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Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity

Abstract

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.

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Fig. 1: Tricyclic antidepressants inhibit FKBP51 SUMO conjugation.
Fig. 2: Tricyclic antidepressants inhibit PIAS4 activity and interaction with FKBP51.
Fig. 3: Clomipramine effect is restricted to FKBP51 SUMO conjugation.
Fig. 4: Clomipramine restores FKBP51 cochaperone activity.
Fig. 5: Clomipramine inhibition is mediated by regulation of PIAS4 activity on FKBP51.
Fig. 6: Proposed model: SUMOylated FKBP51 interacts with Hsp90 and GR, decreases GR ligand binding and its nuclear translocation, leading to the inhibition of GR activity.

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Acknowledgements

We thank Dr. Alejandro Leroux for the technical help in the thermal shift assay. This work was supported by grants from the Max Planck Society, Germany; University of Buenos Aires; CONICET; Agencia Nacional de Promoción Científica y Tecnológica, Argentina; and FOCEM-Mercosur (COF 03/11); “OptiMD” grant of the Federal Ministry of Education and Research Germany (01EE1401D; MVS).

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NCG, MLB, TR, MVS, EA, and ACL designed the experiments; MLB, CS, RG, BU, NCG, and TB performed the experiments; MVS, NCG, TB, and MLB performed the in vivo experiments with mice; SS assisted technically; MLB, TR, EA, and ACL analyzed the data; MLB and ACL collated the data and wrote the manuscript; ACL, TR, NCG, MVS, EA, and EBB discussed and corrected the manuscript. All authors contributed to the manuscript.

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Correspondence to Eduardo Arzt or Ana C. Liberman.

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Budziñski, M.L., Sokn, C., Gobbini, R. et al. Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity. Mol Psychiatry 27, 2533–2545 (2022). https://doi.org/10.1038/s41380-022-01491-0

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