Cardinal role of immunophilins in the regulation of the glucocorticoid receptor action

GALIGNIANA MD

Congreso; 4th Edition of Global Webinar on Endocrinology & Diabetes; 2021

Glucocorticoid steroids activate the glucocorticoid receptor (GR) favouring liver gluconeogenesis and decreasing glucose uptake and utilization in muscle and adipose tissue. Consequently, the GR response enhances hyperglycemia and insulin resistance. The GR primary subcellular localization is cytoplasmic in the absence of steroid. Regardless of this, GR is constantly and dynamically shuttling in and out the nucleus, even when it is accumulated in nuclei upon steroid binding. Like all members of the steroid receptor subfamily of nuclear receptors, GR exists as a heterocomplex assembled on the key heat-shock protein of 90-kDa (Hsp90). In turn, Hsp90 recruits other chaperones and cochaperones, among them, the high molecular weight immunophilins FKBP51 and FKBP52. Importantly, the composition of the final GR-Hsp90 mature heterocomplex is affected by the binding and chemical nature of the steroid hormone, which determines the type of associated immunophilin. This is critical for the mechanism of action of the receptor because such immunophilin regulates the GR subcellular localization and also its steroid-binding capacity and transcriptional activity. Therefore, the chaperone heterocomplex plays an essential role in the final biological action of GR and explains its pleioropic actions depending on the cell type or tissue where GR is expressed. Thus, the cortisol-dependent glycogen storage in hepatocytes contrasts with a glycogenolytic action in mononuclear blood cells, whereas the glucocorticoid-dependent promitotic action in uterin cells contrasts with an apoptotic effect in thymocytes. The GR-associated immunophilins FKBP51 and FKBP52 are the main responsible for these opposite properties triggered by the same hormone bound to the same receptor. Moreover, it has recently been demonstrated that these immunophilins are also relevant for the active transport machinery and biological actions of other unrelated soluble proteins such as NF-kB (among other transcription factors). In this presentation, the whole model for this immunophilin-dependent transport machinery system will be dissected.