Fine-Tuning Protein Fate: Mechanisms of E1, E2, and E3 Enzymes and Deubiquitinases in Cell Signaling

Ubiquitination is a reversible post-translational modification crucial for cellular homeostasis and protein degradation. It is orchestrated by a cascade of ubiquitin-activating enzymes (E1), conjugating enzymes (E2), and ligases (E3) that tag proteins with ubiquitin, and deubiquitinating enzymes (DUBs) that remove these tags. Through this tightly regulated ubiquitination/deubiquitination system, cells control protein turnover, localization, and activity, thereby governing processes ranging from cell cycle progression and DNA repair to immune and stress responses. Here, we review the structural and functional mechanisms of each class of enzymes in the ubiquitin-proteasome system, including E1, E2, E3, and DUBs, and highlight their roles in key signaling pathways and physiological processes. We further discuss how the dysregulation of these enzymes leads to diseases such as cancer, neurodegenerative disorders, and immune diseases, underlining the potential of targeting ubiquitination pathways for therapeutic intervention.