PKCepsilon stimulated arginine methylation of RIP140 for its nuclear-cytoplasmic export in adipocyte differentiation.
BACKGROUND
Receptor 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.


RESULTS
In this study, we determined the activated PKCepsilon as the specific trigger for RIP140 arginine methylation and its subsequent export. We identified two PKCepsilon-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 phosphorylation-deficient mutant RIP140 that resided predominantly in the nucleus, but less so by the phospho-mimetic RIP140 that was exported to the cytoplasm.


CONCLUSIONS
This 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.
Gupta
Pawan
P
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
Ho
Ping-Chih
PC
Huq
M D Mostaqul
MD
Khan
Amjad Ali
AA
Tsai
Nien-Pei
NP
Wei
Li-Na
LN
D048948:14-3-3 Proteins / Q000378:metabolism; D041721:3T3-L1 Cells; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D001120:Arginine / Q000737:chemistry*; D019556:COS Cells; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D019175:DNA Methylation; D047908:Intracellular Signaling Peptides and Proteins; D008780:Methyltransferases / Q000737:chemistry; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry*; D000078723:Nuclear Receptor Interacting Protein 1; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C000627127:NRIP1 protein, human; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D001120:Arginine; D008780:Methyltransferases; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases; D051744:Protein Kinase C-epsilon