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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.