Dimerization with retinoid x receptors and phosphorylation modulate the retinoic acid-induced degradation of retinoic acid receptors α and γ through the ubiquitin-proteasome pathway

In eukaryotic cells, the ubiquitin-proteasome pathway is the major mechanism for targeted degradation of proteins. We show that, in F9 cells and in transfected COS-I cells, the nuclear retinoid receptors, retinoic acid receptor gamma2 (RAR gamma2), RAR alpha1, and retinoid X receptor alpha1 (RXR alpha1) are degraded in a retinoic acid-dependent manner through the ubiquitin-proteasome pathway. The degradation of RAR gamma2 is entirely dependent on its phosphorylation and an its heterodimerization with liganded RXR alpha1. In contrast. RAR alpha1 degradation can occur in the absence of heterodimerization, whereas it is inhibited by phosphorylation, and heterodimerization reverses that inhibition. RXR alpha1 degradation is also modulated by heterodimerization. Thus, each partner of RAR gamma /RXR alpha and RAR alpha /RXR alpha heterodimers modulates the degradation of the other. We conclude that the ligand-dependent degradation of RARs and RXRs by the ubiquitin-proteasome pathway, which is regulated by heterodimerization and by phosphorylation, could be important for the regulation of the magnitude and duration of the effects of retinoid signals.