Interferon-gamma-mediated activation and ubiquitin-proteasome-dependent degradation of PPARgamma in adipocytes.
Interferon-gamma (IFNgamma) treatment of adipocytes results in a down-regulation of the peroxisome proliferator-activated receptor gamma (PPARgamma). The decrease in PPARgamma expression is mediated by inhibition of PPARgamma synthesis and increased degradation of PPARgamma. In this study, we demonstrate that both PPARgamma1 and PPARgamma2 are targeted to the proteasome under basal conditions and that PPARgamma1 is more labile than PPARgamma2. The IFNgamma-induced increase in PPARgamma turnover is blocked by proteasome inhibition and is accompanied by an increase in PPARgamma-polyubiquitin conjugates. In addition, IFNgamma treatment results in the transcriptional activation of PPARgamma. Similar to ligand-dependent activation of PPARgamma, IFNgamma-induced activation was greater in the phosphorylation-deficient S112A form of PPARgamma when compared with wild-type PPARgamma. Moreover, the inhibition of ERKs 1 and 2 with a MEK inhibitor, U1026, lead to an inhibition in the decay of PPARgamma proteins, indicating that serine phosphorylation influences the degradation of PPARgamma in fat cells. Our results also demonstrate that the proteasome-dependent degradation of PPARgamma does not require nuclear export. Taken together, these results indicate that PPARgamma is targeted to the ubiquitin-proteasome pathway for degradation under basal conditions and that IFNgamma leads to an increased targeting of PPARgamma to the ubiquitin-proteasome system in a process that is affected by ERK-regulated serine phosphorylation of PPARgamma proteins.
Floyd
Z Elizabeth
ZE
Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 7080, USA.
Stephens
Jacqueline M
JM
D016475:3T3 Cells; D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism*
D009097:Multienzyme Complexes; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D025801:Ubiquitin; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex