Sumoylation as a regulator of key proteins involved in the stress response

MAIA LUDMILA BUDZIÑSKI; BELEN UGO; NILS GASSEN; EDUARDO ARZT*; CLARA SOKN; SERGIO SENIN; THEO REIN; AC LIBERMAN *; ROMINA GOBBINI; MATHIAS SCHMIDT; ELISABETH BINDER

Congreso; XXXV Reunión Anual SAN 2020; 2020

The hypothalamic-pituitary-adrenal (HPA) axis is critical for controlling the stress response. Glucocorticoids (GCs), the most downstream effectors of the axis, orchestrate the physiologic stress response and are also critical for restoring homeostasis via a negative feedback. Hyperactivity of the axis and increased levels of GCs in patients with depression have mostly been ascribed to impaired feedback regulation, caused by altered function of the glucocorticoid receptor (GR). Antidepressants, in turn, ameliorate neurobiological disturbances in depression, including HPA axis hyperactivity, and alleviate depressive symptoms, which relate to restoring GR functions. FKBP51 is a key inhibitor of GR activity and its increased expression is linked to GR resistance, pointing it out as a therapeutic target. The activity of the GR is regulated by SUMO conjugation to FKBP51 and it is necessary for FKBP51?s Hsp90-dependant inhibitory action on GR transcripcional regulation. We show that antidepressants inhibit FKBP51 SUMOylation by reducing E3 ligase PIAS4 and FKBP51 interaction. Also, that these drugs inhibit FKBP51 interaction with Hsp90 and therefore with GR, thus restoring GR transcriptional activity. These effects are mainly due to the inhibition of FKBP51 SUMOylation. These results describe the action of antidepressants as modulators of FKBP51 SUMOylation as a molecular switch for restoring GR sensitivity, thereby providing new potential mechanisms of antidepressant intervention.