Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor γ coactivator-1α -: Possible link between xenobiotic response and nutritional state

In contrast to the classical nuclear receptors, the constitutive androstane receptor (CAR) is transcriptionally active in the absence of ligand. In the course of searching for the mediator of CAR activation, we found that ligand-independent activation of CAR was achieved in cooperation with the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). PGC-1beta, a PGC-1alpha homologue, also activated CAR to less of an extent than PGC-1alpha. Coexpression of the ligand-binding domain of a heterodimerization partner, retinoid X receptor alpha, enhanced the PGC-1alpha-mediated activation of CAR, although it had a weak effect on the basal activity of CAR in the absence of PGC-1alpha. Both the N-terminal region, with the LXXLL motif, and the C-terminal region, with a serine/arginine-rich domain (RS domain), in PGC-1alpha were required for full activation of CAR. Pull-down experiments using recombinant proteins revealed that CAR directly interacted with both the LXXLL motif and the RS domain. Furthermore, we demonstrated that the RS domain of PGC-1alpha was required for CAR localization at nuclear speckles. These results indicate that PGC-1alpha mediates the ligand-independent activation of CAR by means of subnuclear targeting through the RS domain of PGC-1alpha.