Suppression of receptor interacting protein 140 repressive activity by protein arginine methylation

Abstract

Receptor interacting protein 140 (RIP140), a ligand‐dependent corepressor for nuclear receptors, can be modified by arginine methylation. Three methylated arginine residues, at Arg‐240, Arg‐650, and Arg‐948, were identified by mass spectrometric analysis. Site‐directed mutagenesis studies demonstrated the functionality of these arginine residues. The biological activity of RIP140 was suppressed by protein arginine methyltransferase 1 (PRMT1) due to RIP140 methylation, which reduced the recruitment of histone deacetylases to RIP140 and facilitated its nuclear export by enhancing interaction with exportin 1. A constitutive negative (Arg/Ala) mutant of RIP140 was resistant to the effect of PRMT1, and a constitutive positive (Arg/Phe) mutation mimicked the effect of arginine methylation. The biological activities of the wild type and the mutant proteins were examined in RIP140‐null MEF cells. This study uncovered a novel means to inactivate, or suppress, RIP140, and demonstrated protein arginine methylation as a critical type of modification for corepressor.