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Figure 2: Posttranslational modifications play a crucial role in the regulation of GR activity which impacts on the neuroendocrine and immune regulatory pathways. GCs are the downstream effectors of the HPA axis response. They play a key role in the communication between the neuroendocrine and immune systems to ensure homeostasis. GCs impact on both HPA-mediated stress responses and immune responses. GCs effects are mainly mediated through binding to the GR. A series of mechanisms regulate GR activity to ensure GCs specificity. These mechanisms include modulation of GR by posttranslational modifications (PTMs). Different cellular stressors and also hormone binding can modulate PTMs of target proteins. PTMs do not only target GR but also key molecules involved in the regulation of GR activity such as the cochaperone/chaperone heterocomplex and GR coactivators and corepressors. PTMs regulate protein properties including stability, structure, function, activity, intracellular localization, and interaction with other proteins during cellular processes determining the final outcome. This review focuses on PTMs that target GR and GR modulators such as Hsp90, FKBP52, and GRIP1, fine-tuning GR transcriptional outcome, thus adding complexity and specificity to GCs action. GR and Hsp90 activity is modified by SUMOylation, ubiquitination, acetylation, and phosphorylation. Hsp90 is further regulated by methylation by methylatransferases (MT). GRIP1 is targeted by phosphorylation, ubiquitination, and sumoylation. Finally, FKBP52 by phosphorylation and p300 by methylation.