Novel role for receptor dimerization in post-translational processing and turnover of the GRα
Date
2018
Journal Title
Journal ISSN
Volume Title
Publisher
Nature
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.
Description
CITATION: Wilkinson, L., Verhoog, N. & Louw, A. 2018. Novel role for receptor dimerization in post-translational processing and turnover of the GRα. Scientific Reports, 8:14266, doi:10.1038/s41598-018-32440-z.
The original publication is available at https://www.nature.com
The original publication is available at https://www.nature.com
Keywords
Glucocorticoids, Glucocorticoid -- Receptors, Receptor dimerization, Treatment of inflammation
Citation
Wilkinson, L., Verhoog, N. & Louw, A. 2018. Novel role for receptor dimerization in post-translational processing and turnover of the GRα. Scientific Reports, 8:14266, doi:10.1038/s41598-018-32440-z.