Hsp90 Heterocomplexes Regulate Steroid Hormone Receptors: From Stress Response to Psychiatric Disease

Abstract

The hypothalamus-pituitary-adrenal (HPA) axis directly controls the stress response. Dysregulation of this neuroendocrine system is a common feature among psychiatric disorders. Steroid hormone receptors, like glucocorticoid receptor (GR), function as transcription factors of a diverse set of genes upon activation. This activity is regulated by molecular chaperone heterocomplexes. Much is known about the structure and function of these GR/heterocomplexes. There is strong evidence suggesting altered regulation of steroid receptor hormones by chaperones, particularly the 51 kDa FK506-binding protein (FKBP51), may work with environmental factors to increase susceptibility to various psychiatric illnesses including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and anxiety. This review highlights the regulation of steroid receptor dynamics by the 90kDa heat shock protein (Hsp90)/cochaperone heterocomplexes with an in depth look at how the structural regulation and imbalances in cochaperones can cause functional effects on GR activity. Links between the stress response and circadian systems and the development of novel chaperone-targeting therapeutics are also discussed.

Keywords: CyP40; FKBP51; FKBP52; GR; Hsp90; PP5; circadian rhythms; molecular chaperones; psychiatric disease; steroid hormones; stress response.

Figure 1

Schematic of glucocorticoid receptor (GR) transactivation in response to cortisol (CORT). After stress, the hypothalamus releases corticotropin releasing hormone (CRH) stimulating the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH stimulates CORT release from the adrenal cortex which crosses the plasma membrane of the cell. Through negative feedback, CORT inhibits hormone release from the hypothalamus and anterior pituitary glands. Inside the cell, Hsp70 binds to and unfolds GR in the cytosol. HOP recruits GR:Hsp70 to Hsp90. Cochaperones (including FKBP51 and FKBP52) bind to Hsp90 as HOP is released. p23 binds and stabilizes the GR:Hsp90 heterocomplex. FKBP51 inhibits nuclear transactivation of GR, while FKBP52 and other copchaperones may promote translocation. Subsequently, GR binds CORT, dimerizes and translocates to the nucleus binding to glucocorticoid response elements (GREs).

Figure 2

Schematic of the feedback between the molecular clock and stress response systems. Stress produces CORT, which binds to the GR/Hsp90 heterocomplex. GR forms a homodimer and translocate to the nucleus where it binds the glucocorticoid response elements in the promoter region. This leads to increased FKBP5/FKBP51, which slows GR activity, and increased PER expression, a component of the negative arm of the circadian clock; at the same time, REV-ERBα, a positive arm protein is down regulated.