Sequential Actions of the AAA-ATPase Valosin-containing Protein (VCP)/p97 and the Proteasome 19 S Regulatory Particle in Sterol-accelerated, Endoplasmic Reticulum (ER)-associated Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase

Morris, Lindsey L.; Hartman, Isamu Z.; Jun, Dong Jae; Seemann, Joachim; DeBose‐Boyd, Russell A.

doi:10.1074/jbc.m114.576652

Cited by 49 publications

(47 citation statements)

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“…1. membranes of the ER (panels 5 and 14, respectively). The remaining SCD-associated mutants of UBIAD1 were similarly defective in transport to the Golgi and localized to the ER (panels 3, 4, 6-13, and [15][16][17][18][19][20][21][22]. However, it should be noted that four SCD-associated UBIAD1 mutants, D112G (panel 6), D118G (panel 7), R119G (panel 8), and N232S (panel 18), exhibited partial Golgi localization.…”

Section: Resultsmentioning

confidence: 99%

“…Maximal degradation requires the addition to cells of geranylgeraniol (GGOH), the alcohol derivative of GGpp (16). We postulate that GGOH becomes converted to GGpp, which augments reductase ERAD by enhancing its membrane extraction (21). Recently, we found that sterols also cause reductase to bind to UBIAD1 (12).…”

Section: Cell Culturementioning

confidence: 99%

“…Intracellular accumulation of sterols causes reductase to bind ER membrane proteins called Insigs (15,16), which leads to ubiquitination of the enzyme by Insigassociated ubiquitin ligases (16)(17)(18)(19). Ubiquitinated reductase is then extracted across ER membranes and released into the cytosol for degradation by 26S proteasomes (20,21). Maximal degradation requires the addition to cells of geranylgeraniol (GGOH), the alcohol derivative of GGpp (16).…”

Section: Cell Culturementioning

confidence: 99%

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Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgUbiA prenyltransferase domain-containing protein-1 (UBIAD1) belongs to the UbiA superfamily of integral membrane prenyltransferases (1). These enzymes contain 8-10 transmembrane helices and catalyze transfer of isoprenyl groups to aromatic acceptors, producing a wide range of molecules such as ubiquinones, hemes, chlorophylls, vitamin E, and vitamin K. In animals, UBIAD1 catalyzes transfer of the 20-carbon geranylgeranyl moiety from geranylgeranyl pyrophosphate (GGpp) to menadione released from plant-derived phylloquinone, thereby generating the vitamin K 2 subtype, menaquinone-4 (MK-4) (2, 3).Mutations in the UBIAD1 gene are associated with Schnyder corneal dystrophy (SCD), an autosomal dominant human eye disease characterized by progressive opacification of the cornea, owing to abnormal accumulation of cholesterol and other lipids (4,5). Systemic dyslipidemia appears to be associated with some, but not all, SCD cases (6, 7). Missense mutations that alter 20 amino acid residues in UBIAD1 have been identified in 50 SCD families (8, 9). Several of these altered amino acids reside within the active site of UBIAD1 (10, 11). A link between UBIAD1 and cholesterol metabolism was first provided by coimmunoprecipitation studies that showed an association of UBIAD1 with the cholesterol biosynthetic enzyme, HMGCoA reductase (8). More recently, we showed that UBIAD1 inhibits sterol-accelerated endoplasmic reticulum (ER)-associated degradation (ERAD) of reductase (12), one of several feedback mechanisms that converge on the enzyme to maintain cholesterol homeostasis (13).Abstract UbiA prenyltransferase domain-containing protein-1 (UBIAD1) utilizes geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K 2 subtype menaquinone-4. Previously, we found that sterols trigger binding of UBIAD1 to endoplasmic reticulum (ER)-localized HMG-CoA reductase, the rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. This binding inhibits sterol-accelerated degradation of reductase, which contributes to feedback regulation of the enzyme. The addition to cells of geranylgeraniol (GGOH), which can become converted to GGpp, triggers release of UBIAD1 from reductase, allowing for its maximal degradation and permitting ER-to-Golgi transport of UBIAD1. Here, we further characterize geranylgeranyl-regulated transport of UBIAD1.

