Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
Cold Spring Harb Perspect Biol. 2022 Dec 1;14(12):a041253. doi: 10.1101/cshperspect.a041253.
3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an endoplasmic reticulum (ER)-localized integral membrane protein that catalyzes the rate-limiting step in the synthesis of cholesterol and many nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). HMGCR is subjected to strict feedback control through multiple mechanisms to ensure cells constantly produce essential nonsterol isoprenoids, but do not overaccumulate cholesterol. Here, we focus on the mechanism of feedback control of HMGCR that involves its sterol-induced ubiquitination and ER-associated degradation (ERAD) that is augmented by GGpp. We will also discuss the how GGpp-regulated intracellular trafficking of the vitamin K2 synthetic enzyme UbiA prenyltransferase domain-containing protein-1 (UBIAD1) inhibits HMGCR ERAD to balance the synthesis of sterol and nonsterol isoprenoids. Finally, we will summarize various mouse models, the characterization of which establish that sterol-accelerated, UBIAD1-modulated ERAD plays a major role in regulation of HMGCR and cholesterol metabolism in vivo.
3-羟-3-甲基戊二酰基辅酶 A 还原酶（HMGCR）是一种内质网（ER）定位的整合膜蛋白，它催化胆固醇和许多非固醇异戊二烯的合成限速步骤，包括香叶基香叶基焦磷酸（GGpp）。HMGCR 通过多种机制受到严格的反馈控制，以确保细胞不断产生必需的非固醇异戊二烯，但不会过度积累胆固醇。在这里，我们重点介绍 HMGCR 反馈控制的机制，该机制涉及固醇诱导的泛素化和 ER 相关降解（ERAD），GGpp 增强了该降解。我们还将讨论 GGpp 如何调节维生素 K2 合成酶 UbiA prenyltransferase 结构域包含蛋白-1（UBIAD1）的细胞内运输，以抑制 HMGCR 的 ERAD，从而平衡固醇和非固醇异戊二烯的合成。最后，我们将总结各种小鼠模型的特征，这些模型的特征表明固醇加速的、UBIAD1 调节的 ERAD 在体内调节 HMGCR 和胆固醇代谢中起着重要作用。
