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Entry into the cell cycle is regulated by nutrient availability such that cells do not divide when resources are limited. The Skp1–Cul1–F-box (SCF) ubiquitin ligase with the F-box protein Grr1 (SCF^Grr1) controls the proteolytic turnover of regulators of cell-cycle entry and a glucose sensor, suggesting that it links the cell cycle with nutrient availability. Here, we show that SCF^Grr1 broadly regulates cellular metabolism. We have developed a proteomic screening method that uses high-throughput quantitative microscopy to comprehensively screen for ubiquitin-ligase substrates. Seven new metabolic targets of SCF^Grr1 were identified, including two regulators of glycolysis — the transcription factor Tye7 and Pfk27. The latter produces the second messenger fructose-2,6-bisphosphate that activates glycolysis and inhibits gluconeogenesis. We show that SCF^Grr1 targets Pfk27 and Tye7 in response to glucose removal …