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

SENIN, SERGIO; LIBERMAN, ANA CLARA; SOKN, CLARA; DRUKER, JIMENA; BUDZIÑSKI, MAIA LUDMILA; ARZT, EDUARDO; GOBBINI, ROMINA; ANTUNICA NOGUEROL, MARÍA

Cavtat-Dubrovnik

Conferencia; Ubiquitin and SUMO: From molecular mechanisms to system-wide responses; 2017

European Molecular Biology Organization

Glucocorticoids (GCs), the most downstream effectors of the hypothalamic-pituitary- adrenal axis are the main mediators of the stress reaction. GCs exert their function through binding to the glucocorticoid receptor (GR) which translocates into the nucleus to regulate gene transcription. The activation of GR is regulated by a multiprotein complex. FK506-binding protein 51 (FKBP51) is an Hsp90 co-chaperone that tightly regulates the activity of the GR. Within this complex, FKBP51 inhibits GR activity by decreasing GR hormone-binding affinity and nuclear translocation. We show in vitro and endogenously in cells, that FKBP51 is a novel SUMOylation target. We identify lysine 422 as the SUMO attachment site and PIAS4 as the E3 ligase that enhances its SUMOylation. SUMO conjugation to FKBP51 is required for the inhibition of GR activity. FKBP51 SUMOylation occurs in hippocampal neuronal cells and impacts on GR-dependent neuronal signaling and differentiation. SUMOylation of FKBP51 allows for its interaction with Hsp90 and its recruitment to the GR chaperone complex, and is therefore critical for its inhibitory action on GR hormone binding affinity, nuclear translocation and transcriptional activity. Our findings establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with functional consequences on GR action that impacts on stress-related diseases and their treatment.