Modulation of the Glucocorticoid Receptor Activity by Post-Translational Modifications

Glucocorticoids (GCs) regulate numerous physiologic processes in order to maintain homeostasis. Most of their actions are mediated by an intracellular GC receptor (GR). The dysregulation of the GR function has been associated with different pathologies such as stress-related disorders and inflammatory and autoimmune diseases. The final outcome of GC actions is regulated at multiple levels and has been extensively reported. Nowadays, novel insights into the modulation of the GR activity arise from the study of the multiprotein chaperone/cochaperone machinery, the nuclear receptor cofactors (coactivators and corepressors), and chromatin regulation and their concomitant impact on GR-mediated gene transcription. Nevertheless, the complexity of GR-mediated gene regulation cannot be explained by a finite number of chaperones and cofactors. A further level in the regulation of GR activity is achieved by posttranslational modifications (PTMs) in response to external stimuli. PTMs can regulate protein stability, structure, function, activity, intracellular localization, and interaction with other proteins during cellular processes. Therefore, dynamic regulation of the molecular properties of these proteins by PTMs allows for further understanding the complexity of GR-dependent gene expression and its impact on GR-mediated pathophysiological processes.