SUMOylation is a key modulator of glucocorticoid receptor activity in neuronal cells

MARIA ANTUNICA NOGUEROL; MAIA LUDMILA BUDZIÑSKI; CLARA SOKN; SERGIO SENIN; NILS GASSEN; THEO REIN; ANA C LIBERMAN; EDUARDO ARZT

Congreso; XXX Reunion Cientifica Anual, Sociedad Argentina de Investigación en Neurociencias (SAN); 2015

FK506-binding protein 51 (FKBP51) is an Hsp90 cochaperone that regulates the activity of the glucocorticoid receptor (GR) and is therefore critical for the stress response. The molecular mechanisms underlying its functional regulation remains elusive. Here, we show that FKBP51 is a novel SUMOylation target. We identify lysine 422 as the major small ubiquitin-like modifier (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 and nuclear translocation. Our findings establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR action on differentiation and stress response.