SCFCdc4 acts antagonistically to the PGC-1α transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis

Brian L. Olson, M. Benjamin Hock, Susanna Ekholm-Reed, James A. Wohlschlegel, Kumlesh K. Dev, Anastasia Kralli, Steven I. Reed

Research output: Contribution to journalArticle

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) is a highly regulated transcriptional coactivator that coordinates energy metabolism in mammals. Misregulation of PGC-1α has been implicated in the pathogenesis of several human diseases, including diabetes, obesity, and neurological disorders. We identified SCF Cdc4 as an E3 ubiquitin ligase that regulates PGC-1α through ubiquitin-mediated proteolysis. PGC-1α contains two Cdc4 phosphodegrons that bind Cdc4 when phosphorylated by Glycogen Synthase Kinase 3β (GSK3β) and p38 MAPK, leading to SCFCdc4-dependent ubiquitylation and proteasomal degradation of PGC-1α. Furthermore, SCFCdc4 negatively regulates PGC-1α-dependent transcription. We demonstrate that RNAi-mediated reduction of Cdc4 in primary neurons results in an increase of endogenous PGC-1α protein, while ectopic expression of Cdc4 leads to a reduction of endogenous PGC-1α protein. Finally, under conditions of oxidative stress in neurons, Cdc4 levels are decreased, leading to an increase in PGC-1α protein and PGC-1α-dependent transcription. These results suggest that attenuation of SCFCdc4-dependent proteasomal degradation of PGC-1α has a role in mediating the PGC-1α-dependent transcriptional response to oxidative stress.

Original languageEnglish (US)
Pages (from-to)252-264
Number of pages13
JournalGenes and Development
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2008
Externally publishedYes

Keywords

  • Cdc4
  • Fbw7
  • Oxidative stress
  • PGC-1
  • Protein degradation
  • Ubiquitin-mediated proteolysis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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