F-box only protein 9 is an E3 ubiquitin ligase of PPAR gamma

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a critical regulator of carbohydrate and lipid metabolism, adipocyte differentiation and inflammatory response. Post-translational modification of PPAR gamma and its degradation involve several pathways, including the ubiquitin-proteasome system. Here, we identified F-box only protein 9 (FBXO9) as an E3 ubiquitin ligase of PPAR gamma. We screened interacting partners of PPAR gamma using immunoprecipitation and mass spectrometric analysis and identified FBXO9 as an E3 ubiquitin ligase of PPAR gamma. FBXO9 directly interacted with PPAR gamma through the activation function-1 domain and ligand-binding domain. FBXO9 decreased the protein stability of PPAR gamma through induction of ubiquitination. We found that the F-box motif of FBXO9 was required for its ubiquitination function. The activity of PPAR gamma was significantly decreased by FBXO9 overexpression. Furthermore, FBXO9 overexpression in 3T3-L1 adipocytes resulted in decreased levels of endogenous PPAR gamma and suppression of adipogenesis. These results suggest that FBXO9 is an important enzyme that regulates the stability and activity of PPAR. through ubiquitination.