The SCFMet30 ubiquitin ligase senses cellular redox state to regulate the transcription of sulfur metabolism genes

In yeast, control of sulfur amino acid metabolism relies upon Met4, a transcription factor which activates the expression of a network of enzymes responsible for the biosynthesis of cysteine and methionine. In times of sulfur abundance, the activity of Met4 is repressed via ubiquitination by the SCFMet30 E3 ubiquitin ligase, but the mechanism by which the F-box protein Met30 senses sulfur status to tune its E3 ligase activity remains unresolved. Here, using a combination of genetics and biochemistry, we show that Met30 utilizes exquisitely redox-sensitive cysteine residues in its WD-40 repeat region to sense the availability of sulfur metabolites in the cell. Oxidation of these cysteine residues in response to sulfur starvation inhibits binding and ubiquitination of Met4, leading to induction of sulfur metabolism genes. Our findings reveal how SCFMet30 dynamically senses redox cues to regulate synthesis of these special amino acids, and further highlight the mechanistic diversity in E3 ligase-substrate relationships.