Department of Biological SciencesPeroxisome proliferator-activated receptor ?? (PPAR??) is a ligand-dependent transcription factor which regulates glucose homeostasis and adipocyte differentiation. Its transcriptional activity is regulated by not only ligands but also post-translational modifications (PTMs). In this study, we demonstrate a novel E3 ligase of PPAR??, TRIM25 directly induces ubiquitination of PPAR?? followed by proteasome-dependent degradation. During the adipocyte differentiation, both mRNA and protein expression of TRIM25 significantly decreased and negatively correlated with the expression of PPAR??. Stable expression of TRIM25 reduces PPAR?? protein levels, but not mRNA expression, and suppressed adipocyte differentiation in 3T3-L1 cells. In contrast, specific knock-down of TRIM25 increases PPAR?? protein levels and stimulates adipocyte differentiation. Furthermore, TRIM25 knock-out mouse embryonic fibroblast (MEFs) shows an increased ability for adipocyte differentiation compared with wild-type MEFs. Taken together, these data indicate that TRIM25 is a novel E3 ubiquitin ligase of PPAR??, and depict TRIM25 as a novel target for PPAR??-involved metabolic diseases.ope
