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

Abstract

REV-ERBα (encoded by Nr1d1) is a nuclear receptor that is part of the circadian clock mechanism and regulates metabolism and inflammatory processes. The glucocorticoid receptor (GR, encoded by 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 portion and GR to the N-terminal portion of HSP90α and HSP90β, a chaperone responsible for the activation of proteins to ensure survival of a cell. The presence of REV-ERBα influences the stability and nuclear localization of GR by an unknown mechanism, thereby affecting expression of GR target genes, such as IκBα (Nfkbia) and alcohol dehydrogenase 1 (Adh1). Our findings highlight an important interplay between two nuclear receptors that influence the transcriptional potential of each other. This indicates that the transcriptional landscape is strongly dependent on dynamic processes at the protein level.

Gene activation and repression by the glucocorticoid receptor are mediated by sequestering Ep300 and two modes of chromatin binding

“…Given that the majority of Rev-erbα binding sites in liver lack the RORE motif (75), it is possible that similarly to GR, the enrichment of RORE motif in the GR-activated genes may reflect differential mode of binding rather than differential binding to chromatin. Intriguingly it was recently shown that REV-ERBα binds GR together with HSP90 chaperone and thereby affects GR stability, nuclear localization and the expression of GR target genes (76). Thus it is tempting to speculate that the transcriptional activity of GR is also tuned by the interaction with REV-ERBβ in the cytoplasm of 3134 cells.…”

Circadian physiology of metabolism

“…Coupled with their own cycling levels, these clock proteins can "impose" rhythmic functions to nonclock proteins. For example, CRY and REV-ERB proteins interact with the glucocorticoid receptor (GR) to inhibit its transcriptional activity (15,16). CRY proteins also inhibit signaling downstream of the glucagon receptor, thereby imposing a time-of-day-specific effect of glucagon on gluconeogenesis (17).…”

Circadian Clock Regulation of Hepatic Energy Metabolism Regulatory Circuits

“…The CRY proteins have been shown to negatively regulate glucocorticoid action [37] and it has been proposed that REV-ERBA facilitates circadian recruitment of GR to GC-responsive genes [65]. It has also been suggested that REV-ERBα can affect the nuclear localisation and the stability of GR [72].…”