Role of Antidepressants in the modulation of SUMO-conjugation and its impact on FKBP51 activity as GR co-chaperone

GOBBINI, ROMINA; GASSEN, NILS; ARZT, EDUARDO; BUDZIÑSKI, MAIA LUDMILA; SENIN, SERGIO; REIN, THEO; LIBERMAN, ANA CLARA; SOKN, CLARA; SCHMIDT, MATHIAS; BINDER, ELISABETH

Buenos Aires

Simposio; Frontiers in Biosciences 3; 2018

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

FK506-binding protein 51 (FKBP51) is an Hsp90 co-chaperone that tightly regulates the activity of the GR and is therefore critical for the stress response. Within GR complex, FKBP51 inhibits GR activity by decreasing GR hormone-binding affinity and nuclear translocation. Abnormal FKBP51 function, arising from genetic variations or enhanced protein expression, and its impact on GR activity, has been widely related to stress-related diseases and to the response to antidepressant treatment. Our group has recently demonstrated the key role of FKBP51 SUMO conjugation in the regulation of Hsp90-mediated inhibitory effect on GR activity. Taking this into consideration, we propose to study the role of antidepressants on FKBP51 SUMOylation and its impact on GR activity.Our findings suggest that antidepressants inhibit FKBP51 SUMOylation by different molecular mechanisms. Tricyclic antidepressants such as Clomipramine may inhibit PIAS4 E3 ligase activity on FKBP51 SUMO-conjugation, while SSRI antidepressant Fluoxetine may inhibit Ubc9 E2 or even E1 activity. We also report that Clomipramine and Fluoxetine inhibit FKBP51 SUMO-dependant interaction with Hsp90 and GR, providing a possible mechanism for restoring GR transcriptional activity.