Abstract
Peroxisome proliferator–activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor which controls lipid and glucose metabolism. It is also the master regulator of adipogenesis. In adipocytes, ligand-dependent PPARγ activation is associated with proteasomal degradation; therefore, regulation of PPARγ degradation may modulate its transcriptional activity. Here, we show that neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4), an E3 ubiquitin ligase, interacts with the hinge and ligand binding domains of PPARγ and is a bona fide E3 ligase for PPARγ. NEDD4 increases PPARγ stability through the inhibition of its proteasomal degradation. Knockdown of NEDD4 in 3T3-L1 adipocytes reduces PPARγ protein levels and suppresses adipocyte conversion. PPARγ correlates positively with NEDD4 in obese adipose tissue. Together, these findings support NEDD4 as a novel regulator of adipogenesis by modulating the stability of PPARγ.
Highlights
Peroxisome proliferator–activated receptor γ(PPARγ) is a nuclear hormone receptor which is activated by its endogenous ligands, such as fatty acids and eicosanoids[1]
Using co-immunoprecipitation approaches, we found that the endogenous NEDD4 and PPARγproteins could be pulled down together in 3T3-L1 cells, mouse fat tissue lysates, and HEK293 cells transiently overexpressing NEDD4 and Peroxisome proliferator–activated receptor-γ (PPARγ)2 cDNAs (Fig. 1A–C)
Co-IP results showed that NEDD4 binds the hinge and ligand-binding domain (LBD) domains of PPARγ(Fig. 2D)
Summary
Peroxisome proliferator–activated receptor γ(PPARγ) is a nuclear hormone receptor which is activated by its endogenous ligands, such as fatty acids and eicosanoids[1]. The complex process of adipocyte differentiation from preadipocytes is orchestrated by PPARγand the CCAAT/enhancer-binding protein (C/EBP) family transcription factors. Regulation of PPARγdegradation may provide novel regulatory mechanisms of its transcriptional activity. Several PPARγubiquitin-protein ligases (E3s) have been identified in adipocytes[15,16,17]. E6-AP Carboxyl Terminus (HECT)-type E3 ubiquitin ligase, is the prototypical member in NEDD4 family of proteins. These proteins have conserved roles in mediating ubiquitin-dependent trafficking and/or degradation of plasma membrane proteins[18]. Our data suggest that NEDD4 directly ubiquitinates PPARγand increases its stability through the inhibition of its proteasomal degradation
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