Upregulation of SIRT1 by 17β-estradiol depends on ubiquitin-proteasome degradation of PPAR-γ mediated by NEDD4-1.
10.1007/s13238-013-2124-z
- Author:
Limin HAN
1
;
Pan WANG
;
Ganye ZHAO
;
Hui WANG
;
Meng WANG
;
Jun CHEN
;
Tanjun TONG
Author Information
1. Peking University Research Center on Aging, Peking University Health Science Center, Beijing 100191, China.
- Publication Type:Journal Article
- MeSH:
Amino Acid Motifs;
Animals;
Cellular Senescence;
Down-Regulation;
drug effects;
Endosomal Sorting Complexes Required for Transport;
antagonists & inhibitors;
genetics;
metabolism;
Estradiol;
pharmacology;
Female;
HeLa Cells;
Humans;
Mice;
Mice, Inbred BALB C;
Nedd4 Ubiquitin Protein Ligases;
PPAR gamma;
genetics;
metabolism;
Proteasome Endopeptidase Complex;
metabolism;
Protein Structure, Tertiary;
RNA Interference;
RNA, Small Interfering;
metabolism;
Sirtuin 1;
genetics;
metabolism;
Ubiquitin;
metabolism;
Ubiquitin-Protein Ligases;
antagonists & inhibitors;
genetics;
metabolism;
Ubiquitination;
drug effects;
Up-Regulation;
drug effects
- From:
Protein & Cell
2013;4(4):310-321
- CountryChina
- Language:English
-
Abstract:
17β-estradiol (E2) treatment of cells results in an upregulation of SIRT1 and a down-regulation of PPARγ. The decrease in PPARγ expression is mediated by increased degradation of PPARγ. Here we report that PPARγ is ubiquitinated by HECT E3 ubiquitin ligase NEDD4-1 and degraded, along with PPARγ, in response to E2 stimulation. The PPARγ interacts with ubiquitin ligase NEDD4-1 through a conserved PPXY-WW binding motif. The WW3 domain in NEDD4-1 is critical for binding to PPARΓ. NEDD4-1 overexpression leads to PPARγ ubiquitination and reduced expression of PPARγ. Conversely, knockdown of NEDD4-1 by specific siRNAs abolishes PPARΓ ubiquitination. These data indicate that NEDD4-1 is the E3 ubiquitin ligase responsible for PPARγ ubiquitination. Here, we show that NEDD4-1 delays cellular senescence by degrading PPARΓ expression. Taken together, our data show that E2 could upregulate SIRT1 expression via promoting the PPARΓ ubiquitination-proteasome degradation pathway to delay the process of cell senescence.
