Significance of UBIAD1 in Regulation of HMG CoA Reductase Degradation, Mevalonate Metabolism, and Menaquinone-4 Synthesis

UBIAD1 在调节 HMG CoA 还原酶降解、甲羟戊酸代谢和 Menaquinone-4 合成中的意义

• 批准号: 10316648
• 负责人: SARAH Louise BOOTH
• 金额: $ 49.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316648
• 关键词: Acinar Cell; Adult; Binding; Biology; Blood; Cardiovascular Diseases; Cause of Death; Cells; Cholesterol; Cholesterol Homeostasis; Clinical; Cornea; Coronary Arteriosclerosis; Cultured Cells; Dimethylallyltranstransferase; Diphosphates; Disease; Dolichol; Drug Prescriptions; Embryo; Endoplasmic Reticulum; Enzymes; Exhibits; Eye diseases; Feedback; Functional disorder; Germ Lines; Goals; Golgi Apparatus; Grant; Hepatic; Histologic; Homeostasis; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA reductase; Incidence; Injury; Intestines; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; Light; Liver; Mediating; Membrane; Metabolism; Missense Mutation; Modality; Morphology; Mus; Muscle; Mutation; Myocardial Infarction; Myopathy; Nuclear Receptors; Outcome; Pancreas; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Plasma; Process; Proteins; Reaction; Regulation; Reporting; Resistance; Role; Schnyder corneal dystrophy; Site; Skeletal Muscle; Sterols; Tissues; Ubiquinone; Ubiquitination; Vitamin K; Vitamin K 2; Xenobiotics; cholesterol control; clinical effect; farnesyl pyrophosphate; geranylgeranyl pyrophosphate; insight; isoprenoid; knock-down; knockout gene; mevalonate; mutant; pregnane X receptor; prevent; protein degradation; receptor binding; response; sensor; targeted treatment

UbiA prenyltransferase domain-containing protein-1 (UBIAD1) uses the nonsterol isoprenoid geranylgeranyl pyrophosphate (GGpp) to synthesize a form of vitamin K called menaquinone-4 (MK-4). UBIAD1 is multifunctional as indicated by the association of mutations in human UBIAD1 with Schnyder corneal dystrophy (SCD). This rare autosomal dominant eye disease is characterized by progressive corneal opacification owing to abnormal accumulation of cholesterol. Our studies revealed that sterols cause UBIAD1 to bind endoplasmic reticulum (ER)-localized HMG CoA reductase (HMGCR), the rate-limiting enzyme in synthesis of cholesterol and essential nonsterol isoprenoids including farnesyl pyrophosphate, GGpp, MK-4, ubiquinone, and dolichol. Sterol- induced ubiquitination is obligatory for ER-associated degradation (ERAD) of HMGCR that is augmented by GGpp and constitutes one mechanism for feedback control of the enzyme. GGpp blocks sterol-induced binding of UBIAD1 to HMGCR, which enhances its ERAD and permits ER-to-Golgi transport of UBIAD1. SCD- associated mutants of UBIAD1 resist GGpp-induced displacement from HMGCR and remain sequestered in the ER to inhibit ERAD, which contributes to enhanced synthesis and intracellular accumulation of cholesterol. Gene knockout studies in mice were attempted to elucidate the role of UBIAD1 in tissue-specific distribution of MK-4, which remains a major unresolved question in vitamin K biology. However, homozygous germ-line deletion of Ubiad1 caused embryonic lethality. We recently generated homozygous deletion of Ubiad1 in knock- in mice expressing ubiquitination-resistant HMGCR, which implies embryonic lethality associated with Ubiad1 deficiency results from enhanced ERAD of HMGCR and depletion of mevalonate metabolites distinct from MK- 4. We will now elucidate tissue-specific roles of UBIAD1 in regulating HMGCR ERAD and MK-4 synthesis by pursuing the following Specific Aims: 1) Explore role of UBIAD1-mediated sensing of GGpp in regulation of HMGCR ERAD and mevalonate metabolism in the liver; 2) Determine contribution of UBIAD1-mediated synthesis of MK-4 to skeletal muscle homeostasis; 3) Establish roles for UBIAD1 in pancreatic subsistence and function; and 4) Examine role of UBIAD1 in morphology and function of the intestine. Combined efforts of the PIs, who have complementary expertise in mechanisms underlying regulation of cholesterol metabolism (DeBose-Boyd) and vitamin K biology (Booth), will lead to discovery of tissue-specific pathways/processes modulated by MK-4. In addition, these studies will have immediate clinical implications. HMGCR is the target of statins, widely prescribed drugs that lower plasma LDL-cholesterol and reduce incidence of cardiovascular disease (CVD). However, statins trigger responses that cause accumulation of HMGCR, which blunts their clinical effects. Part of this increase results from UBIAD1-mediated inhibition of HMGCR ERAD. Our studies may expose UBIAD1-mediating sensing of GGpp as a target of therapies that prevent statin-induced accumulation of HMGCR, increasing statin efficacy and ultimately reducing incidence of CVD and heart attacks.

