Abstract
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.
Highlights
Adipose tissue plays a pivotal role in storing excess energy and is a center for energy metabolism[1]
tripartite motif-containing 25 (TRIM25) interacts with PPARγ To identify potential post-translational modifications (PTMs) modulators of PPARγ, we performed proteomic analyses of binding complexes formed with PPARγ
Among the multiple PPARγ-associated proteins identified, TRIM25 was of particular interest because it functions as a ubiquitin E3 ligase and as an ISG15 E3 ligase[29,32]
Summary
Adipose tissue plays a pivotal role in storing excess energy and is a center for energy metabolism[1]. Adipocytes exhibit an altered energy homeostasis status to store energy and to generate and secrete hormones and cytokines called adipokines[1,3]. The expression of insulin resistance-inducing adipokines, including tumor necrosis factor-α, interleukin-1, and resistin is increased in the adipose tissue of obese individuals, whereas the production of the insulin-. C/EBP-α-null embryonic fibroblast cells fail to undergo adipogenesis, but this defect can be restored by the overexpression of PPARγ7,8. Forced expression of C/EBP-α in PPARγ-null embryonic fibroblast cells prevents the cells from differentiating[7].
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