Steroid receptor folding and signaling is regulated by the Hsp70 cochaperones BAG-1M and HspBP1

A correct conformation is essential for all proteins to exert their cellular functions. Approximately 15% of all proteins depend on folding assistance by chaperones, including steroid receptors such as the glucocorticoid receptor (GR). Mis-folding of GR leads to severe malfunctioning and represents a potential cause for the glucocrticoid resistance observed in many depressed patients. One of the essential players in protein folding is heat shock protein 70 (hsc/hsp70). Assisted protein folding is an energy-dependent process and requires ATPase activity of hsc70, which additionally involves nuclear exchange factors (NEFs). Two structurally distinct proteins acting as NEF for hsc70 are known: bcl-2 associated athanogene 1 (BAG-1) and hsp70 binding protein 1 (HspBP1). BAG-1M was shown to bind to GR and to inhibit its action as transcription factor. The effect of HspBP1 on GR or related steroid receptors is not known. In this study, we demonstrate that over expression of HspBP1 inhibits GR similarly to BAG-1M but exhibits a different effect on androgen receptor (AR) function. We show minor differences in the binding profile of receptors and cofactors to the two NEFs. Furthermore, both proteins inhibit MR function in an hsp70- and hormone-dependent manner. Taken together, our results suggest, that HspBP1, and BAG-1M possess characteristics to be a candidate causing glucocorticoid resistance.