Abstract
Glucocorticoids are among the most widely used drugs to treat many autoimmune and inflammatory diseases. Although much research has been focused on investigating glucocorticoid activity, it remains unclear how glucocorticoids regulate distinct processes in different cells. Glucocorticoids exert their effects through the glucocorticoid receptor (GR), which, upon glucocorticoid binding, interacts with regulatory proteins, affecting its activity and function. These protein-protein interactions are necessary for the resolution of glucocorticoid-dependent physiological and pharmacological processes. In this study, we discovered a novel protein interaction between the glucocorticoid receptor and β-arrestin-1, a scaffold protein with a well-established role in G protein-coupled receptor signaling. Using co-immunoprecipitation and in situ proximity ligation assays in A549 cells, we observed that β-arrestin-1 and unliganded GR interact in the cytoplasm and that, following glucocorticoid binding, the protein complex is found in the nucleus. We show that siRNA-mediated β-arrestin-1 knockdown alters GR protein turnover by up-regulating the E3 ubiquitin ligase Pellino-1, which catalyzes GR ubiquitination and thereby marks the receptor for proteasomal degradation. The enhanced GR turnover observed in β-arrestin-1-deficient cells limits the duration of the glucocorticoid response on GR target genes. These results demonstrate that β-arrestin-1 is a crucial player for the stability of the glucocorticoid receptor. The GR/β-arrestin-1 interaction uncovered here may help unravel mechanisms that contribute to the cell type-specific activities of glucocorticoids.