Accelerated degradation of HMG CoA reductase mediated by binding of Insig-1 to its sterol-sensing domain
Accelerated degradation of HMG CoA reductase mediated by binding of Insig-1 to its sterol-sensing domain
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DOI：
10.1016/s1097-2765(02)00822-5
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发表时间：
2003-01-01
期刊：
影响因子：
16
通讯作者：
DeBose-Boyd, RA
中科院分区：
文献类型：
--
作者：
Sever, N;Yang, T;DeBose-Boyd, RA
硬脂酸加速ER酶3-羟基-3-甲基戊二酰CoA还原酶（HMG CoA还原酶）的降解，该酶催化胆固醇生物合成中的速率控制步骤。这种降解有助于反馈抑制胆固醇和非固醇类异戊二烯的合成。在这里，我们表明，HMG CoA还原酶的降解是加速的甾醇诱导的结合，其甾醇敏感结构域的ER蛋白insig-1。SREBP裂解激活蛋白（SCAP）的甾醇敏感结构域的过表达抑制加速降解，表明这两种蛋白质结合到insig-1上的相同位点。尽管insig-1与SCAP结合导致ER滞留，但insig-1与HMG CoA还原酶结合导致加速降解，其被蛋白酶体抑制剂阻断。Insig-1似乎在两种具有甾醇敏感结构域的蛋白质HMG CoA还原酶和SCAP的甾醇介导的运输中发挥重要作用。
Sterols accelerate degradation of the ER enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase), which catalyzes a rate-controlling step in cholesterol biosynthesis. This degradation contributes to feedback inhibition of synthesis of cholesterol and nonsterol isoprenoids. Here, we show that degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1. Accelerated degradation is inhibited by overexpression of the sterol-sensing domain of SREBP cleavage-activating protein (SCAP), suggesting that both proteins bind to the same site on insig-1. Whereas insig-1 binding to SCAP leads to ER retention, insig-1 binding to HMG CoA reductase leads to accelerated degradation that is blocked by proteasome inhibitors. Insig-1 appears to play an essential role in the sterol-mediated trafficking of two proteins with sterol-sensing domains, HMG CoA reductase and SCAP.