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

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a critical regulator of carbohydrate and lipid metabolism, adipocyte differentiation and inflammatory response. Post-translational modification of PPARγ 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 PPARγ. We screened interacting partners of PPARγ using immunoprecipitation and mass spectrometric analysis and identified FBXO9 as an E3 ubiquitin ligase of PPARγ. FBXO9 directly interacted with PPARγ through the activation function-1 domain and ligand-binding domain. FBXO9 decreased the protein stability of PPARγ through induction of ubiquitination. We found that the F-box motif of FBXO9 was required for its ubiquitination function. The activity of PPARγ was significantly decreased by FBXO9 overexpression. Furthermore, FBXO9 overexpression in 3T3-L1 adipocytes resulted in decreased levels of endogenous PPARγ and suppression of adipogenesis. These results suggest that FBXO9 is an important enzyme that regulates the stability and activity of PPARγ through ubiquitination. Insights into the control of a protein that regulates carbohydrate and fat metabolism could assist in treating obesity and diabetes. Kyong Soo Park and co-workers at Seoul National University, with colleagues elsewhere in South Korea, investigated the “peroxisome proliferator-activated receptor gamma” protein (PPARγ). Through its effect on metabolism, this protein influences the growth of fat cells and the process of inflammation. The researchers found that another protein called FBXO9 interacts with PPARγ. They suggest this interaction regulates the stability and action of PPARγ as it is required for the attachment of PPARγ to a third protein, a common regulatory protein called ubiquitin. Understanding these steps in this network of protein interactions could identify new targets for drugs to treat obesity and diabetes.