Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A 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-1 alpha (PGC-1 alpha). PGC-1 beta, a PGC-1 alpha homologue, also activated CAR to less of an extent than PGC-1 alpha. Coexpression of the ligand-binding domain of a heterodimerization partner, retinoid X receptor alpha, enhanced the PGC-1 alpha-mediated activation of CAR, although it had a weak effect on the basal activity of CAR in the absence of PGC-1 alpha. Both the N-terminal region, with the LXXLL motif, and the C-terminal region, with a serine/arginine-rich domain (RS domain), in PGC-1 alpha 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-1 alpha was required for CAR localization at nuclear speckles. These results indicate that PGC-1 alpha mediates the ligand-independent activation of CAR by means of subnuclear targeting through the RS domain of PGC-1 alpha.
Shiraki
Takuma
T
Department of Molecular Biology, Biomolecular Engineering Research Institute, 6-2-3, Furuedai, Suita-City, Osaka 565-0874, Japan.
Sakai
Noriko
N
Kanaya
Eiko
E
Jingami
Hisato
H
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D017931:DNA Primers; D019281:Dimerization; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D018613:Microscopy, Confocal; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D015262:Xenobiotics / Q000494:pharmacology*
D000090702:Constitutive Androstane Receptor; D017931:DNA Primers; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D015262:Xenobiotics; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D005947:Glucose