Intracellular localization of RORα is isoform and cell line-dependent

The retinoid-related orphan receptor alpha (ROR alpha) belongs to the nuclear receptor superfamily and comprises four isoforms generated by different promotor usage and alternative splicing. To better understand its function, the subeellular distribution of ROR alpha was investigated. We could show that subcellular distribution of ROR alpha is cell line and isoform-dependent. Isoform specific differences were mediated by the A/B domains which with the exception of ROR alpha 1 contain a signal that mediates cytoplasmic localization. The lack of this signal in ROR alpha 1 results in a complete nuclear localization and prevents cell membrane association observed for ROR alpha 2, 3, and 4. The region responsible for membrane association was identified as the C-terminal alpha-helix 12. Furthermore, the hinge region/ligand binding domain mediates nuclear localization. Our results show that isoform specific activity of ROR alpha is not only regulated by different expression and DNA binding affinities but also by different subcellular distribution. Different access to the nucleus reveals an important mechanism regulating the activity of this constitutively active nuclear receptor. (c) 2006 Elsevier B.V. All rights reserved.