Alternative effects of the ubiquitin-proteasome pathway on glucocorticoid receptor down-regulation and transactivation are mediated by CHIP, an E3 ligase.
Alternative effects of the ubiquitin-proteasome pathway on glucocorticoid receptor down-regulation and transactivation are mediated by CHIP, an E3 ligase.
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DOI：
10.1210/me.2004-0383
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发表时间：
2005-06
影响因子：
--
通讯作者：
Xinjia Wang;D. DeFranco
中科院分区：
文献类型：
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作者：
Xinjia Wang;D. DeFranco
泛素/蛋白酶体依赖的蛋白降解途径(UPP)是慢性糖皮质激素暴露细胞中糖皮质激素受体(GR)水平加速下调的原因。虽然激素依赖的GR下调在大多数细胞中起作用，但无论是培养的胚胎海马神经元还是HT22海马细胞系，长期使用糖皮质激素处理后，GR受体都不下调。在这份报告中，我们证明了稳定过表达热休克蛋白70相互作用蛋白(CHIP)E3连接酶的羧基末端可以恢复HT22细胞中激素依赖的GR下调。蛋白酶体抑制剂的研究表明，泛素化的GR可以在ChIP过表达时有效地与蛋白酶体结合，这与亲本HT22细胞的情况不同。除了对GR下调的影响外，CHIP过表达还改变了UPP和GR反式激活之间的偶联。与其他类固醇受体不同，蛋白酶体抑制通常会降低类固醇受体的反式激活特性，而HT22细胞和其他细胞株的GR反式激活在蛋白酶体抑制时会增强。然而，在过度表达CHIP的HT22细胞中，蛋白酶体抑制会导致GR反式激活活性降低。因此，单个反式激活子(即GR)对UPP的不同反应可以由ChIP决定，ChIP是一种E3连接酶，也可以作为蛋白酶体靶向因子。
The ubiquitin/proteasome-dependent protein degradation pathway (UPP) is responsible for the accelerated down-regulation of glucocorticoid receptor (GR) levels in cells subjected to chronic glucocorticoid exposure. Whereas hormone-dependent down-regulation of GR operates in most cells, the receptor is not down-regulated after long-term glucocorticoid treatment of either cultured embryonic hippocampal neurons or the HT22 hippocampal cell line. In this report, we show that stable overexpression of the carboxy terminus of heat shock protein 70-interacting protein (CHIP) E3 ligase can restore hormone-dependent down-regulation of GR in HT22 cells. Proteasome inhibitor studies establish that ubiquitylated GR can be efficiently engaged with the proteasome upon CHIP overexpression, unlike the case in parental HT22 cells. In addition to its impact on GR down-regulation, CHIP overexpression alters the coupling between the UPP and GR transactivation. Unlike other steroid receptors whose transactivation properties are typically reduced upon proteasome inhibition, GR transactivation in HT22 cells and other cell lines is enhanced upon proteasome inhibition. However, in HT22 cells overexpressing CHIP, proteasome inhibition leads to a reduction in GR transactivation activity. Thus, the divergent response of a single transactivator (i.e. GR) to the UPP can be dictated by CHIP, an E3 ligase that also functions as a proteasome-targeting factor.