The Ubiquitin Script: writing protein fates in chains

Ubiquitination is a fundamental post-translational modification that orchestrates a wide range of cellular processes. This modification is executed through a cascade of enzymatic steps involving E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. Among these, E2 enzymes and specific E3 ligases primarily dictate the type of ubiquitin linkage formed. Ubiquitination system can form chains of ubiquitin on any of its seven lysine residues or its N-terminal methionine, each generating a distinct three-dimensional topology. These structurally diverse polyubiquitin chains are selectively recognized by ubiquitin receptors, influencing substrate stability, localization, and interactions. These topologically diverse polyubiquitin chains function as discrete molecular signals, each with distinct physiological outcomes. This review focuses on key developments in our understanding of how specific ubiquitin linkage types participate in various cellular pathways and their implications on the fate and function of the protein.