The role of SUMOylation as a master regulator of the glucocorticoid receptor activity in the neruoendocrine and inflammatory context

AC LIBERMAN

Simposio; International Symposium of Neuroinflammation; 2017

The hypothalamic-pituitary-adrenal axis plays a fundamental role in the response to stressful stimuli. Glucocorticoids (GCs), the most downstream effectors of the 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 and is therefore critical for the stress response. Within this 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. The molecular mechanisms underlying its functional regulation remains elusive. SUMOylation is a post-translational modification that plays an important role in the regulation of the GR activity. It can fine tune the cellular response to GCs depending the enviromental context. We also demosntrate that FKBP51 is a novel SUMOylation target and we identified 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 master regulator of GR activity wich can directly or indirectly modulate GR action on differentiation and stress response.