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.

Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways

“…Heat shock protein 90 (Hsp90) is a kind of molecular chaperone protein that functions in client protein folding processes to maintain correct protein conformations [14][15][16][17][18]. Inhibiting the interactions between Hsp90 and chaperone proteins usually causes ubiquitination and subsequent proteasome degradation of client proteins.…”

Generation of human induced trophoblast stem cells

“…This was accompanied with the expression of CREB3 and FOS that can mediate the transcription of estrogen responsive genes, and the upregulation of keratin genes, such as KRT17, KRT18 and KRT19, in line with the morphological changes associated with the formation of epithelial hTSC ( Figure S3C). Conversely to hTSC, hPSC expressed FKBP5 and HSP90AB1 which can form a complex that inhibits the translocation of the estrogen receptor to the nucleus (Baker et al, 2018).…”

Molecular Psychiatry: Trends and Study Examples

“…The role of corticosteroid receptors in psychiatric diseases has been recognized for a long time, in part as executors of the stress response that is pivotal in a number of diseases. The review of Baker et al illustrates this while focusing on the molecular mechanisms regulating steroid receptor activity [1]. The authors summarize our current knowledge on the control of glucocorticoid receptor (GR) activity by the heat shock protein (Hsp) 90 based chaperone system, with a focus on the established stress factor and co-chaperone FK506 binding protein (FKBP) 51.…”