title: The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51.
abstract: FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.|Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Antunica-Noguerol
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.
authors.forename: M L
authors.initials: ML
authors.lastname: Budziñski
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.
authors.forename: J
authors.initials: J
authors.lastname: Druker
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: N C
authors.initials: NC
authors.lastname: Gassen
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.
authors.forename: M C
authors.initials: MC
authors.lastname: Sokn
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.
authors.forename: S
authors.initials: S
authors.lastname: Senin
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.|Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina.
authors.forename: F
authors.initials: F
authors.lastname: Aprile-Garcia
authors.affiliation: Department of Clinical Research, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Rein
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.
authors.forename: A C
authors.initials: AC
authors.lastname: Liberman
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires C1425FQD, Argentina.|Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428EGA, Argentina.
authors.forename: E
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D000075223:Poly-ADP-Ribose Binding Proteins / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D058207:Sumoylation; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D018841:HSP90 Heat-Shock Proteins; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D008239:Lysine