Palmitoylation Regulates 17β-Estradiol-Induced Estrogen Receptor-α Degradation and Transcriptional Activity
Palmitoylation Regulates 17β-Estradiol-Induced Estrogen Receptor-α Degradation and Transcriptional Activity
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DOI：
10.1210/me.2011-1208
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发表时间：
2012-05-01
影响因子：
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通讯作者：
Acconcia, Filippo
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作者：
La Rosa, Piergiorgio;Pesiri, Valeria;Acconcia, Filippo
雌激素受体-α（ER α）是一种转录因子，通过与其同源激素17 β-雌二醇（E2）结合来调节基因表达。ER α转录活性受E2诱导的26 S蛋白酶体介导的ER α降解和ER α丝氨酸（S）残基118磷酸化的调节。此外，ER α通过激活信号级联如MAPK/ERK和磷酸肌醇-3-激酶/v-akt小鼠胸腺瘤病毒癌基因同源物1途径介导对E2的快速细胞应答。这些E2快速效应需要通过棕榈酰化（一种由棕榈酰-酰基-转移酶介导的动态酶促修饰）位于细胞质膜上的ER α群体。然而，膜启动和转录ER α活动是否整合在一个独特的图片或代表平行的途径仍然有待明确。因此，我们在此评估了ER α棕榈酰化对E2诱导的ER α降解和S118磷酸化的影响。棕榈酰化的缺乏使得ER α更容易受到E2依赖性降解的影响，阻断ER α S118磷酸化并阻止E2诱导的ER α雌激素响应元件的启动子占据。因此，ER α转录活性被阻止，受体被定位于核基质亚核区室。这些数据揭示了一个电路，其中受体棕榈酰化连接E2依赖性ER α降解，S118磷酸化和转录活性在一个独特的分子机制。我们建议，快速E2依赖的信号可以被认为是ER α转录活性的先决条件，并建议ER α细胞内信号的整合模型，其中E2依赖的早期细胞核效应控制晚期受体依赖的核行动。（分子内分泌学26：762-774，2012）
The estrogen receptor-alpha (ER alpha) is a transcription factor that regulates gene expression through the binding to its cognate hormone 17 beta-estradiol (E2). ER alpha transcriptional activity is regulated by E2-evoked 26S proteasome-mediated ER alpha degradation and ER alpha serine (S) residue 118 phosphorylation. Furthermore, ER alpha mediates fast cell responses to E2 through the activation of signaling cascades such as the MAPK/ERK and phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog 1 pathways. These E2 rapid effects require a population of the ER alpha located at the cell plasma membrane through palmitoylation, a dynamic enzymatic modification mediated by palmitoyl-acyl-transferases. However, whether membrane-initiated and transcriptional ER alpha activities integrate in a unique picture or represent parallel pathways still remains to be firmly clarified. Hence, we evaluated here the impact of ER alpha palmitoylation on E2-induced ER alpha degradation and S118 phosphorylation. The lack of palmitoylation renders ER alpha more susceptible to E2-dependent degradation, blocks ER alpha S118 phosphorylation and prevents E2-induced ER alpha estrogen-responsive element-containing promoter occupancy. Consequently, ER alpha transcriptional activity is prevented and the receptor addressed to the nuclear matrix subnuclear compartment. These data uncover a circuitry in which receptor palmitoylation links E2-dependent ER alpha degradation, S118 phosphorylation, and transcriptional activity in a unique molecular mechanism. We propose that rapid E2-dependent signaling could be considered as a prerequisite for ER alpha transcriptional activity and suggest an integrated model of ER alpha intracellular signaling where E2-dependent early extranuclear effects control late receptor-dependent nuclear actions. (Molecular Endocrinology 26: 762-774, 2012)