Nuclear import of the retinoid X receptor, the vitamin D receptor, and their mutual heterodimer

The nuclear receptor retinoid X receptor (RXR) can regulate transcription through homotetramers, homodimers, and heterodimers with other nuclear receptors such as the vitamin D receptor (VDR). The mechanisms that underlie the nuclear import of RXR, VDR, and RXR-VDR heterodimers were investigated. We show that RXR and VDR translocate into the nucleus by distinct pathways. RXR strongly bound to importin beta and was predominantly nuclear in the absence of ligand. Importin binding and nuclear localization of RXR were modestly enhanced by its ligand, 9-cis-retinoic acid. On the other hand, VDR selectively associated with importin alpha. Importin association and correspondingly nuclear import of VDR were markedly augmented by 1,25(OH) D-2(3). RXR-VDR dimerization inhibited the ability of RXR to bind importin beta and to mobilize into the nucleus using its own nuclear localization signal. In contrast, VDR recruited RXR-VDR heterodimers to importin alpha and mediated nuclear import of the heterodimers in response to 1,25(OH)(2)D-3. Hence nuclear import of RXR-VDR heterodimers is mediated preferentially by VDR and is controlled by the VDR ligand. The observations reveal a novel mechanism by which an RXR heterodimerization partner dominates the activity of the heterodimers.