier of circulating levels of plasma LDL cholesterol (43,44). A similar association with MARCH6 has not been reported yet in genomewide association studies, and investigations geared toward examining the contribution of rare MARCH6 variants to this lipid trait are warranted.…”

Section: Discussionmentioning

confidence: 94%

A MARCH6 and IDOL E3 ubiquitin ligase circuit uncouples cholesterol synthesis from lipoprotein uptake in hepatocytes

et al. 2016

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“…Next to this sterol-independent function, our finding may still have implications for cholesterol metabolism. Common genetic variation in the IDOL locus has been identified in genome-wide association studies as a modifier of circulating levels of LDL in humans (18), and we have recently identified the first rare IDOL loss of function variant in individuals with low levels of circulating LDL cholesterol (19). Most of the studies on IDOL, ours included, have largely focused on functional coding variants.…”

Section: Lxr␣␤mentioning

confidence: 99%

“…The clinical relevance of IDOL in humans is highlighted by recent studies that found an association between common and * This work was supported in part by Landsteiner Foundation for Blood Trans- rare genetic variance in the IDOL locus and circulating levels of LDL cholesterol. This establishes the E3 IDOL as a potential therapeutic target to treat hypercholesterolemia (18,19). Substrate ubiquitylation promoted by E3s can be effectively reversed through the opposing activity of deubiquitylases (DUBs) (20).…”

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confidence: 99%

Deubiquitylase Inhibition Reveals Liver X Receptor-independent Transcriptional Regulation of the E3 Ubiquitin Ligase IDOL and Lipoprotein Uptake

Nelson

Cook

Loregger

et al. 2016

Journal of Biological Chemistry

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Cholesterol metabolism is subject to complex transcriptional and nontranscriptional regulation. Herein, the role of ubiquitylation is emerging as an important post-translational modification that regulates cholesterol synthesis and uptake. Similar to other post-translational modifications, ubiquitylation is reversible in a process dependent on activity of deubiquitylating enzymes (DUBs). Yet whether these play a role in cholesterol metabolism is largely unknown. As a first step to test this possibility, we used pharmacological inhibition of cellular DUB activity. Short term (2 h) inhibition of DUBs resulted in accumulation of high molecular weight ubiquitylated proteins. This was accompanied by a dramatic decrease in abundance of the LDLR and attenuated LDL uptake into hepatic cells. Importantly, this occurred in the absence of changes in the mRNA levels of the LDLR or other SREBP2-regulated genes, in line with this phenotype being a post-transcriptional event. Mechanistically, we identify transcriptional induction of the E3 ubiquitin ligase IDOL in human and rodent cells as the underlying cause for ubiquitylation-dependent lysosomal degradation of the LDLR following DUB inhibition. In contrast to the established transcriptional regulation of IDOL by the sterol-responsive liver X receptor (LXR) transcription factors, induction of IDOL by DUB inhibition is LXR-independent and occurs in Lxr␣␤ ؊/؊ MEFs.Consistent with the role of DUBs in transcriptional regulation, we identified a 70-bp region in the proximal promoter of IDOL, distinct from that containing the LXR-responsive element, which mediates the response to DUB inhibition. In conclusion, we identify a sterol-independent mechanism to regulate IDOL expression and IDOL-mediated lipoprotein receptor degradation.Elevated levels of plasma LDL represent a major risk factor for development of atherosclerosis and cardiovascular disease (1). Because of its ability to promote LDL uptake into cells, the LDL receptor (LDLR) 2 is a major determinant of plasma LDL levels (2). The pivotal role of the LDLR in LDL metabolism is exemplified by the fact that LDLR mutations account for most incidences of familial hypercholesterolemia, a disease characterized by reduced hepatic LDL clearance, elevated plasma cholesterol levels, and accelerated cardiovascular disease (1, 3).The LDLR is subject to tight transcriptional and post-transcriptional regulation, which is largely governed by the intracellular levels of cholesterol (4). At the level of transcription, these pathways are regulated by two nuclear transcription factor families: SREBP1 and SREBP2 (5-7), and the liver X receptor ␣ and ␤ (LXRs) (8, 9). When cellular sterol levels decline, SREBPs are activated to induce genes required for de novo cholesterol biosynthesis, as well as the LDLR to increase uptake of LDL cholesterol (4). In contrast, when sterol levels rise, LXRs become activated by their endogenous ligands. These ligands include oxidized cholesterol derivatives (oxysterols) and intermediates of the cholesterol synthes...

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Identification of a loss-of-function inducible degrader of the low-density lipoprotein receptor variant in individuals with low circulating low-density lipoprotein

Abstract: Our results support the notion that IDOL contributes to variation in circulating levels of LDL-C. Strategies to inhibit IDOL activity may therefore provide a novel therapeutic venue to treating dyslipidaemia.

Cited by 50 publications

References 48 publications

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

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

A MARCH6 and IDOL E3 ubiquitin ligase circuit uncouples cholesterol synthesis from lipoprotein uptake in hepatocytes

Deubiquitylase Inhibition Reveals Liver X Receptor-independent Transcriptional Regulation of the E3 Ubiquitin Ligase IDOL and Lipoprotein Uptake

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