Orphan receptor TR3 attenuates the p300-induced acetylation of retinoid X receptor-alpha.
Acetylation modification regulates the functions of histone and nonhistone proteins, including transcriptional activity, protein interaction, and subcellular localization. Although many nuclear receptors have been shown to be modified by acetylation, whether retinoid X receptors (RXRs) are acetylated and how the acetylation is regulated remains unknown. Here, we provide the first evidence of RXRalpha acetylation by p300 on lysine 145. Acetylation of RXRalpha by p300 facilitated its DNA binding and subsequently increased its transcriptional activity. Furthermore, we discovered that TR3, an orphan receptor, exerted a negative regulation on p300-induced RXRalpha acetylation. TR3 significantly reduced the p300-induced RXRalpha acetylation and transcriptional activity, and such inhibition required the interaction of TR3 with RXRalpha. Binding of TR3 to RXRalpha resulted in the sequestration of RXRalpha from p300. 9-cis retinoic acid, a ligand for RXRalpha, enhanced the association of RXRalpha with TR3, rather than acetylation of RXRalpha by p300. Biological function analysis revealed that the mitogenic activity of RXRalpha stimulated by p300 was acetylation dependent and could be repressed by TR3. Upon the treatment of 9-cis retinoic acid, RXRalpha was translocated with TR3 from the nucleus to the mitochondria, and apoptosis was induced. Taken together, our data demonstrate the distinct regulatory mechanisms of p300 and TR3 on RXRalpha acetylation and reveal a previously unrecognized role for orphan receptor in the transcriptional control of retinoid receptors.
Zhao
Wen-Xiu
WX
Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
Tian
Min
M
Zhao
Bi-Xing
BX
Li
Gui-Deng
GD
Liu
Bo
B
Zhan
Yan-Yan
YY
Chen
Hang-Zi
HZ
Wu
Qiao
Q
D000107:Acetylation; D000077556:Alitretinoin; D017209:Apoptosis; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011485:Protein Binding; D021381:Protein Transport; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology
C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D000077556:Alitretinoin; D014212:Tretinoin; D004247:DNA; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D008239:Lysine