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Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation
S Hauser1, G Adelmant, P Sarraf
1Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor that regulates several crucial biological processes such as adipogenesis, glucose homeostasis, and cell growth. It is also the functional receptor for a new class of insulin-sensitizing drugs, the thiazolidinediones, now widely used in the treatment of type 2 diabetes mellitus. Here we report that PPARgamma protein levels are significantly reduced in adipose cells and fibroblasts in response to specific ligands such as thiazolidinediones. Studies with several doses of different ligands illustrate that degradation of PPARgamma correlates well with the ability of ligands to activate this receptor. However, analyses of PPARgamma mutants show that, although degradation does not strictly depend on the transcriptional activity of the receptor, it is dependent upon the ligand-gated activation function 2 (AF2) domain. Proteasome inhibitors inhibited the down-regulation of PPARgamma and ligand activation enhanced the ubiquitination of this receptor. These data indicate that, although ligand binding and activation of the AF2 domain increase the transcriptional function of PPARgamma, these same processes also induce ubiquitination and subsequent degradation of this receptor by the proteasome.
Insights
Ligand activation of peroxisome proliferator-activated receptor (PPAR) gamma, crucial for glucose homeostasis and diabetes treatment, leads to its degradation. This process involves ubiquitination and proteasome pathways, independent of transcriptional activity but dependent on the AF2 domain.
Area of Science:
- Molecular Biology
- Endocrinology
- Biochemistry
Background:
- Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear hormone receptor regulating adipogenesis and glucose homeostasis.
- It serves as the functional receptor for thiazolidinediones, a class of drugs used to treat type 2 diabetes mellitus.
Purpose of the Study:
- To investigate the effect of specific ligands on PPARgamma protein levels.
- To elucidate the mechanism of PPARgamma regulation by its ligands.
Main Methods:
- Treatment of adipose cells and fibroblasts with various ligands.
- Analysis of PPARgamma protein levels and ubiquitination.
- Studies using PPARgamma mutants and proteasome inhibitors.
Main Results:
- Ligand activation, including thiazolidinediones, significantly reduces PPARgamma protein levels.
- PPARgamma degradation correlates with ligand-induced receptor activation.
- Degradation is dependent on the activation function 2 (AF2) domain but not strictly on transcriptional activity.
- Proteasome inhibitors block PPARgamma down-regulation, and ligand activation enhances its ubiquitination.
Conclusions:
- Ligand binding and AF2 domain activation of PPARgamma induce its ubiquitination and subsequent proteasomal degradation.
- This degradation pathway is a critical regulatory mechanism for PPARgamma function, impacting its role in biological processes and therapeutic applications.