SCF^Cdc4 acts antagonistically to the PGC-1α transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis

Abstract

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 Cdc4 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 Mitochondrial dysfunction and alterations in PGC-1 levels have been implicated in the pathogenesis of several diseases, including diabetes, heart disease, and neurological disorders Leone et al. 2005;Cui et al. 2006;Finck and Kelly 2006;St-Pierre et al. 2006). The reduced levels of PGC-1␣ and PGC-1␤ in the muscle of type 2 diabetic patients and individuals predisposed to diabetes, have been proposed to underlie decreased mitochondrial function and the development of insulin resistance (Mootha et al. 2003;Patti et al. 2003). Loss of PGC-1␣ activity in the heart correlates with heart fail-

Plk2 regulates centriole duplication through phosphorylation-mediated degradation of Fbxw7 (human Cdc4)

“…It would be intriguing to find out if this DNA-damage-induced phosphorylation plays a role in Fbxw7 regulation. Interestingly, the protein levels of the Fbxw7a isoform decrease in response to oxidative stress (Olson et al, 2008). Of note, Fbxw7a was shown to be phosphorylated by serum and glucocorticoid inducible kinase (SGK1) on S227, which promotes Notch1-IC degradation through enhanced ubiquitylation (Mo et al, 2011).…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…Akt and glycogen synthase kinase 3 (GSK3) both mediate inhibitory PGC-1 phosphorylation events [64,65]. Prior negative phosphorylation is also required for polyubiquitination of PGC-1 which targets the protein for proteasomal degradation [66].…”

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…The acetylation state of PGC-1α1 can be modified by acetyltransferases such as GCN5 [25] or deacetylases like sirtuin 1 (SIRT1) [26,27]. Additionally, ubiquitylation by specific E3 ligases directly regulates PGC-1α protein stability [24,28,29]. Together, these multiple levels of regulation ensure that under any given condition the cellular PGC-1α activity is appropriate to regulate the gene programs necessary to adapt to the new biological environment.…”

“…In addition, PGC-1α activity can be modulated by a plethora of post-translational modifications, including phosphorylation, acetylation and ubiquitylation. Kinases that target PGC-1α1 include p38 mitogen-activated protein kinase [20], protein kinase B [21], S6 kinase [22], AMPK [23] and glycogen synthase kinase 3β (GSK3β) [24]. These different phosphorylation events constitute a code that changes PGC-1α1 biological activity by, for example, dictating association with specific transcription factors [3].…”