Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity.

FKBP51 is an important inhibitor of the glucocorticoid receptor (GR) signaling. High FKBP51 levels are associated to stress-related disorders, which are linked to GR resistance. SUMO conjugation to FKBP51 is necessary for FKBP51's inhibitory action on GR. The GR/FKBP51 pathway is target of antidepressant action. Thus we investigated if these drugs could inhibit FKBP51 SUMOylation and therefore restore GR activity. Screening cells using Ni2+ affinity and in vitro SUMOylation assays revealed that tricyclic antidepressants- particularly clomipramine- inhibited FKBP51 SUMOylation. Our data show that clomipramine binds to FKBP51 inhibiting its interaction with PIAS4 and therefore hindering its SUMOylation. The inhibition of FKBP51 SUMOylation decreased its binding to Hsp90 and GR facilitating FKBP52 recruitment, and enhancing GR activity. Reduction of PIAS4 expression in rat primary astrocytes impaired FKBP51 interaction with GR, while clomipramine could no longer exert its inhibitory action. This mechanism was verified in vivo in mice treated with clomipramine. These results describe the action of antidepressants as repressors of FKBP51 SUMOylation as a molecular switch for restoring GR sensitivity, thereby providing new potential routes of antidepressant intervention.

SUMO conjugation as regulator of the glucocorticoid receptor-FKBP51 cellular response to stress.

In order to adequately respond to stressful stimuli, glucocorticoids (GCs) target almost every tissue of the body. By exerting a negative feedback loop in the hypothalamic-pituitary-adrenal (HPA) axis GCs inhibit their own synthesis and restore homeostasis. GCs actions are mostly mediated by the GC receptor (GR), a member of the nuclear receptor superfamily. Alterations of the GR activity have been associatedto different diseases including mood disorders and can lead to severe complication. Therefore, understanding the molecular complexity of GR modulation is mandatory for the development of new and effective drugs for treating GR-associated disorders. FKBP51 is a GR chaperone that has gained much attention because it is a strong inhibitor of GR activity and has a crucial role in psychiatric diseases. Both GR and FKBP51 activity are regulated by SUMOylation, a posttranslational (PTM). In this review, we focus on the impact of SUMO-conjugation as a regulator of this pathway.

Regulatory and Mechanistic Actions of Glucocorticoids on T and Inflammatory Cells.

Glucocorticoids (GCs) play an important role in regulating the inflammatory and immune response and have been used since decades to treat various inflammatory and autoimmune disorders. Fine-tuning the glucocorticoid receptor (GR) activity is instrumental in the search for novel therapeutic strategies aimed to reduce pathological signaling and restoring homeostasis. Despite the primary anti-inflammatory actions of GCs, there are studies suggesting that under certain conditions GCs may also exert pro-inflammatory responses. For these reasons the understanding of the GR basic mechanisms of action on different immune cells in the periphery (e.g., macrophages, dendritic cells, neutrophils, and T cells) and in the brain (microglia) contexts, that we review in this chapter, is a continuous matter of interest and may reveal novel therapeutic targets for the treatment of immune and inflammatory response.