UbiA 异戊二烯基转移酶结构域蛋白 1 (UBIAD1) 使用非甾醇类异戊二烯香叶基香叶基焦磷酸 (GGpp) 合成一种称为 menaquinone-4 (MK-4) 的维生素 K。人类 UBIAD1 突变与施奈德角膜营养不良 (SCD) 的关联表明 UBIAD1 具有多功能性。这种罕见的常染色体显性眼病的特点是由于胆固醇异常积累而导致进行性角膜混浊。我们的研究表明，甾醇导致 UBIAD1 结合内质网 (ER) 定位的 HMG CoA 还原酶 (HMGCR)，这是胆固醇和必需非甾醇类异戊二烯（包括法呢基焦磷酸、GGpp、MK-4、泛醌和多萜醇）合成的限速酶。甾醇诱导的泛素化对于 HMGCR 的 ER 相关降解 (ERAD) 是必需的，而 GGpp 增强了这种降解，并构成了酶反馈控制的一种机制。 GGpp 阻断甾醇诱导的 UBIAD1 与 HMGCR 的结合，从而增强其 ERAD 并允许 UBIAD1 从 ER 转运至高尔基体。 UBIAD1 的 SCD 相关突变体抵抗 GGpp 诱导的 HMGCR 位移，并保留在 ER 中以抑制 ERAD，这有助于增强胆固醇的合成和细胞内积累。小鼠基因敲除研究试图阐明 UBIAD1 在 MK-4 组织特异性分布中的作用，这仍然是维生素 K 生物学中一个未解决的主要问题。然而，Ubiad1 的纯合种系缺失导致胚胎致死。我们最近在表达泛素化抗性 HMGCR 的敲入小鼠中产生了 Ubiad1 纯合缺失，这意味着与 Ubiad1 缺陷相关的胚胎致死性是由于 HMGCR 的 ERAD 增强和不同于 MK-4 的甲羟戊酸代谢物的消耗所致。现在我们将阐明组织特异性UBIAD1 通过追求以下具体目标在调节 HMGCR ERAD 和 MK-4 合成中的作用：1) 探索UBIAD1 介导的 GGpp 传感在 HMGCR ERAD 和肝脏甲羟戊酸代谢调节中的作用； 2)确定UBIAD1介导的MK-4合成对骨骼肌稳态的贡献； 3) 确定UBIAD1在胰腺生存和功能中的作用； 4) 检查 UBIAD1 在肠道形态和功能中的作用。 PI 在胆固醇代谢调节机制 (DeBose-Boyd) 和维生素 K 生物学 (Booth) 方面拥有互补的专业知识，他们的共同努力将导致发现 MK-4 调节的组织特异性途径/过程。此外，这些研究将具有直接的临床意义。 HMGCR 是他汀类药物的靶点，他汀类药物是广泛使用的药物，可降低血浆 LDL 胆固醇并降低心血管疾病 (CVD) 的发病率。然而，他汀类药物会引发导致 HMGCR 积累的反应，从而削弱其临床效果。这种增加的部分原因是 UBIAD1 介导的 HMGCR ERAD 抑制。我们的研究可能揭示 UBIAD1 介导的 GGpp 感知作为预防他汀类药物诱导的 HMGCR 积累的治疗靶标，提高他汀类药物的疗效并最终降低 CVD 和心脏病的发病率。