Interferon-γ (IFNγ) treatment of adipocytes results in a down-regulation of the peroxisome proliferator-activated receptor γ (PPARγ). The decrease in PPARγ expression is mediated by inhibition of PPARγ synthesis and increased degradation of PPARγ. In this study, we demonstrate that both PPARγ1 and PPARγ2 are targeted to the proteasome under basal conditions and that PPARγ1 is more labile than PPARγ2. The IFNγ-induced increase in PPARγ turnover is blocked by proteasome inhibition and is accompanied by an increase in PPARγ-polyubiquitin conjugates. In addition, IFNγ treatment results in the transcriptional activation of PPARγ. Similar to ligand-dependent activation of PPARγ, IFNγ-induced activation was greater in the phosphorylation-deficient S112A form of PPARγ when compared with wild-type PPARγ. Moreover, the inhibition of ERKs 1 and 2 with a MEK inhibitor, U1026, lead to an inhibition in the decay of PPARγ proteins, indicating that serine phosphorylation influences the degradation of PPARγ in fat cells. Our results also demonstrate that the proteasome-dependent degradation of PPARγ does not require nuclear export. Taken together, these results indicate that PPARγ is targeted to the ubiquitin-proteasome pathway for degradation under basal conditions and that IFNγ leads to an increased targeting of PPARγ to the ubiquitin-proteasome system in a process that is affected by ERK-regulated serine phosphorylation of PPARγ proteins.
Publication Source (Journal or Book title)
Journal of Biological Chemistry
Elizabeth Floyd, Z., & Stephens, J. (2002). Interferon-γ-mediated activation and ubiquitin-proteasome-dependent degradation of PPARγ in adipocytes. Journal of Biological Chemistry, 277 (6), 4062-4068. https://doi.org/10.1074/jbc.M108473200