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.

A comprehensive platform for the analysis of ubiquitin-like protein modifications using in vivo biotinylation

“…Expression of the E2 conjugases and/or E3 ligases, together with the bioUbL construct, might give rise to non-physiological modifications in cells, but this approach might facilitate the identification of novel targets below the sensitivity of other methods, or address substrate preferences for particular E3s or E2/E3 combinations. The co-expression strategy has been widely used in the literature for various UbLs, as it can be seen in some recent examples3064656667686970. With caution in mind, we could not find specific reports showing that exogenous UBC9 or UFC1 drives unspecific modification of substrates.…”

The FKBP51 Glucocorticoid Receptor Co-Chaperone: Regulation, Function, and Implications in Health and Disease

“…Although several phosphorylation sites are known for FKBP51 ( ), their functional relevance has not been revealed yet. However, the two peptide modifications ubiquitination and SUMOylation have been reported in the modulation of FKBP51 and its function [ 124 ]. SUMOylation of proteins involves the covalent addition of a member of the SUMO (small ubiquitin-like modifier) family of proteins to a protein target.…”

“…FKBP51 can be SUMOylated at Lys 422 to allow for its association to the GR complex though interaction with Hsp90 [ 124 ]. Accordingly, FKBP51 mutants that could not be SUMOylated failed to interact with Hsp90 and GR, suggesting an important modification in FKBP51’s activity on GR signaling [ 124 ]. FKBP51 is further modified by the ubiquitin specific peptidase (UPS) 49.…”

Post-translational modifications and stress adaptation: the paradigm of FKBP51

“…The sirtuin SIRT7 has been identified as deacetylase acting at these sites [44]. SUMOylation of FKBP51 was detected and mapped to lysine 422 [45]. It regulates the inhibitory action of FKBP51 on GR [45].…”

“…SUMOylation of FKBP51 was detected and mapped to lysine 422 [45]. It regulates the inhibitory action of FKBP51 on GR [45].…”