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Interferon-gamma-mediated activation and ubiquitin-proteasome-dependent degradation of PPARgamma in adipocytes

Z Elizabeth Floyd1, Jacqueline M Stephens

  • 1Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 7080, USA.

The Journal of Biological Chemistry
|December 26, 2001
PubMed

Insights

Interferon-gamma (IFNgamma) treatment reduces peroxisome proliferator-activated receptor gamma (PPARgamma) in fat cells by increasing its proteasomal degradation. This process involves ERK-regulated phosphorylation and targets PPARgamma to the ubiquitin-proteasome system.

Area of Science:

  • Cell Biology
  • Molecular Endocrinology
  • Signal Transduction

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARgamma) is crucial for adipocyte function.
  • Interferon-gamma (IFNgamma) is known to down-regulate PPARgamma expression in adipocytes.
  • The precise mechanisms of PPARgamma regulation by IFNgamma are not fully understood.

Purpose of the Study:

  • To investigate the role of the ubiquitin-proteasome system in IFNgamma-mediated PPARgamma degradation.
  • To elucidate the influence of phosphorylation on PPARgamma stability and degradation.
  • To determine the impact of IFNgamma on PPARgamma transcriptional activity.

Main Methods:

  • Treatment of adipocytes with IFNgamma and proteasome inhibitors.
  • Analysis of PPARgamma protein levels, polyubiquitination, and transcriptional activity.
  • Site-directed mutagenesis to create phosphorylation-deficient PPARgamma variants (S112A).
  • Inhibition of Extracellular signal-regulated kinases (ERKs) using a MEK inhibitor (U1026).

Main Results:

  • IFNgamma treatment increases PPARgamma degradation via the proteasome, evidenced by increased polyubiquitin conjugates.
  • Both PPARgamma1 and PPARgamma2 are degraded by the proteasome, with PPARgamma1 being more labile.
  • IFNgamma treatment also leads to transcriptional activation of PPARgamma.
  • ERK-mediated serine phosphorylation at S112 influences PPARgamma degradation, as inhibiting MEK stabilizes PPARgamma.
  • Proteasome-dependent degradation of PPARgamma occurs independently of nuclear export.

Conclusions:

  • PPARgamma is constitutively degraded through the ubiquitin-proteasome pathway in adipocytes.
  • IFNgamma enhances PPARgamma targeting to the proteasome, increasing its turnover.
  • ERK-regulated serine phosphorylation plays a significant role in modulating PPARgamma protein stability and degradation in response to IFNgamma.

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