Upregulation of SIRT1 by 17β-estradiol depends on ubiquitin-proteasome degradation of PPAR-γ mediated by NEDD4-1

Limin Han1,2, Pan Wang1,2, Ganye Zhao1,2, Hui Wang1,2, Meng Wang1,2, Jun Chen1,2(), Tanjun Tong1,2()

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Protein Cell ›› 2013, Vol. 4 ›› Issue (4) : 310-321. DOI: 10.1007/s13238-013-2124-z
RESEARCH ARTICLE
RESEARCH ARTICLE

Upregulation of SIRT1 by 17β-estradiol depends on ubiquitin-proteasome degradation of PPAR-γ mediated by NEDD4-1

  • Limin Han1,2, Pan Wang1,2, Ganye Zhao1,2, Hui Wang1,2, Meng Wang1,2, Jun Chen1,2(), Tanjun Tong1,2()
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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.

Keywords

17β-estradiol / PPARγ / senescence / SIRT1 / ubiquitination

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Limin Han, Pan Wang, Ganye Zhao, Hui Wang, Meng Wang, Jun Chen, Tanjun Tong. Upregulation of SIRT1 by 17β-estradiol depends on ubiquitin-proteasome degradation of PPAR-γ mediated by NEDD4-1. Prot Cell, 2013, 4(4): 310‒321 https://doi.org/10.1007/s13238-013-2124-z

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