Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Crit Rev Biochem Mol Biol. 2010 Jun;45(3):185-98. doi: 10.3109/10409238.2010.485605.
Multiple mechanisms for feedback control of cholesterol synthesis converge on the rate-limiting enzyme in the pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase. This complex feedback regulatory system is mediated by sterol and nonsterol metabolites of mevalonate, the immediate product of reductase activity. One mechanism for feedback control of reductase involves rapid degradation of the enzyme from membranes of the endoplasmic reticulum (ER). This degradation results from the accumulation of sterols in ER membranes, which triggers binding of reductase to ER membrane proteins called Insig-1 and Insig-2. Insig binding leads to the recruitment of a membrane-associated ubiquitin ligase called gp78 that initiates ubiquitination of reductase. Ubiquitinated reductase then becomes extracted from ER membranes and is delivered to cytosolic 26S proteasomes through an unknown mechanism that is mediated by the gp78-associated ATPase Valosin-containing protein/p97 and appears to be augmented by nonsterol isoprenoids. Here, we will highlight several advances that have led to the current view of mechanisms for sterol-accelerated, ER-associated degradation of reductase. In addition, we will discuss potential mechanisms for other aspects of the pathway such as selection of reductase for gp78-mediated ubiquitination, extraction of the ubiquitinated enzyme from ER membranes, and the contribution of Insig-mediated degradation to overall regulation of reductase in whole animals.
多种反馈控制胆固醇合成的机制都集中在该途径的限速酶，即 3-羟-3-甲基戊二酰辅酶 A 还原酶上。这个复杂的反馈调节系统由固醇和甲羟戊酸的非固醇代谢物介导，而甲羟戊酸是还原酶活性的直接产物。还原酶反馈控制的一种机制涉及内质网（ER）膜中该酶的快速降解。这种降解是由于 ER 膜中的固醇积累引起的，这会触发还原酶与 ER 膜蛋白 Insig-1 和 Insig-2 的结合。Insig 结合导致膜相关泛素连接酶 gp78 的募集，从而引发还原酶的泛素化。然后，泛素化的还原酶从 ER 膜中提取出来，并通过一种未知的机制被递送到胞质 26S 蛋白酶体中，该机制由 gp78 相关的 ATP 酶 Valosin 含有蛋白/p97 介导，并且似乎被非固醇异戊二烯增强。在这里，我们将重点介绍几个导致目前对固醇加速的内质网相关还原酶降解机制的观点的进展。此外，我们将讨论该途径的其他方面的潜在机制，例如还原酶选择 gp78 介导的泛素化、从 ER 膜中提取泛素化酶，以及 Insig 介导的降解对整个动物中还原酶的整体调节的贡献。
