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A Novel Interaction between Glucocorticoid Receptor and beta‐arrestin proteins

Glucocorticoids (GCs), vital stress hormones released as the end products of the hypothalamic‐pituitary‐adrenal axis, are involved in controlling inflammation. The actions of glucocorticoids occur through the activation of the glucocorticoid receptor (GR) which, like other members of the steroid hormone receptor superfamily, functions as a ligand‐activated transcriptional regulator. Throughout its intracellular journey, liganded GR creates physical contacts with regulatory proteins, thus affecting its activity and function. The protein‐protein interactions of GR are decisive for the resolution of the glucocorticoid‐dependent physiological processes. We have recently discovered a new interaction between GR and beta‐arrestin‐1 (barr‐1). Beta‐arrestin‐1 plays a well‐established role in participating in agonist‐mediated desensitization of G‐protein‐coupled receptors (GPCRs). However, it has become increasingly appreciated as a scaffold protein, thus conferring novel signaling properties independent of GPCR activity. These functions include interfering with the ubiquitin‐proteasome machinery. Moreover, recent studies, from our lab, have demonstrated that glucocorticoids can promote the transcription of beta‐arrestin‐1, thereby contributing to modulating its function. These findings led us to investigate the possibility that barr‐1 and GR can either form a tightly regulated loop, or that barr‐1 may contribute to the activity of the GR. To investigate whether the association of barr‐1 with GR affects the activity of GR, RNA sequencing in control‐ and barr‐1 knock down‐ A549 cell line has been performed. The transcriptome analysis identified post‐translational modifications as one of the top‐ranked cellular functions significantly altered by the lack of barr‐1. Notably, lack of barr‐1 reshaped the GR gene signature, regulating a cohort of genes responsible for the activation of the ubiquitin‐proteasome machinery. Among these genes, PELI1 (Pellino E3 Ubiquitin Protein Ligase 1) resulted the most upregulated glucocorticoid‐responsive gene. Indeed, in vitro data demonstrated that when beta‐arrestin‐1 was knocked down, it accelerated GC‐induced GR degradation reducing its half‐life and promoting its ubiquitination via PELI1 activation. These observations strongly suggest that barr‐1 is required for regulating GR expression, by limiting proteasomal degradation of GR. Playing a pivotal role in homeostasis, GR is susceptible to numerous stimuli that modulate its activity, and discovering a novel protein partnership between GR and barr‐1 may help in developing new glucocorticoids, as well as combination therapies that sustain the beneficial effects of glucocorticoids limiting the risks.