Molecular mechanism for the nuclear receptor degradation

最近的证据表明，雌激素受体α（ERα）的反式激活需要雌激素依赖性受体的泛素化和降解。在这里，我们表明，雌激素未结合（unliganded）ERα也是泛素化和降解通过泛素-蛋白酶体途径。为了研究这种泛素-蛋白酶体途径，我们纯化了未配体ERα的泛素连接酶复合物，并鉴定了含有Hsc 70相互作用蛋白（CHIP）羧基末端的蛋白复合物。CHIP优先与错误折叠的ERα结合并使其泛素化以诱导降解。配体与受体的结合诱导CHIP从ERα上解离。在CHIP-/-细胞中，未配体ERα的降解被消除，然而，观察到雌激素诱导的降解程度与CHIP+/+细胞相同。我们的研究结果表明，ERα是由两个独立的泛素-蛋白酶体途径，这是通过配体结合ERα切换。一条途径是受体反式激活所必需的，另一条途径参与受体的质量控制。

Recent evidence indicates that the transactivation of estrogen receptor α (ERα) requires estrogen-dependent receptor ubiquitination and degradation. Here we show that estrogen-unbound (unliganded) ERα is also ubiquitinated and degraded through an ubiquitin-proteasome pathway. To investigate this ubiquitin-proteasome pathway, we purified the ubiquitin ligase complex for unliganded ERα and identified a protein complex containing the carboxyl terminus of Hsc70-interacting protein (CHIP). CHIP preferentially bound to misfolded ERα and ubiquitinated it to induce degradation. Ligand binding to the receptor induced the dissociation of CHIP from ERα. In CHIP-/-cells, the degradation of unliganded ERα was abrogated, however, estrogen-induced degradation was observed to the same extent as in CHIP+/+ cells. Our findings suggest that ERα is regulated by two independent ubiquitin-proteasome pathways, which are switched by ligand binding to ERα. One pathway is necessary for the transactivation of the receptor and the other is involved in the quality control of the receptor.