title: Upregulation of SIRT1 by 17β-estradiol depends on ubiquitin-proteasome degradation of PPAR-γ mediated by NEDD4-1.
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.
authors.affiliation: Peking University Research Center on Aging, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Han
authors.forename: Pan
authors.initials: P
authors.lastname: Wang
authors.forename: Ganye
authors.initials: G
authors.lastname: Zhao
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Tanjun
authors.initials: T
authors.lastname: Tong
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D016922:Cellular Senescence; D015536:Down-Regulation / Q000187:drug effects; D056827:Endosomal Sorting Complexes Required for Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D000075702:Nedd4 Ubiquitin Protein Ligases; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D047495:PPAR gamma; D034741:RNA, Small Interfering; D025801:Ubiquitin; D004958:Estradiol; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D056564:Sirtuin 1
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