Effect of stress on protein homeostasis mediated by FKBP51 as a possible mechanism underlying stress-related disorders [thesis]

Silvia Martinelli, Mathias Schmidt
2019
Homeostasis is a dynamic equilibrium fundamental for a healthy system. A major challenge to homeostasis is environmental stress to which the organism reacts with the stress response. The hypothalamic-pituitary-adrenal (HPA) axis is the main regulator of the stress response that, upon activation, leads to the release of glucocorticoids (GCs). GCs are steroid hormones that exert their function via glucocorticoid receptors (GR). They trigger on one hand the appropriate stress response in the
more » ... sponse in the periphery, and, on the other, inhibit the HPA axis itself via negative feedback to restore homeostasis. FK506-binding protein 51 (FKBP51) is a co-chaperone able to modulate the GR, and therefore the HPA axis. Furthermore the expression of FKBP5, the gene coding for FKBP51, is induced by GR activation. In the last decade, increasing evidence has unveiled additional roles of FKBP51 in the regulation of several cellular pathways and functions that are independent from its inhibitory role on GR. Among these, FKBP51 has been shown to link stress signaling to macroautophagy, a lytic type of autophagy pathway. Autophagy represents one of the main mechanisms regulating cellular homeostasis and response to stress. For this reason, in the first part of this doctoral thesis, the role of GR-mediated stress was investigated on two further autophagic pathways: 1) the chaperone-mediated autophagy (CMA), a selective type of lytic autophagy, and 2) the secretory autophagy, an unconventional secretory mechanism regulated by autophagy-related proteins and found to be involved in extracellular signaling of immune response. For this aim, an in vitro approach was adopted using human and murine cell lines that were treated with dexamethasone (Dex), a synthetic GR agonist. For the first pathway, biochemical assays indicated that Dex-induced GR activation enhances CMA-mediated degradation of known CMA target proteins and that this process is dependent on FKBP51. Furthermore, the underlying molecular mechanism could be revealed by co-immunoprecipitation [...]
doi:10.5282/edoc.25423 fatcat:tuocy3j37fevxb5uliqc3cioj4