The Nuclear Export and Ubiquitin-Proteasome-Dependent Degradation of PPARγ Induced By Angiotensin II

Abstract

Evidence has documented local angiotensin II (Ang II) as a pro-oxidant and pro-inflammatory molecule contributes to progressive deterioration of organ function in diseases. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor, plays crucial roles in protection against oxidative stress and inflammation. Ang II stimulation decreases PPARγ protein in multiple types of cells, while the regulatory role of Ang II on PPARγ is not clear. Here we show that Ang II down-regulated PPARγ in ECV304 cells through 2 actions, inducing nuclear export and loss of protein. The nuclear export of PPARγ occurred transiently in the early phase, while the reduction in PPARγ protein happened in the later phase and was more persistent. Both alterations in PPARγ were accompanied by the decrease in PPARγ-DNA binding activity. Reduction of PPARγ protein levels was also coupled with the inhibition of PPARγ target genes. In addition, activation of PPARγ by its ligand troglitazone could completely counteract both 2 actions of Ang II on PPARγ. Further studies demonstrated that the decline of PPARγ protein was in association with ubiquitin-proteasome-dependent degradation, which was supported by the increase in polyubiquitin-PPARγ conjugates and the inhibitory effect of lactacystin, a specific proteasome inhibitor, on the loss of PPARγ. Taken together, this study uncovers a novel means by which Ang II down-regulates PPARγ. This down-regulation disrupts nuclear PPARγ function, which may lead to the loss of beneficial effects of PPARγ in response to Ang II stress.

The E3 Ubiquitin Ligase RBCK1 Promotes The Invasion and Metastasis of Hepatocellular Carcinoma By Destroying The PPARγ/PGC1α Complex

“…RBCK1 interacts with different substrates in order to exert its effects. Studies have reported that the ubiquitin-proteasome-mediated degradation of PPARγ is the critical mechanism by which PPARγ levels are regulated in cells [33]. Similarly, our results suggest, for the rst time, that RBCK1 destroyed the PPARγ/PGC1α complex by promoting the ubiquitination and degradation of PPARγ.…”

Prognostic and Genomic Analysis of Proteasome 20S Subunit Alpha (PSMA) Family Members in Breast Cancer

“…We recently reported that the high levels of PSMC family members, including PSMC1, PSMC3, PSMC4, PSMC5, and PSMC6, were positively correlated with the poor survival rates of BRCA patients [ 45 ]. Peroxisome proliferator-activated receptor γ (PPARγ) is also associated with ubiquitin–proteasome-dependent degradation and response to the angiotensin II (Ang II) system [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. However, whether PSMA family genes are also involved in BRCA development still needs to be more thoroughly investigated.…”

Microglial Pdcd4 deficiency mitigates neuroinflammation-associated depression via facilitating Daxx mediated PPARγ/IL-10 signaling

“…In this article, we found microglial Pdcd4 deletion abolished LPSinduced microglia activation via up-regulating PPARγ expression and nucleus translocation. We thought there is a causal link between PPARγ up-regulation and nucleus transportation, for rapidly ubiquitinproteasome mediated degradation of cytosol distributed PPARγ [25]. E3 RING ubiquitin ligases have reported, such as NEDD4-1, TRIM25, FBXO9, MKRN1, CUL4B, and FBXO4, regulate PPARγ protein levels which contribute to adipogenesis [26][27][28][29][30][31].…”