Interplay between ubiquitylation and SUMOylation: Empowered by phase separation

Ubiquitin and the ∼20 human ubiquitin-like proteins regulate numerous aspects of cell biology via interlinked mechanisms that have not been fully elucidated. Sha et al. now explore the interplay between ubiquitylation and SUMOylation, finding that inhibition of ubiquitylation enhances SUMOylation of hundreds of newly synthesized proteins and that the resultant pools are stored in phase-separated protein condensates called PML nuclear bodies. These unexpected outcomes identify a new role for SUMOylation and raise new questions about cell behavior under normal and stress conditions.