Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor
Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor
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DOI：
10.1038/sj.emboj.7600472
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发表时间：
2004-12-08
期刊：
影响因子：
11.4
通讯作者：
Yanagisawa, J
中科院分区：
文献类型：
--
作者：
Tateishi, Y;Kawabe, Y;Yanagisawa, J
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泛素化和降解。在这里，我们表明，未结合雌激素（未配体）的 ERα 也通过泛素-蛋白酶体途径被泛素化和降解。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 Hsc70 相互作用蛋白 (CHIP) 羧基末端的蛋白质复合物。 CHIP 优先与错误折叠的 ERα 结合并将其泛素化以诱导降解。配体与受体的结合诱导 CHIP 从 ERα 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 ERalpha 受到两条独立的泛素蛋白酶体途径的调节，这些途径通过配体与 ERalpha 的结合进行切换。一种途径是受体反式激活所必需的，另一种途径涉及受体的质量控制。
Recent evidence indicates that the transactivation of estrogen receptor alpha (ERalpha) requires estrogen-dependent receptor ubiquitination and degradation. Here we show that estrogen-unbound (unliganded) ERalpha is also ubiquitinated and degraded through a ubiquitin-proteasome pathway. To investigate this ubiquitin-proteasome pathway, we purified the ubiquitin ligase complex for unliganded ERalpha and identified a protein complex containing the carboxyl terminus of Hsc70-interacting protein (CHIP). CHIP preferentially bound to misfolded ERalpha and ubiquitinated it to induce degradation. Ligand binding to the receptor induced the dissociation of CHIP from ERalpha. In CHIP-/- cells, the degradation of unliganded ERalpha was abrogated; however, estrogen-induced degradation was observed to the same extent as in CHIP+/+ cells. Our findings suggest that ERalpha is regulated by two independent ubiquitin-proteasome pathways, which are switched by ligand binding to ERalpha. One pathway is necessary for the transactivation of the receptor and the other is involved in the quality control of the receptor.