Orphan Receptor TR3 Attenuates The PRMT1-induced Methylation

Post-translational modification of proteins which contains phosphorylation, acetylation and methylation has attracted more and more attention because of its important role in organism.As the predominant protein arginine methyltransferases, PRMT1 modulates various cellular processes,including singal transduction,RNA processing,DNA repair,and protein-protein interaction.Although PRMT1 methylates nuclear orphan receptor HNF4,whether TR3,another orphan receptor,is methylated by PRMT1 and how the methyltransferase activity of PRMT1 is affected by nuclear receptor remain largely unknown.In the current study,we identified that TR3 is not a substrate of PRMT1 methylation although TR3 contains a glycine- and arginine-rich motif which is the classic substrate motif of PRMT1.In addition,we described an intriguing property of TR3 to inhibit the methyltransferase activity of PRMT1 by targeting to the PRMT1 catalytic region,resulting in the loss of the ability of PRMT1 for methylating its substrates.This thus may explain why PRMT1 can not methylate TR3.We focused on PRMT1 major substrate H4 R3 to determine TR3 specifically attenuates PRMT1 methyltransferase activity and the correlation between TR3 protein levels and PRMT1 activity.In addition,we choose two substrates of PRMT1 with different functions (Sam68,STAT3) to investigate their functional changes of repressing PRMT1 methyltransferase activity by TR3.We observed the negative correlation between TR3 expression levels and methylation of H4 R3.Furthermore,TR3 could block nuclear import of Sam68 induced by PRMT1 and the transcriptional activity of STAT3 induced by PRMT1.Of particular interest is that an agonist for TR3 can attenuate methyltransferase activity of PRMT1 through activating TR3 and increasing the interaction between TR3 and PRMT1.Taken together,our data not only identifies the distinct regulatory mechanisms of TR3 on methytransferase activity of PRMT1,but also reveals a TR3 novel function in modulating post-translational modification of proteins.