The Cochaperone SGTA (Small Glutamine-rich Tetratricopeptide Repeat-containing Protein Alpha) Demonstrates Regulatory Specificity for the Androgen, Glucocorticoid, and Progesterone Receptors
The Cochaperone SGTA (Small Glutamine-rich Tetratricopeptide Repeat-containing Protein Alpha) Demonstrates Regulatory Specificity for the Androgen, Glucocorticoid, and Progesterone Receptors
复制标题
DOI：
10.1074/jbc.m113.535229
复制
发表时间：
2014-05-30
影响因子：
4.8
通讯作者：
Cox, Marc B.
中科院分区：
文献类型：
--
作者：
Paul, Atanu;Garcia, Yenni A.;Cox, Marc B.
背景：辅伴侣蛋白在类固醇激素受体的折叠和激活中起重要作用。结果：雄激素受体相关辅伴侣SGTA结合Hsp 70和Hsp 90，并调节孕酮和糖皮质激素受体。结论：SGTA是一种受体特异性辅伴侣，调节受体伴侣循环中的不同步骤。重要性：SGTA是依赖于雄激素、孕激素和/或糖皮质激素的疾病的相关因子。类固醇激素受体是配体依赖性转录因子，其需要多分子伴侣复合物的有序组装以实现转录活性。虽然热休克蛋白（Hsp）90和Hsp 70是这个过程中的关键球员，多个Hsp 70和Hsp 90相关的cochaperones与受体伴侣复合物，以调节受体的折叠和激活。小谷氨酰胺丰富的tetratricopeptide repeat-containing protein alpha（SGTA）最近被鉴定为Hsp 70和Hsp 90相关的辅助伴侣，特异性调节雄激素受体活性。然而，SGTA对类固醇激素受体超家族其他成员的特异性以及SGTA调节受体活性的机制仍不清楚。在这里，我们报告，SGTA协会和专门调节雄激素，糖皮质激素和孕激素受体，并没有影响盐皮质激素和雌激素受体在酵母和哺乳动物细胞为基础的报告分析。在这两种系统中，SGTA敲低/缺失增强受体活性，而SGTA过表达抑制受体活性。我们证明，SGTA直接结合到Hsp 70和Hsp 90在体外具有相似的亲和力，但主要沉淀与Hsp 70从细胞裂解物，这表明SGTA在早期，Hsp 70介导的折叠的作用。此外，SGTA表达完全消除了FKBP 52（52-kDa FK 506结合蛋白）对受体功能的调节，FKBP 52在伴侣循环的后期发挥作用。总之，我们的数据表明，SGTA在不同的步骤中的伴侣依赖性调节雄激素，糖皮质激素和孕酮受体活性的作用。
Background: Cochaperones are important for the folding and activation of steroid hormone receptors. Results: The androgen receptor-associated cochaperone SGTA binds both Hsp70 and Hsp90 and regulates progesterone and glucocorticoid receptors. Conclusion: SGTA is a receptor-specific cochaperone that regulates distinct steps in the receptor chaperoning cycle. Significance: SGTA is a relevant factor in diseases that depend on androgens, progestins and/or glucocorticoids.Steroid hormone receptors are ligand-dependent transcription factors that require the ordered assembly of multichaperone complexes for transcriptional activity. Although heat shock protein (Hsp) 90 and Hsp70 are key players in this process, multiple Hsp70- and Hsp90-associated cochaperones associate with receptor-chaperone complexes to regulate receptor folding and activation. Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) was recently characterized as an Hsp70 and Hsp90-associated cochaperone that specifically regulates androgen receptor activity. However, the specificity of SGTA for additional members of the steroid hormone receptor superfamily and the mechanism by which SGTA regulates receptor activity remain unclear. Here we report that SGTA associates with and specifically regulates the androgen, glucocorticoid, and progesterone receptors and has no effect on the mineralocorticoid and estrogen receptors in both yeast and mammalian cell-based reporter assays. In both systems, SGTA knockdown/deletion enhances receptor activity, whereas SGTA overexpression suppresses receptor activity. We demonstrate that SGTA binds directly to Hsp70 and Hsp90 in vitro with similar affinities yet predominately precipitates with Hsp70 from cell lysates, suggesting a role for SGTA in early, Hsp70-mediated folding. Furthermore, SGTA expression completely abrogates the regulation of receptor function by FKBP52 (52-kDa FK506-binding protein), which acts at a later stage of the chaperone cycle. Taken together, our data suggest a role for SGTA at distinct steps in the chaperone-dependent modulation of androgen, glucocorticoid, and progesterone receptor activity.