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

doi:10.1007/s13238-013-2124-z

Prot Cell

2013, Vol. 4

Issue (4) : 310-321 https://doi.org/10.1007/s13238-013-2124-z PMID: 23549616

RESEARCH ARTICLE

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

Limin Han^1,2, Pan Wang^1,2, Ganye Zhao^1,2, Hui Wang^1,2, Meng Wang^1,2, Jun Chen^1,2(

), Tanjun Tong^1,2(

)

1. Peking University Research Center on Aging, Peking University Health Science Center, Beijing 100191, China; 2. Department of Biochemistry & Molecular Biology, School of Basic Medicine, Peking University Health Science Center, Beijing 100191, China

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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

Corresponding Author(s): Chen Jun,Email:chenjun0511@yahoo.com; Tong Tanjun,Email:ttj@bjmu.edu.cn

Issue Date: 01 April 2013

Cite this article:

Limin Han,Pan Wang,Ganye Zhao, et al. Upregulation of SIRT1 by 17β-estradiol depends on ubiquitin-proteasome degradation of PPAR-γ mediated by NEDD4-1[J]. Prot Cell, 2013, 4(4): 310-321.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-013-2124-z
https://academic.hep.com.cn/pac/EN/Y2013/V4/I4/310

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