A Transcriptional Activator Is Part of an SCF Ubiquitin Ligase to Control Degradation of Its Cofactors

Multisubunit protein complexes pose a challenge to the coordinated regulation of individual components. We show how the yeast transactivating factor Met4 functions as a component of the SCFMet30 ubiquitin ligase to synchronize its own activity with cofactor assembly. Cells maintain Met4 in a dormant state by a regulatory ubiquitin chain assembled by SCFMet30. Nutritional and heavy-metal stress block Met4 ubiquitylation resulting in Met4 activation, which induces a stress-response program including cell-cycle arrest. Met4 relies on assembly with various cofactors for promoter binding. We report here that the stability of these DNA-binding cofactors is regulated by SCFMet30. Remarkably, the transcriptional activator Met4 functions as a substrate-specificity factor in the context of SCFMet30/Met4 to coordinate cofactor degradation with its own activity status. Our results establish an additional layer for substrate recruitment by SCF ubiquitin ligases and provide conceptual insight into coordinated regulation of protein complexes.