A feedback regulatory loop between methyltransferase PRMT1 and orphan receptor TR3.
PRMT1, an arginine methyltransferase, plays an important role in numerous cellular processes. In this study, we demonstrate a feedback regulatory loop between PRMT1 and the orphan receptor TR3. Unlike another orphan receptor HNF4, TR3 is not methylated by PRMT1 although they physically interact with each other. By delaying the TR3 protein degradation, PRMT1 binding leads to the elevation of TR3 cellular protein level, thereby enhances the DNA binding and transactivation activity of TR3 in a non-methyltransferase manner. Another coactivator SRC-2 acts synergistically with PRMT1 to regulate TR3 functions. In turn, TR3 binding to the catalytic domain of PRMT1 causes an inhibition of the PRMT1 methyltransferase activity. This repression results in the functional changes in some of PRMT1 substrates, including STAT3 and Sam68. The negative regulation of PRMT1 by TR3 was further confirmed in both TR3-knockdown cells and TR3-knockout mice with the use of an agonist for TR3. Taken together, our study not only identifies a regulatory role of PRMT1, independent on methyltransferase activity, in TR3 transactivation, but also characterizes a novel function of TR3 in the repression of PRMT1 methyltransferase activity.
Lei
Na-zi
NZ
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.
Zhang
Xiao-yan
XY
Chen
Hang-zi
HZ
Wang
Yuan
Y
Zhan
Yan-yan
YY
Zheng
Zhong-hui
ZH
Shen
Yue-mao
YM
Wu
Qiao
Q
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011987:Receptors, Steroid / Q000819:agonists / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases