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

Peroxisome proliferator-activated receptor (PPAR ) coactivator-1 (PGC-1 ) is a highly regulated transcriptional coactivator that coordinates energy metabolism in mammals. Misregulation of PGC-1 has been implicated in the pathogenesis of several human diseases, including diabetes, obesity, and neurological disorders. We identified SCF as an E3 ubiquitin ligase that regulates PGC-1 through ubiquitin-mediated proteolysis. PGC-1 contains two Cdc4 phosphodegrons that bind Cdc4 when phosphorylated by Glycogen Synthase Kinase 3 (GSK3 ) and p38 MAPK, leading to SCF-dependent ubiquitylation and proteasomal degradation of PGC-1 . Furthermore, SCF negatively regulates PGC-1 -dependent transcription. We demonstrate that RNAi-mediated reduction of Cdc4 in primary neurons results in an increase of endogenous PGC-1 protein, while ectopic expression of Cdc4 leads to a reduction of endogenous PGC-1 protein. Finally, under conditions of oxidative stress in neurons, Cdc4 levels are decreased, leading to an increase in PGC-1 protein and PGC-1 -dependent transcription. These results suggest that attenuation of SCF-dependent proteasomal degradation of PGC-1 has a role in mediating the PGC-1 -dependent transcriptional response to oxidative stress.