Ubiquitylation

Ubiquitylation, also known as ubiquitination, is a post-translational modification in which the small regulatory protein ubiquitin is covalently attached to substrate proteins. Ubiquitin is a 76-amino-acid polypeptide that can be attached as a single unit or as polyubiquitin chains, altering the fate and function of the substrate. This modification regulates protein stability, localization, activity, and interactions and is essential for numerous cellular processes.

Attachment proceeds through a three-enzyme cascade. An E1 activating enzyme uses ATP to form a thioester bond with ubiquitin, which is then transferred to an E2 conjugating enzyme. An E3 ligase confers substrate specificity and facilitates transfer of ubiquitin from E2 to the substrate. E3s are categorized into RING, HECT, and RBR families, with different mechanisms for ubiquitin transfer. Ubiquitin itself can form chains via isopeptide bonds on lysine residues; the chain topology encodes the outcome.

Polyubiquitin chains containing lysine-48 are the best known signal for proteasomal degradation, while other linkages (such as lysine-63) regulate processes like DNA damage response, endocytosis, and signaling. Monoubiquitination can modulate activity or trafficking of a protein without marking it for destruction. Reversibility is provided by deubiquitinating enzymes that remove ubiquitin.

Ubiquitylation is central to cell cycle control, DNA repair, immune signaling, and development. Dysregulation can contribute to cancer, neurodegenerative diseases, and inflammatory disorders. The pathway is a major target for therapeutic intervention, including proteasome inhibitors and modulators of E3 ligases.