Beta‐arrestin 1: A novel partner in the regulation of the glucocorticoid receptor activity

Glucocorticoids (GCs) are one of the most widely used drugs to treat many autoimmune and inflammatory diseases. Although much research has been focused on investigating the glucocorticoid actions, it remains puzzling how glucocorticoids regulate distinct processes in different cells. Glucocorticoids exert their actions through the glucocorticoid receptor (GR). Upon binding with glucocorticoids, the glucocorticoid receptor undergoes activation and the complex translocates into the nucleus where it binds specific DNA responsive elements to regulate the transcription of thousands of target genes. Throughout its intracellular journey, liganded‐GR interacts with regulatory proteins, thus affecting its activity and function. These protein‐protein interactions are necessary for the resolution of the glucocorticoid‐dependent physiological and pharmacological processes. We have discovered the β‐arrestin‐1 (ARRB1) is a novel binding partner and regulator of the glucocorticoid receptor. Beta‐arrestin‐1 plays a well‐established role in participating in agonist‐mediated desensitization of G‐protein‐coupled receptors (GPCRs), and it has become more appreciated as scaffold protein, thus conferring novel signaling properties independent of GPCR activation. We have previously shown that β‐arrestin‐1 is a glucocorticoid‐responsive gene. These findings led us to explore the possibility that β‐arrestin‐1 may contribute to the activity of GR. Indeed, RNA sequencing performed in control‐ and ARRB1 knockdown‐ A549 cells treated with glucocorticoids, showed β‐arrestin‐1 reshaped the glucocorticoid‐regulated transcriptome by altering the transcription of ~1500 new genes. Cell cycle, cell morphology and post‐translational modifications are several of the cellular functions significantly altered by knockdown of β‐arrestin‐1. Interestingly, among the post‐translational modifications, genes involved in the ubiquitin‐proteasome machinery were activated. Among these genes, we found the E3 ligase PELI1 was the most upregulated glucocorticoid‐responsive gene. In vitro data demonstrated that when β‐arrestin‐1 was knocked‐down, it upregulates PELI1 which is responsible for reducing GR half‐life by promoting its ubiquitination and proteasomal degradation. Consistent with this, knockdown of β‐arrestin‐1 and PELI1 , protects the glucocorticoid receptor from its enhanced degradation. Overall, these results demonstrate that β‐arrestin‐1 acts as a crucial player not only for the transcriptional activity of the glucocorticoid receptor but also in its stability. The novel GR/β‐arrestin‐1 partnership may help unravel new mechanisms that contribute to cell‐type specific actions of glucocorticoids. Support or Funding Information This work was supported by the Intramural Research Program of the U.S. National Institutes of Health (NIH) National Institute of Environmental Health Sciences This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .