Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase
Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase
复制标题
DOI：
10.1016/j.molcel.2005.08.009
复制
发表时间：
2005-09-16
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：
Song, BL;Sever, N;DeBose-Boyd, RA
甾醇调节的泛素化是HIVIG CoA还原酶（胆固醇合成的限速酶）ER相关降解（ERAD）的一个必要步骤。还原酶的加速降解是动物细胞用来限制胆固醇产生的几种策略之一，需要固醇诱导的酶与称为Insigs的ER膜蛋白的结合。一旦形成，还原酶-Insig复合物被推定的膜相关泛素连接酶（E3）识别，所述膜相关泛素连接酶（E3）介导还原酶泛素化反应。在这里，我们表明，gp 78，膜结合E3，结合到Insig-1，并需要甾醇调节的泛素化还原酶。此外，gp 78通过与VCP结合将调节的泛素化偶联到还原酶的降解，VCP是一种在ERAD底物的识别和降解中起关键作用的ATP酶。目前的结果确定gp 78作为E3启动甾醇加速降解的还原酶，和Insig-1作为gp 78/VCP和还原酶底物之间的桥梁。
Sterol-regulated ubiquitination is an obligatory step in ER-associated degradation (ERAD) of HIVIG CoA reductase, a rate-limiting enzyme in cholesterol synthesis. Accelerated degradation of reductase, one of several strategies animal cells use to limit production of cholesterol, requires sterol-induced binding of the enzyme to ER membrane proteins called Insigs. Once formed, the reductase-Insig complex is recognized by a putative membrane-associated ubiquitin ligase (E3) that mediates the reductase ubiquitination reaction. Here, we show that gp78, a membrane bound E3, binds to Insig-1 and is required for sterol-regulated ubiquitination of reductase. In addition, gp78 couples regulated ubiquitination to degradation of reductase by binding to VCP, an ATPase that plays a key role in recognition and degradation of ERAD substrates. The current results identify gp78 as the E3 that initiates sterol-accelerated degradation of reductase, and Insig-1 as a bridge between gp78/VCP and the reductase substrate.