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的受体泛素化和降解。在这里，我们表明雌激素非结合(去连接)的ERα也是泛素化的，并通过泛素-蛋白酶体途径降解。为了研究这种泛素-蛋白酶体途径，我们纯化了未连接的内质网α的泛素连接酶复合体，并鉴定了一个含有Hsc70相互作用蛋白的羧基末端的蛋白质复合体(CHIP)。ChIP优先与错误折叠的ERα结合，并泛素化它以诱导降解。与受体的配基结合可引起内质网α芯片的解离。在CHIP-/-细胞中，未连接的ERα的降解被抑制，而雌激素诱导的降解程度与CHIP+/+细胞相同。我们的发现表明，ERα受两条独立的泛素-蛋白酶体途径的调节，这两条途径通过与ERα的配体结合来切换。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.