RING-E3泛素连接酶调控低密度脂蛋白受体的研究进展

Advances in the regulation of low density lipoprotein receptor by RING-E3 ubiquitin ligase

摘要:

动脉粥样硬化性心血管疾病的发生发展与血浆低密度脂蛋白胆固醇(LDLC)水平的异常升高密切相关。低密度脂蛋白受体(LDLR)通过介导LDLC的内吞清除,在维持胆固醇稳态中发挥核心作用,而细胞膜表面LDLR丰度与LDLR的表达水平和再循环密切相关。近年的研究发现,RING-E3泛素连接酶可通过双重机制调控LDLR水平:一方面直接泛素化修饰LDLR,促进其经内体-溶酶体途径降解；另一方面通过激活肝X受体(LXR)通路或抑制固醇调节元件结合蛋白(SREBP)核转位,减少LDLR的合成。这两种机制共同导致细胞膜LDLR丰度降低,削弱胆固醇代谢平衡并加剧LDLC蓄积。因此,靶向抑制RING-E3泛素连接酶活性可能成为调控LDLR表达、降低血浆LDLC水平及防治心血管疾病的新策略。该文综述了RING-E3泛素连接酶调控LDLR的作用机制及其相关研究进展。

Abstract:

The occurrence and development of atherosclerotic cardiovascular diseases is closely related to abnormally elevated plasma low density lipoprotein cholesterol (LDLC) level. Low density lipoprotein receptor (LDLR) plays a central role in the maintenance of cholesterol homeostasis by mediating the endocytotic clearance of LDLC, and the abundance of LDLR on the surface of the cell membrane is closely related to the expression level and recirculation of LDLR. Recent studies have found that RING-E3 ubiquitin ligase can regulate LDLR levels through a dual mechanism:on the one hand, it directly ubiquitinates and modifies LDLR to promote its degradation via the endosome-lysosome pathway; on the other hand, it reduces LDLR synthesis through activation of the liver X receptor (LXR) pathway or inhibition of the nuclear translocation of sterol regulatory element-binding protein (SREBP). Together, these two mechanisms lead to a decrease in cell membrane LDLR abundance, impairing cholesterol metabolic homeostasis and exacerbating LDLC accumulation. Therefore, targeted inhibition of RING-E3 ubiquitin ligase activity may be a novel strategy to regulate LDLR expression, reduce plasma LDLC levels, and combat cardiovascular disease. This article reviews the mechanism of action of RING-E3 ubiquitin ligase in regulating LDLR and its related research progress.