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Section: Resultsmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

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Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Schumacher

Jun

et al. 2016

Journal of Lipid Research

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“…Insig binding is mediated entirely by the membrane domain of HMGCR, which contains eight transmembrane helices and precedes a cytosolic catalytic domain (7,8). Insig-associated ubiquitin ligases facilitate ubiquitination of cytosolically exposed lysine residues in the membrane domain of HMGCR (9 -11), marking the enzyme for extraction across ER membranes and dislocation into the cytosol for proteasomal degradation (12,13).…”

Section: Reductase (Hmgcr) Is a Polytopic Protein Of Endoplasmic Retimentioning

confidence: 99%

Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver

Hwang

Hartman

Calhoun

et al. 2016

Journal of Biological Chemistry

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Accumulation of sterols in endoplasmic reticulum membranes stimulates the ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which catalyzes a ratelimiting step in synthesis of cholesterol. This ubiquitination marks HMGCR for proteasome-mediated degradation and constitutes one of several mechanisms for feedback control of cholesterol synthesis. Mechanisms for sterol-accelerated ubiquitination and degradation of HMGCR have been elucidated through the study of cultured mammalian cells. However, the extent to which these reactions modulate HMGCR and contribute to control of cholesterol metabolism in whole animals is unknown. Here, we examine transgenic mice expressing in the liver the membrane domain of HMGCR (HMGCR (TM1-8)), a region necessary and sufficient for sterol-accelerated degradation, and knock-in mice in which endogenous HMGCR harbors mutations that prevent sterol-induced ubiquitination. Characterization of transgenic mice revealed that HMGCR (TM1-8) is appropriately regulated in the liver of mice fed a high cholesterol diet or chow diet supplemented with the HMGCR inhibitor lovastatin. Ubiquitination-resistant HMGCR protein accumulates in the liver and other tissues disproportionately to its mRNA, indicating that sterol-accelerated degradation significantly contributes to feedback regulation of HMGCR in vivo.Results of these studies demonstrate that HMGCR is subjected to sterol-accelerated degradation in the liver through mechanisms similar to those established in cultured cells. Moreover, these studies designate sterol-accelerated degradation of HMGCR as a potential therapeutic target for prevention of atherosclerosis and associated cardiovascular disease.

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“…TRC8, MARCH6, and gp78 were identified as 3 key membraneanchored E3 ubiquitin-protein ligases involved in 25HC-stimulated HMGCR degradation (Song et al 2005;Jo et al 2011;Zelcer et al 2014). Subsequently, HMGCR is extracted from the ER membrane into the cytosol in a valosincontaining protein (VCP/p97)-dependent manner, enabling HMGCR degradation by the 26S proteasome (Elsabrouty et al 2013;Morris et al 2014). Through this mechanism, 25HC inhibits the rate-limiting step of cholesterol biosynthesis.…”

Section: Hc: Oxysterol Regulator Of Sterol Homeostasismentioning

confidence: 99%

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

2015

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Abstract:The metabolic interplay between hosts and viruses plays a crucial role in determining the outcome of viral infection. Viruses reorchestrate the host's primary metabolic gene networks, including genes associated with mevalonate and isoprenoid synthesis, to acquire the necessary energy and structural components for their viral life cycles. Recent work has demonstrated that the interferon-mediated antiviral response suppresses the sterol pathway through production of a signalling molecule, 25-hydroxycholesterol (25HC). This oxysterol has been shown to exert multiple effects, both through incorporation into host cellular membranes as well as through transcriptional control. Herein, we summarize our current understanding of the multifunctional roles of 25HC in the mammalian innate antiviral response.Key words: 25-hydroxycholesterol, cholesterol-25-hydroxylase, metabolism, virus, immunity.Résumé : Les interactions métaboliques entre les hôtes et les virus jouent un rôle crucial qui déterminera l'issue de l'infection virale. Les virus réorganisent les réseaux de gènes métaboliques primaires de l'hôte, dont les gènes liés à la synthèse du mévalonate et des isoprénoïdes, afin d'acquérir l'énergie et les éléments structuraux néces-saires à leur cycle de vie. Des travaux récents ont démontré que la réponse antivirale activée par les interférons supprime la voie des stérols par la production d'une molécule de signalisation, le 25-hydroxycholestérol (25HC). On a révélé que cet oxystérol avait plus d'un effet, tant par son intégration dans les membranes de la cellule-hôte que par le contrôle de la transcription. Nous résumons ici notre conception actuelle des rôles multifonctionnels du 25HC dans la réponse antivirale innée chez les mammifères. [Traduit par la Rédaction] -clés : 25-hydroxycholestérol, cholestérol-25-hydroxylase, métabolisme, virus, immunité. Mots

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Sequential Actions of the AAA-ATPase Valosin-containing Protein (VCP)/p97 and the Proteasome 19 S Regulatory Particle in Sterol-accelerated, Endoplasmic Reticulum (ER)-associated Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase

Cited by 49 publications

References 48 publications

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi

Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

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