IDOL Stimulates Clathrin-Independent Endocytosis and Multivesicular Body-Mediated Lysosomal Degradation of the Low-Density Lipoprotein Receptor

Scotti, Eleonora; Calamai, Martino; Goulbourne, Chris N.; Zhang, Li; Hong, Cynthia; Lin, Ron R.; Choi, Jor-Shan; Pilch, Paul F.; Fong, Loren G.; Zou, Peng; Ting, Alice Y.; Pavone, Francesco S.; Young, Stephen G.; Tontonoz, Peter

doi:10.1128/mcb.01716-12

Cited by 71 publications

(70 citation statements)

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“…Unfortunately, IDOL protein levels could not be measured because of the nonspecifi city of the available commercial antibodies ( 41 ). However, IDOL mRNA levels did not differ in PCSK9 KO tissues (supplementary Fig.…”

Section: Synergistic Effect Of Ovariectomy and Pcsk9 Defi Ciency On Pmentioning

confidence: 99%

“…Aside from PCSK9, another "degrader" of the LDLR is the inducible degrader of LDLR (IDOL), an E3 ubiquitin ligase that ubiquitinates the cytosolic tail of the LDLR, VLDLR, or apoER2 ( 39 ), leading to their subsequent degradation by lysosomes ( 40,41 ), and that is known to be induced by liver X receptor activation in response to elevated levels of cellular cholesterol. Unfortunately, IDOL protein levels could not be measured because of the nonspecifi city of the available commercial antibodies ( 41 ).…”

Section: Synergistic Effect Of Ovariectomy and Pcsk9 Defi Ciency On Pmentioning

confidence: 99%

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PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice

Roubtsova

Chamberland

Marcinkiewicz

et al. 2015

Journal of Lipid Research

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These PCs are encoded by genes designated PCSK1 to PCSK9 , except for the third and eighth members furin and SKI-1/S1P, whose genes were named FURIN and MBTPS1 , respectively. PCSK9 was the third gene known to be involved in autosomal dominant hypercholesterolemia ( 2 ) after those encoding the LDL receptor (LDLR) and apolipoprotein B. PCSK9 binds to the LDLR and directs it to the endosomal/lysosomal pathway for degradation ( 3, 4 ). Gain-of-function mutations in PCSK9 were shown to enhance the degradation of the LDLR ( 2, 4 ), with ensuing increased LDL-cholesterol levels in plasma. Conversely, PCSK9 loss-of-function mutations result in hypocholesterolemia ( 5 ). Low concentrations of active PCSK9 are also associated with a lower incidence of atherosclerosis ( 6 ), myocardial infarction ( 7 ), and stroke ( 8 ). Individuals entirely lacking functional PCSK9 are healthy and have extremely low levels of LDL-cholesterol ( ‫ف‬ 0.4 mM) ( 9-11 ). Accordingly, monoclonal antibodies directed against PCSK9 that disrupt the PCSK9-LDLR interaction are effi cient in reducing LDL-cholesterol levels (by >50%) and are commercially available (reviewed in Ref. 12 ).Like all other PCs, PCSK9 is synthesized as a precursor (proPCSK9; 74 kDa) that undergoes an autocatalytic cleavage at the VFAQ 152 ↓ site, allowing it to exit the endoplasmic reticulum ( 4, 13 ). However, the inhibitory prosegment remains tightly bound to PCSK9 ( 14,15 ), and the complex is secreted. Thus, mature PCSK9 has no catalytic activity in trans but acts as a binding protein to specifi c receptors.Abstract Proprotein convertase subtilisin kexin type 9 (PCSK9), the last member of the family of Proprotein Convertases related to Subtilisin and Kexin, regulates LDL-cholesterol by promoting the endosomal/lysosomal degradation of the LDL receptor (LDLR). Herein, we show that the LDLR cell surface levels dramatically increase in the liver and pancreatic islets of PCSK9 KO male but not female mice. In contrast, in KO female mice, the LDLR is more abundant at the cell surface enterocytes, as is the VLDL receptor (VLDLR) at the cell surface of adipocytes. Ovariectomy of KO female mice led to a typical KO male pattern, whereas 17 ␤ -estradiol (E2) treatment restored the female pattern without concomitant changes in LDLR adaptor protein 1 (also known as ARH), disabled-2, or inducible degrader of the LDLR expression levels. We also show that this E2-mediated regulation, which is observed only in the absence of PCSK9, is abolished upon feeding the mice a high-cholesterol diet. The latter dramatically represses PCSK9 expression and leads to high surface levels of the LDLR in the hepatocytes of all sexes and genotypes. In conclusion, the absence of PCSK9 results in a sex-and tissue-specifi c subcellular distribution of the LDLR and VLDLR, which is determined by E2 levels. 82946 and 102741 (N.G.S. and A.P.) and 5605 (J.J.B.), by the Leducq Foundation (N.G.S. and A.P.), and by a Canada Research Chair (N.G.S.). 18 August 2015. Published, JLR Papers in Press, August 31, 2015...

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Section: Synergistic Effect Of Ovariectomy and Pcsk9 Defi Ciency On Pmentioning

confidence: 99%

Section: Synergistic Effect Of Ovariectomy and Pcsk9 Defi Ciency On Pmentioning

confidence: 99%

PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice

Roubtsova

Chamberland

Marcinkiewicz

et al. 2015

Journal of Lipid Research

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“…From this analysis the 4 proteins APOE, MYOC, ELANE (UniProt ID: P08246) and KNG1 (UniProt ID: P01042) in this cluster are found to be involved in heparin binding. [21][22][23][24] Further, based on the localization of the proteins [25][26][27][28][29][30][31] in Cluster 2 ( Figure 3) it is most probable that STAT3 (UniProt ID: P40763) interacts with POAG proteins APOE and CYP1B1 in the cytoplasm. Also MYOC might interact with POAG proteins FN1 and CYP1B1 in the endoplasmic reticulum.…”

Section: Validation Of the Toolmentioning

confidence: 99%

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Pj³

et al. 2015

JBPR

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A growing number of diseases seem to be associated with protein aggregation and each disease has several proteins involved in it. To obtain a better understanding of the diseases, the proteins involved in them and their primary interaction partners were collected and clustered. A tool is developed to aid in clustering these proteins and all their primary interactors. The tool is used to cluster proteins involved in Primary Open Angle Glaucoma and their primary interactors. A cluster was selected for analysis based on the availability of experimental analysis in literature. The localization of the proteins in the chosen cluster was collected. On analyzing, four of the proteins in the cluster was found to be associated with heparin binding. Primary open angle glaucoma is known to be associated with loss of retinal vasculature. The tool has helped in finding a cluster of protein interactions with more experimental data. Also it has helped in finding out the 4 proteins associated with the disease that are involved in heparin binding from 10500 proteins. This would not have been possible to do manually. Further studying the role of these four proteins based on heparin binding and loss of vasculature in primary open angle glaucoma would give a better understanding of the disease and the molecular mechanism involved in it.

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“…Although IDOL can interact with LDLR at multiple steps in its cellular itinerary, plasma membrane-localized LDLR is particularly sensitive to IDOL-mediated ubiquitylation (16). Once ubiquitylated, LDLR is rapidly removed from the plasma membrane and sorted by the ESCRT (endosomal sorting complexes required for transport) machinery toward the lysosome for degradation (16,17). 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.…”

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confidence: 99%

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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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IDOL Stimulates Clathrin-Independent Endocytosis and Multivesicular Body-Mediated Lysosomal Degradation of the Low-Density Lipoprotein Receptor

Cited by 71 publications

References 71 publications

PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice

PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice

Untitled

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

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