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

Protein Cell. 2013 Apr;4(4):310-21. doi: 10.1007/s13238-013-2124-z.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cellular Senescence
  • Down-Regulation / drug effects
  • Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Estradiol / pharmacology*
  • Female
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Nedd4 Ubiquitin Protein Ligases
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Structure, Tertiary
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / drug effects
  • Up-Regulation / drug effects*

Substances

  • Endosomal Sorting Complexes Required for Transport
  • PPAR gamma
  • RNA, Small Interfering
  • Ubiquitin
  • Estradiol
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Nedd4l protein, mouse
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • Sirtuin 1