Lei Na-zi, Zhang Xiao-yan, Chen Hang-zi, Wang Yuan, Zhan Yan-yan, Zheng Zhong-hui, Shen Yue-mao, Wu Qiao
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.
Nucleic Acids Res. 2009 Feb;37(3):832-48. doi: 10.1093/nar/gkn941. Epub 2008 Dec 18.
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.
精氨酸甲基转移酶PRMT1在众多细胞过程中发挥着重要作用。在本研究中，我们证明了PRMT1与孤儿受体TR3之间存在反馈调节环。与另一个孤儿受体HNF4不同，尽管TR3与PRMT1相互作用，但PRMT1不会使其甲基化。通过延迟TR3蛋白降解，PRMT1的结合导致TR3细胞蛋白水平升高，从而以非甲基转移酶的方式增强TR3的DNA结合和反式激活活性。另一个共激活因子SRC-2与PRMT1协同作用来调节TR3的功能。反过来，TR3与PRMT1催化结构域的结合会抑制PRMT1的甲基转移酶活性。这种抑制导致包括STAT3和Sam68在内的一些PRMT1底物发生功能变化。在TR3敲低细胞和TR3基因敲除小鼠中，使用TR3激动剂进一步证实了TR3对PRMT1的负调控。综上所述，我们的研究不仅确定了PRMT1在TR3反式激活中独立于甲基转移酶活性的调节作用，还表征了TR3在抑制PRMT1甲基转移酶活性方面的新功能。
