Abstract
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.
Highlights
Cochaperones are important for the folding and activation of steroid hormone receptors
Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) is a cochaperone that has been shown to interact with heat shock protein 70 (Hsp70) and Hsp90 by coimmunoprecipitation [13, 23,24,25] and to down-regulate androgen receptor signaling in mammalian reporter assays by promoting cytoplasmic retention of the receptor [16] and/or regulating AR ligand sensitivity [20]
Studies in the budding yeast, S. cerevisiae, have contributed much to the current knowledge regarding cochaperone regulation of steroid hormone receptor function, and our data firmly establish the relevance of the yeast system for the study of functional SGTA-steroid receptor interactions (Figs. 1 and 2)
Summary
Cochaperones are important for the folding and activation of steroid hormone receptors. Heat shock protein (Hsp) 90 and Hsp are key players in this process, multiple Hsp70and 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 Hsp and Hsp90-associated cochaperone that regulates androgen receptor activity. We report that SGTA associates with and 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. Our data suggest a role for SGTA at distinct steps in the chaperone-dependent modulation of androgen, glucocorticoid, and progesterone receptor activity. Steroid hormone receptors are ligand-dependent transcription factors that require the dynamic, ordered assembly of the heat shock protein 70 (Hsp70) and Hsp chaperone machinery to reach a functional conformation.
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