ubiquitinylation

Ubiquitinylation, also known as ubiquitination or ubiquitylation, is a post-translational modification in which one or more ubiquitin molecules are covalently attached to a substrate protein. Ubiquitin is a small, highly conserved protein found in almost all eukaryotic organisms. The process of ubiquitinylation is highly regulated and involves a cascade of enzymes, typically including an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ubiquitin ligase. The E3 ligase is crucial as it confers substrate specificity to the reaction.

Ubiquitinylation can occur in various forms, including monoubiquitinylation (attachment of a single ubiquitin), multi-monoubiquitinylation (attachment of multiple single ubiquitin molecules to different sites), and polyubiquitinylation (attachment of a chain of ubiquitin molecules). The type of ubiquitin chain formed, determined by the lysine residue on ubiquitin used for chain elongation (e.g., K48, K63), dictates the fate of the substrate protein.

The primary and best-characterized function of K48-linked polyubiquitinylation is the targeting of proteins for degradation by the 26S proteasome. This pathway is essential for cellular quality control, removing damaged or misfolded proteins, and regulating the levels of short-lived regulatory proteins. However, ubiquitinylation also plays diverse roles independent of proteasomal degradation. For instance, K63-linked polyubiquitin chains are involved in DNA repair, signal transduction pathways, and protein trafficking. Monoubiquitinylation can regulate protein localization, interactions, and activity without leading to degradation. The reversible nature of ubiquitinylation, through the action of deubiquitinating enzymes (DUBs), further adds to its complexity and regulatory potential.