Abstract
BackgroundReceptor interacting protein 140 (RIP140) is a versatile transcriptional co-repressor that plays roles in diverse metabolic processes including fat accumulation in adipocytes. Previously we identified three methylated arginine residues in RIP140, which rendered its export to the cytoplasm; but it was unclear what triggered RIP140 arginine methylation.Methodology/Principal FindingsIn this study, we determined the activated PKCε as the specific trigger for RIP140 arginine methylation and its subsequent export. We identified two PKCε–phosphorylated residues of RIP140, Ser-102 and Ser-1003, which synergistically stimulated direct binding of RIP140 by 14-3-3 that recruited protein arginine methyl transferase 1 to methylate RIP140. The methylated RIP140 then preferentially recruited exportin 1 for nuclear export. As a result, the nuclear gene-repressive activity of RIP140 was reduced. In RIP140 null adipocyte cultures, the defect in fat accumulation was effectively rescued by the phosphoylation-deficient mutant RIP140 that resided predominantly in the nucleus, but less so by the phospho-mimetic RIP140 that was exported to the cytoplasm.Conclusions/SignificanceThis study uncovers a novel means, via a cascade of protein modifications, to inactivate, or suppress, the nuclear action of an important transcription coregulator RIP140, and delineates the first specific phosphorylation-arginine methylation cascade that could alter protein subcellular distribution and biological activity.
Highlights
Receptor-interacting protein 140 (RIP140) known as NRIP1 (Nuclear Receptor Interacting Protein 1) is a versatile co-repressor for nuclear receptors and many transcription factors and contains several autonomous repressive domains [1,2,3,4,5]
In our previous study, [12] we have established the export of Receptor interacting protein 140 (RIP140) to the cytoplasm, which was stimulated by its specific arginine methylation
This study extends our previously reported finding of arginine methylation on RIP140 that triggers its export to the cytoplasm in differentiating adipocytes, and provides mechanistic insights into the signal that triggers the activation of a specific pathway that leads to the action of PRMT1 to methylate RIP140
Summary
Receptor-interacting protein 140 (RIP140) known as NRIP1 (Nuclear Receptor Interacting Protein 1) is a versatile co-repressor for nuclear receptors and many transcription factors and contains several autonomous repressive domains [1,2,3,4,5]. Established PTMs of RIP140 include phosphorylation [4,13], acetylation [14], methylation [12] and pyridoxal 59-phosphate (PLP) conjugation [15]. All these PTMs affect the biological activity of RIP140. Of particular significance is protein arginine methyl transferase (PRMT)-mediated arginine methylation on three specific arginine residues of RIP140, Arg240 650 948, which negatively regulates its biological activity in the nucleus (gene repression) by reducing its interaction with a corepressive enzyme machinery containing HDAC3 and facilitating its export to the cytoplasm via the exportin (CRM1)-containing export machinery [12]. We identified three methylated arginine residues in RIP140, which rendered its export to the cytoplasm; but it was unclear what triggered RIP140 arginine methylation
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