The Ubiquitin Ligase SCF^Ucc1 Acts as a Metabolic Switch for the Glyoxylate Cycle

Highlights

• SCF^Ucc1 regulates the level of Cit2 protein to maintain citrate homeostasis

• Ucc1 transcription is downregulated in cells grown on C₂-compounds

• Oxaloacetate-dependent positive feedback loop inhibits Cit2 ubiquitination

• SCF^Ucc1 acts as a metabolic switch for the glyoxylate cycle

Summary

Despite the crucial role played by the glyoxylate cycle in the virulence of pathogens, seed germination in plants, and sexual development in fungi, we still have much to learn about its regulation. Here, we show that a previously uncharacterized SCF^Ucc1 ubiquitin ligase mediates proteasomal degradation of citrate synthase in the glyoxylate cycle to maintain metabolic homeostasis in glucose-grown cells. Conversely, transcription of the F box subunit Ucc1 is downregulated in C₂-compound-grown cells, which require increased metabolic flux for gluconeogenesis. Moreover, in vitro analysis demonstrates that oxaloacetate regenerated through the glyoxylate cycle induces a conformational change in citrate synthase and inhibits its recognition and ubiquitination by SCF^Ucc1, suggesting the existence of an oxaloacetate-dependent positive feedback loop that stabilizes citrate synthase. We propose that SCF^Ucc1-mediated regulation of citrate synthase acts as a metabolic switch for the glyoxylate cycle in response to changes in carbon source, thereby ensuring metabolic versatility and flexibility.