Figure 1: GR activity is regulated by the chaperone/cochaperone complex and also by coactivators/corepressors which in turn are targets of posttranslational modifications. The GR is associated with chaperones (e.g. Hsp90) and cochaperones (e.g. FKBP51 and FKBP52), which are implicated in regulating the function, folding and trafficking of the GR. Upon ligand binding, FKBP51 is exchanged for FKBP52 and translocates to the nucleus. Several PTMs directly target GR and also GR heterocomplex further regulating its activity. GR-mediated promoter activation relies on GR DNA binding on simple GREs, on a coordinated binding of a GR/TF complex onto composite GRE or on GR/TF tethering. The latter two mechanisms are also implicated in GR-mediated repression. GR uses chaperone/cochaperone complexes containing Hsp90 to facilitate dynamic interactions with target sites. Hormone release from GR and GR release from chromatin might require complexes with Hsp90.GR may be ubiquitinated and degraded by the proteasome or reused. Coactivator and corepressor are required for GR-mediated transcriptional regulation. Most recruited coactivators display enzymatic activities, such as histone acetyl-transferase (HAT), histone methyl-transferase (HMT), and ATP-dependent chromatin remodeling. They mediate chromatin modification and facilitate the association of RNA polymerase II complex with the general transcription machinery. Corepressors include ATP-dependent chromatin remodeling complexes, basal corepressors, and subcomplexes that may contain histone deacetylase (HDAC) activity and specific corepressors. The GR can bind to coactivators to inhibit HAT activity directly and recruite HDAC2, which reverses histone acetylation leading to suppression of TF-activated inflammatory genes. Therefore, HATs, HDACs, and HMTs support the key role of PTMs in indirectly regulating GR activity.