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

Peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator-1 alpha (PGC-1 alpha) is a highly regulated transcriptional coactivator that coordinates energy metabolism in mammals. Misregulation of PGC-1 alpha has been implicated in the pathogenesis of several human diseases, including diabetes, obesity, and neurological disorders. We identified SCFCdc4 as an E3 ubiquitin ligase that regulates PGC-1 alpha through ubiquitin-mediated proteolysis. PGC-1 alpha contains two Cdc4 phosphodegrons that bind Cdc4 when phosphorylated by Glycogen Synthase Kinase 3 beta ( GSK3 beta) and p38 MAPK, leading to SCFCdc4-dependent ubiquitylation and proteasomal degradation of PGC-1 alpha. Furthermore, SCFCdc4 negatively regulates PGC-1 alpha-dependent transcription. We demonstrate that RNAi-mediated reduction of Cdc4 in primary neurons results in an increase of endogenous PGC-1 alpha protein, while ectopic expression of Cdc4 leads to a reduction of endogenous PGC-1 alpha protein. Finally, under conditions of oxidative stress in neurons, Cdc4 levels are decreased, leading to an increase in PGC-1 alpha protein and PGC-1 alpha-dependent transcription. These results suggest that attenuation of SCFCdc4-dependent proteasomal degradation of PGC-1 alpha has a role in mediating the PGC-1 alpha-dependent transcriptional response to oxidative stress.