The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation

Sorrentino, Vincenzo; Nelson, Jessica K.; Maspero, Elena; Marques, André R. A.; Scheer, Lilith; Polo, Simona; Zelcer, Noam

doi:10.1194/jlr.m037713

Cited by 65 publications

(55 citation statements)

References 58 publications

(78 reference statements)

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“…20 Briefly, HepG2 or A431 cells were incubated in sterol-depleted medium for 16 hours before adding LDL. Cells were incubated with 5 μg/mL DyLight488-labeled LDL in DMEM supplemented with 0.5% BSA for 3 hours at 37°C or 4°C.…”

Section: Ldl Uptake Assaysmentioning

confidence: 99%

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Meima

Nelson

et al. 2016

Circulation Research

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T he (pro)renin receptor [(P)RR] has been implicated as a receptor for renin/prorenin (denoted as [pro]renin)-stimulated signaling, and plays a role in local renin-angiotensin system activation by nonproteolytically activating bound prorenin. 1 In experimental assays (pro)renin-(P)RR signaling results in extracellular signal-regulated kinase 1/2 (Erk1/2) activation, and as a consequence upregulation of profibrotic factors, such as transforming growth factor β, collagen, and fibronectin. [2][3][4][5][6] However, the physiological relevance of the (pro)renin-(P)RR interaction is questionable because the (pro)renin concentrations required are >1000× higher than observed under (patho) physiological conditions. 7,8 Recently, (pro)renin-independent functions for (P)RR have been reported, including a function as an accessory protein of the vacuolar H + -ATPase (V-ATPase). 9 V-ATPases are multisubunit complexes, and they are expressed virtually in all cells types. They play an important role in protein trafficking, receptor recycling, and lysosomal degradation by acidifying intracellular compartments.10,11 Depletion of the (P)RR results in decreased protein levels of V-ATPase subunits, impaired acidification of intracellular compartments, and defects in autophagy.12-14 V-ATPases are also found at the plasma membrane in certain cell types, such as intercalated cells of the collecting duct. Accordingly, we previously reported that the (P)RR is required for both prorenin-dependent and proreninindependent regulation of V-ATPase activity in collecting duct cells.15 The (P)RR has been also recently implicated in canonical Wnt and PCP signaling, [16][17][18] emphasizing the notion that our understanding of (P)RR function remains incomplete. In This Issue, see p 183Editorial, see p 187To address this, we used an unbiased proteomics approach to discover potential novel functions of the (P)RR. We mapped the (P)RR-interactome and identified sortilin 1 (SORT1) as Objective: To uncover renin-angiotensin system-independent functions of the (P)RR. Methods and Results: We used a proteomics-based approach to purify and identify (P)RR-interacting proteins.This resulted in identification of sortilin-1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (

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Section: Ldl Uptake Assaysmentioning

confidence: 99%

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Meima

Nelson

et al. 2016

Circulation Research

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“…We have previously reported that IDOL preferentially targets the LDLR pool present at the plasma membrane (16). Therefore, to substantiate the notion that the effect of DUB inhibition requires IDOL activity, we determined the cell surface levels of the LDLR in cells.…”

Section: Resultsmentioning

confidence: 99%

“…Determination of Cell Surface LDLR-Surface LDLR density in the different cells was determined as previously reported (16). Briefly, the cells were treated as indicated, dissociated, and incubated in FACS blocking buffer for 30 min on ice.…”

Section: Plasmids and Expression Constructs-expressionmentioning

confidence: 99%

“…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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As a matter of fat: Emerging roles of lipid‐sensitive E3 ubiquitin ligases

Gawden‐Bone,

Lehner,

Volkmar

2023

BioEssays

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The dynamic structure and composition of lipid membranes need to be tightly regulated to control the vast array of cellular processes from cell and organelle morphology to protein‐protein interactions and signal transduction pathways. To maintain membrane integrity, sense‐and‐response systems monitor and adjust membrane lipid composition to the ever‐changing cellular environment, but only a relatively small number of control systems have been described. Here, we explore the emerging role of the ubiquitin‐proteasome system in monitoring and maintaining membrane lipid composition. We focus on the ER‐resident RNF145 E3 ubiquitin ligase, its role in regulating adiponectin receptor 2 (ADIPOR2), its lipid hydrolase substrate, and the broader implications for understanding the homeostatic processes that fine‐tune cellular membrane composition.

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The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation

Cited by 65 publications

References 58 publications

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism

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

As a matter of fat: Emerging roles of lipid‐sensitive E3 ubiquitin ligases

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