PKCepsilon stimulated arginine methylation of RIP140 for its nuclear‐cytoplasmic export in adipocyte differentiation

Abstract

Receptor interacting protein 140 (RIP140) is a transcriptional co‐regulator that plays roles in regulating metabolic processes including fat metabolism in adipocytes. Previously we identified methylation of RIP140 in three arginie residues which promotes RIP140 export to the cytoplasm. Here, we determined the activated PKCepsilon as a trigger for RIP140 arginine methylation by phosphorylating RIP140 at Ser‐102 and Ser‐1003 which synergistically stimulated the formation of RIP140 protein complex, including 14‐3‐3 and protein arginine methyl transferase 1 to methylate RIP140. The methylated RIP140 then preferentially recruited exportin 1 for nuclear export. As a result, the trans‐suppresive activity of RIP140 was reduced. In RIP140 null adipocytes, the defect in fat accumulation was effectively rescued by phosphorylation‐deficient mutant of RIP140 that resided predominantly in the nucleus, but less so by the phosphor‐mimetic RIP140 that was exported to the cytoplasm. This study reveals the role of PKCepsilon in modulating fat metabolism in adipocyte by regulating the cellular distribution of RIP140 through a specific phosphorylation‐arginie methylation mechanism. This work was support by DK54733, DK60521, K02‐DA13926 and DA11190 to L.‐N. Wei.