The SUMOylation of FKBP51 shapes its activity as Hsp90 based glucocorticoid receptor co-chaperone

C SOKN; N GASSEN; E ARZT* ; ML BUDZIÑSKI; S SENIN; AC LIBERMAN*; M ANTUNICA NOGUEROL; R GOBBINI; T REIN

Buenos Aires

Simposio; Frontiers in Bioscience 2; 2016

Instituto de Investigación en Biomedicina de Buenos Aires ? CONICET ? Instituto Partner de la Sociedad Max Planck de Alemania

The hypothalamic-pituitary-adrenal (HPA) axis plays a fundamental role in the response to external and internal stimuli. Glucocorticoids (GCs) are the main mediators of the stress reaction. GCs play a prominent role in regulating the magnitude and duration of the HPA axis activation through a negative feedback loop exerted at the pituitary, hypothalamus and extrahypothalamic structures, mainly the hippocampus. GCs exert their function through binding to the glucocorticoid receptor (GR), which translocates to the nucleus and modulates gene transcription. FK506-binding protein 51 (FKBP51) is an Hsp90 cochaperone that tightly regulates the activity of the GR and is therefore critical for the stress response. Within this complex, FKBP51 inhibits GR activity by decreasing GR hormone-binding affinity and nuclear translocation. Notably, abnormal FKBP51 function, arising from genetic variations or enhanced protein expression, and its impact on GR activity, have been widely related to stress-related diseases and response to antidepressant treatment. Post-translational modifications in general and small ubiquitin-like modifier (SUMO) conjugation in particular, play a critical role in regulating GR response. Taking this into consideration, we propose to study the role of SUMO conjugation to FKBP51 and its impact on GR activity.