REV-ERBα influences stability and nuclear localization of the glucocorticoid receptor

Abstract

REV-ERBα (Nr1d1) is a nuclear receptor that is part of the circadian clock mechanism and regulates metabolism and inflammatory processes. The glucocorticoid receptor (GR, Nr3c1) influences similar processes, but is not part of the circadian clock although glucocorticoid signaling affects resetting of the circadian clock in peripheral tissues. Because of their similar impact on physiological processes we studied the interplay between these two nuclear receptors. We found that REV-ERBα binds to the C-terminal part and GR to the N-terminal part of HSP90, a chaperone responsible for the activation of proteins to ensure survival of a cell. The presence of REV-ERBα influences stability and nuclear localization of GR by an unknown mechanism, thereby affecting GR target gene expression such as IκB and alcohol dehydrogenase 1 (Adh1). Our findings highlight an important interplay between two nuclear receptors that influence each others transcriptional potential. This indicates that the transcriptional landscape is strongly dependent on dynamic processes at the protein level.