Examining Mechanism and Physiological Significance of HMG CoA Reductase ER-Associated Degradation

检查 HMG CoA 还原酶 ER 相关降解的机制和生理意义

基本信息

批准号：
10396981
负责人：
Russell Alfred DeBose-Boyd
金额：
$ 42.93万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396981
关键词：
25-hydroxycholesterol 26S proteasome Acceleration Atherosclerosis Binding Cardiovascular Diseases Cell physiology Cells Cholesterol Clinical Complex Cornea Cultured Cells Cytosol Detergents Development Dimethylallyltranstransferase Dislocations Dolichol Drug Prescriptions Effectiveness Electron Microscopy Endoplasmic Reticulum Enzymes Eye diseases Feedback Glean Goals Golgi Apparatus Grant Heme Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Hydroxymethylglutaryl-CoA reductase Incidence Knock-in Knock-in Mouse LDL Cholesterol Lipoproteins Liver Mediating Membrane Membrane Proteins Molecular Molecular Conformation Molecular Structure Mus Mutation Myocardial Infarction Outcome Pharmaceutical Preparations Pharmacology Physiological Plasma Process Production Proteins Reaction Regulation Resistance Schnyder corneal dystrophy Sterols Structure System Time Ubiquinone Ubiquinone Q2 Ubiquitination Vitamin K 2 Wild Type Mouse X-Ray Crystallography cholesterol control clinical effect cryogenics farnesyl pyrophosphate geranylgeranyl pyrophosphate high throughput screening hypercholesterolemia insight isoprenoid multicatalytic endopeptidase complex novel strategies novel therapeutics prevent protein degradation response synthetic enzyme ubiquitin ligase

项目摘要

Project Summary Multiple feedback mechanisms converge on the polytopic, ER (endoplasmic reticulum)-localized enzyme HMG CoA reductase (HMGCR), which catalyzes a key step in synthesis of cholesterol and essential nonsterol isoprenoids including Fpp (farnesyl pyrophosphate) and GGpp (geranylgeranyl pyrophosphate). Fpp and GGpp can become attached to many cellular proteins and are utilized in synthesis of dolichol, ubiquinone, heme, and vitamin K2. One mechanism for feedback control of HMGCR involves sterol-induced ubiquitination, which marks the enzyme for extraction across ER membranes and subsequent release into the cytosol for proteasome- mediated ERAD (ER-associated degradation). GGpp augments ERAD of HMGCR by enhancing its membrane extraction. We recently discovered that GGpp inhibits sterol-induced binding of HMGCR to UBIAD1 (UbiA prenyltransferase domain-containing protein-1), which utilizes GGpp to synthesize vitamin K2. This inhibition allows for membrane extraction of HMGCR and ER-to-Golgi transport of UBIAD1. Mutations in UBIAD1 cause SCD (Schnyder corneal dystrophy), an autosomal dominant eye disease characterized by corneal accumulation of cholesterol. SCD-associated UBIAD1 resists GGpp-induced release from HMGCR and becomes trapped in the ER where it blocks HMGCR ERAD. Building on discoveries summarized above, we are now poised to 1) elucidate mechanisms through which sterols promote ubiquitination of HMGCR; 2) determine the molecular structure of HMGCR; 3) establish how ubiquitinated HMGCR is removed from ER membranes for ERAD; and 4) ascertain the physiological significance of HMGCR ERAD. Collectively, these studies will provide key information regarding mechanisms by which polytopic HMGCR is removed from ER membranes and delivered cytosolic proteasomes for ERAD. In addition, these studies have significant clinical implications. HMGCR is the target of statins, widely prescribed drugs that lower plasma LDL-cholesterol and reduce cardiovascular disease. However, statins trigger responses that cause accumulation of HMGCR, which blunts their clinical effects. This increase results in part, from slowed ERAD of HMGCR. Thus, elucidating mechanisms for HMGCR ERAD holds promise for development of new therapies that increase the efficacy of statins and further reduce heart attacks.

项目摘要多种反馈机制会收敛于多种反应ER（内质网）临时酶HMG COA还原酶（HMGCR），它催化合成胆固醇和必需非蛋白酶的关键步骤类异普尼类动物，包括FPP（Farnesyl pyrophophate）和GGPP（香烷基凝酰焦磷酸盐）。 FPP和GGPP 可以与许多细胞蛋白相连，并用于合成多利果醇，泛氨基酮，血红素和维生素K2。 HMGCR反馈控制的一种机制涉及固醇诱导的泛素化，该机制标记为标记该酶用于跨质膜提取的酶，随后释放到细胞质中，以进行蛋白酶体 - 介导的ERAD（与ER相关的降解）。 GGPP通过增强其膜增强HMGCR的ERAD 萃取。最近，我们发现GGPP抑制了固醇诱导的HMGCR与UBIAD1的结合（UBIA 含前转移酶结构蛋白1），该蛋白1）利用GGPP合成维生素K2。这种抑制作用允许将UbiAD1的HMGCR和er-Golgi转运膜提取。 UBIAD1的突变原因 SCD（SCD（Schnyder Corneal营养不良），一种常染色体显性眼病，其特征是角膜积累胆固醇。 SCD相关的UBIAD1抵抗GGPP引起的HMGCR释放，并被困在急诊室阻止了HMGCR的ERAD。在上面总结的发现的基础上，我们现在已经准备好1）阐明机制固醇促进HMGCR的泛素化； 2）确定HMGCR的分子结构； 3）建立如何从ER膜中除去泛素化的HMGCR； 4）确定生理 HMGCR ERAD的意义。总的来说，这些研究将提供有关机制的关键信息通过其中，从ER膜中去除多物质HMGCR并为ERAD递送胞质蛋白酶体。在此外，这些研究具有重大的临床意义。 HMGCR是他汀类药物的目标，广泛规定降低血浆LDL-胆固醇并减少心血管疾病的药物。但是，他汀类药物触发反应这会导致HMGCR的积累，从而钝其临床作用。这种增加部分原因是放缓 HMGCR的ERAD。因此，阐明HMGCR的机制有望开发新的增加他汀类药物疗效并进一步降低心脏病发作的疗法。