The Co-repressor Hairless Protects RORα Orphan Nuclear Receptor from Proteasome-mediated Degradation

• Published in: The Journal of biological chemistry Vol. 278; no. 52; p. 52511
• Main Authors: Anna N. Moraitis, Vincent Giguère
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 26.12.2003
• DOI: 10.1074/jbc.M308152200
• ISSN: 0021-9258

RORα is a constitutively active orphan nuclear receptor essential for cerebellar development and is previously shown to regulate genes involved in both myogenesis and adipogenesis. The transcriptional activity of RORα is dependent on the presence of a ubiquitous ligand and can be abolished by interaction with Hairless (Hr), a ligand-oblivious nuclear receptor co-repressor. In this study, we first demonstrate that RORα is a short-lived protein and that treatment with the MG-132 proteasome inhibitor results in the accumulation of ubiquitin-conjugated receptor and inhibition of transcription. These data show that RORα transcriptional activity and degradation are intrinsically linked. In addition, the introduction of inactivation mutations in the ligand-binding pocket and co-regulator-binding surface of RORα significantly increases protein stability, indicating that ligand and/or co-regulator binding perpetuates RORα degradation. Strikingly, expression of the co-repressor Hr results in the stabilization of RORα because of an inhibition of proteasome-mediated degradation of the receptor. Stabilization of RORα by Hr requires intact nuclear receptor recognition L XX LL motifs within Hr. Interestingly, the co-repressor nuclear receptor co-repressor (NCoR) has no effect on RORα protein turnover. This study shows that stabilization of RORα is an essential component of Hr-mediated repression and suggests a molecular mechanism to achieve transcriptional repression by a liganded receptor-co-repressor complex.