Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors
Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors
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DOI：
10.1073/pnas.160257997
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发表时间：
2000-08-01
影响因子：
11.1
通讯作者：
Cheng, SY
中科院分区：
文献类型：
--
作者：
Dace, A;Zhao, L;Cheng, SY
甲状腺激素3,3'，5-三碘- l -甲状腺原氨酸（T3）对生长、分化和发育至关重要。其生物活性是由T3核受体（TRs）介导的，目前，T3如何调控TR蛋白以及由此产生的功能后果尚不清楚。对生长素产生的GC细胞内源性TR的免疫荧光分析显示，t3诱导的TR的快速降解被泛素-蛋白酶体降解途径的选择性抑制剂lactacystin特异性阻断。免疫印迹显示转染的TR β 1被泛素化，且泛素化与T3无关。对一系列截断的TR β 1的研究表明，激素结合结构域足以通过蛋白酶体降解途径使t3诱导的TR β 1快速降解。T3还诱导了TR β 2和TR α 1的快速降解。相比之下，不与T3结合的TR α 2和不与T3结合的自然发生的TR β 1突变体的稳定性不受T3处理的影响，这表明激素与受体的结合对于野生型受体的降解至关重要。在存在蛋白酶体蛋白酶抑制剂的情况下，总TR β 1蛋白和泛素化TR β 1蛋白的水平均升高，但t3依赖性转录激活和生长激素基因的表达减弱。本研究揭示了T3通过泛素-蛋白酶体降解途径调节Tn的受体水平，从而调节Tn的功能。
The thyroid hormone 3,3',5-triiodo-L-thyronine (T3) is essential for growth, differentiation, and development. Its biological activities are mediated by T3 nuclear receptors (TRs), At present, how T3 regulates TR proteins and the resulting functional consequences are still unknown. Immunofluorescence analyses of endogenous TR in the growth hormone-producing GC cells showed that the T3-induced rapid degradation of TR was specifically blocked by lactacystin, a selective inhibitor of the ubiquitin-proteasome degradation pathway. Immunoblots demonstrated that the transfected TR beta 1 was ubiquitinated and that the ubiquitination was T3 independent. Studies with a series of truncated TR beta 1 showed that the hormone-binding domain was sufficient for the T3-induced rapid degradation of TR beta 1 by the proteasome degradation pathway. T3 also induced rapid degradation of TR beta 2 and TR alpha 1. In contrast, the stability of the non-T3-binding TR alpha 2 and naturally occurring TR beta 1 mutants that do not bind T3 was not affected by T3 treatment, indicating that hormone binding to receptor was essential for the degradation of the wild type receptors. In the presence of proteasome protease inhibitors, the levels of both total and ubiquitinated TR beta 1 protein increased, yet T3-dependent transcriptional activation and the expression of the growth hormone gene were diminished, suggesting that proteasome-mediated degradation played a novel role in modulating transcriptional activation by TR. The present study reveals a role of T3 in modulating the functions of Tn by regulating its receptor level via the ubiquitin-proteasome degradation pathway.