Orphan Receptor TR3 Attenuates The P300-induced Acetylation Of Retinoid X Receptor α

Acetylation regulates the functions of histone and nonhistone proteins, including transactivation activity, protein interaction, and subcellular localization. Although many transcription factors, including nuclear receptors, have been shown to be modified by acetylation, whether retinoid X receptors (RXRs) are acetylated and how their acetylation is regulated remains unknown. Here, we provided the first evidence of RXRαacetylation by p300 at lysine 145. Acetylation of RXRαfacilitated its binding to DNA and increased its transcriptional activity. Importantly, we discovered that TR3, an orphan receptor, exerted a negative regulation on p300-induced RXRαacetylation. Firstly, TR3 significantly reduced the p300-induced RXRαacetylation, and such inhibition required the TR3-RXRαinteraction. Secondary, TR3 competed with p300 binding to RXRα. Moreover, treatment of cells with RXRαligand 9-cis retinoic acid enhanced the interaction of RXRαwith TR3 more than that with p300. Under this circumstance, p300-induced RXRαacetylation and transcriptional activity was inhibited, whereas the TR3/RXRαtranslocation had been facilitated. Finally, biological function analysis revealed that p300 stimulated the mitogenic activity by RXRαin HeLa cells in an acetylation-dependent manner. In contrast, TR3 repressed the p300-induced cell proliferation, and itself was translocated with RXRαto mitochondria to induce apoptosis of HeLa cells in response to 9-cis retinoic aicd. Together, our data demonstrate the distinct regulatory mechanisms of p300 and TR3 on RXRαacetylation, and reveal a previously unrecognized role for orphan receptor in the transcriptional control of retinoid receptors.