The E3 ubiquitin ligase TRIM25 regulates adipocyte differentiation via proteasome-mediated degradation of PPARγ

• Published in: Experimental & molecular medicine 2018-10, Vol.50 (10), p.1-11
• Main Authors: Lee, Jae Min, Choi, Sun Sil, Lee, Yo Han, Khim, Keon Woo, Yoon, Sora, Kim, Byung-gyu, Nam, Dougu, Suh, Pann-Ghill, Myung, Kyungjae, Choi, Jang Hyun
• Format: Article
• Language: English
• Subjects: 13/89; 14/1; 14/63; 3T3-L1 Cells; 42/109; 45/90; 631/136/142; 631/80/458/582; 82/83; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Cell Differentiation - genetics; Embryo fibroblasts; Embryos; Gene expression; HEK293 Cells; Homeostasis; Humans; Medical Biochemistry; Mice; Molecular Medicine; Post-translation; PPAR gamma - metabolism; Protease inhibitors; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein Binding; Protein Stability; Proteins; Proteolysis; Stem Cells; Transcription Factors - genetics; Transcription Factors - metabolism; Tripartite Motif Proteins - genetics; Tripartite Motif Proteins - metabolism; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0162-6

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that regulates adipocyte differentiation and glucose homeostasis. The transcriptional activity of PPARγ is regulated not only by ligands but also by post-translational modifications (PTMs). In this study, we demonstrate that a novel E3 ligase of PPARγ, tripartite motif-containing 25 (TRIM25), directly induced the ubiquitination of PPARγ, leading to its proteasome-dependent degradation. During adipocyte differentiation, both TRIM25 mRNA and protein expression significantly decreased and negatively correlated with the expression of PPARγ. The stable expression of TRIM25 reduced PPARγ protein levels and suppressed adipocyte differentiation in 3T3-L1 cells. In contrast, the specific knockdown of TRIM25 increased PPARγ protein levels and stimulated adipocyte differentiation. Furthermore, TRIM25-knockout mouse embryonic fibroblasts (MEFs) exhibited an increased adipocyte differentiation capability compared with wild-type MEFs. Taken together, these data indicate that TRIM25 is a novel E3 ubiquitin ligase of PPARγ and that TRIM25 is a novel target for PPARγ-associated metabolic diseases. Metabolic disorders: TRIM-ming the fat A protein that targets peroxisome proliferator-activated receptor γ (PPARγ) (a key regulator of fat cell formation) for degradation suppresses the formation of fat. Excess fat can lead to obesity and cause type 2 diabetes and cardiovascular disease, yet little is known about the mechanisms through which fat cells arise from progenitor cells. Jang Hyun Choi and colleagues at the Ulsan National Institute of Science and Technology, Korea, have found that TRIM25, a protein implicated in cancer and antiviral immune responses, reduces the activity of PPARγ by adding a small regulatory protein that acts as a signal for degradation. Reducing the levels of TRIM25 in progenitor cells increases their ability to differentiate into fat cells. These findings suggest that TRIM25 could be a useful target for developing new therapies against obesity and metabolic disorders.