Disassembling SCF ubiqutin ligases

Skp–cullin–F-box (SCF) ubiquitin ligases contain an F-box protein, which confers the specificity of the ligase by binding to substrates. Yen et al. now describe in detail how, in response to cadmium stress, the activity of an SCF containing the F-box protein Met30 (SCF^Met30) is also regulated by dissociation of Met30. They found that, in Saccharomyces cerevisiae, the AAA-ATPase Cdc48 interacts with Met30 in a cadmium-dependent manner; this correlates with the dissociation of Met30 from Skp1. Interestingly, Cdc48 was recruited to autoubiquitylated Met30. Under normal conditions, SCF^Met30 ubiquitylates the transcriptional activator Met4 to repress its activity; however, Met4 is stabilized in response to cadmium and mediates the cadmium stress response. Met4 was persistently ubiquitylated in Cdc48 mutants under cadmium stress, indicating that Cdc48 is required for SCF^Met30 inactivation under these conditions. This study provides mechanistic insight into how a SCF ubiquitin ligase can be regulated by dissociation of its F-box component.