Abstract
Glucocorticoids (GCs), acting via the glucocorticoid receptor (GRα), remain the mainstay therapeutic choice for the treatment of inflammation. However, chronic GC use, aside from generating undesirable side-effects, results in GRα down-regulation, often coupled to a decrease in GC-responsiveness, which may culminate in acquired GC resistance. The current study presents evidence for a novel role of the dimerization state of the GRα in mediating GC-mediated GRα turnover. Through comparing the effects of dimerization promoting GCs on down-regulation of a transfected human wild type GRα (hGRwt) or a dimerization deficient GRα mutant (hGRdim), we established that a loss of receptor dimerization restricts GRα turnover, which was supported by the use of the dimerization abrogating Compound A (CpdA), in cells containing endogenous GRα. Moreover, we showed that the dimerization state of the GRα influenced the post-translational processing of the receptor, specifically hyper-phosphorylation at Ser404, which influenced the interaction of GRα with the E3 ligase, FBXW7α, thus hampering receptor turnover via the proteasome. Lastly, the restorative effects of CpdA on the GRα pool, in the presence of Dex, were demonstrated in a combinatorial treatment protocol. These results expand our understanding of factors that contribute to GC-resistance and may be exploited clinically.
Highlights
Synthetic glucocorticoids (GCs) continue to be the preferred therapeutics for the treatment of diseases associated with chronic inflammation[1,2], despite two major limitations, namely, the generation of undesirable side effects and the development of resistance to GC treatment[3,4,5,6]
Free plasma F levels range from 10 nM to 50 nM during the circadian cycle in unstressed individuals[58,59], which corresponds to a 15–39% reduction in the hGRwt pool, while the free plasma Dex levels range from 1–20 nM following a low dose administration[60], which correlates with a 43–60% reduction in hGRwt levels
GC resistance is characterized by a loss of GC sensitivity, which has been shown to be directly proportional to the available functional pool of GRα14–16,63
Summary
Synthetic glucocorticoids (GCs) continue to be the preferred therapeutics for the treatment of diseases associated with chronic inflammation[1,2], despite two major limitations, namely, the generation of undesirable side effects and the development of resistance to GC treatment[3,4,5,6]. More common is the development of an acquired GC resistance, often linked to disease-progression[20,21,22] or prolonged GC treatment[23,24,25], which reduces the level of the GR protein pool[26]. The level of the GRα protein pool is maintained by two opposing cellular processes namely, synthesis and degradation. GC-mediated regulation has been noted at the level of synthesis[27,28,29], it is well documented that GC-mediated regulation of the GRα protein pool occurs at the level of protein degradation, via the ubiquitin-proteasome system (UPS)[30,31]. Proteins are tagged through covalent post-translational modifications (PTMs), which provide the signal for recognition by the catalytic proteasome that subsequently mediates the degradation of the protein substrates[32]
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