polyubiquitination

Polyubiquitination is the covalent attachment of multiple ubiquitin molecules to a substrate protein, forming a polyubiquitin chain. Ubiquitin is a small, highly conserved protein that can be attached as a single unit (monoubiquitination) or as polymers. Ubiquitin molecules are linked through one of seven internal lysine residues or the N-terminal methionine, generating different chain topologies. The process uses a cascade of enzymes: E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase that provides substrate specificity. Chains are built by successive rounds of ubiquitin transfer, resulting in homotypic, heterotypic, or branched chains. Deubiquitinating enzymes (DUBs) can remove or remodel chains, making the modification reversible.

The topology of the chain determines the fate of the substrate. K48-linked polyubiquitin chains most often signal degradation by the 26S proteasome. K63-linked and other linkages regulate non-degradative processes such as signaling, DNA repair, endocytosis, and trafficking. Linear (M1-linked) chains, formed by the LUBAC complex, participate in immune and inflammatory signaling. The same substrate can carry different chains, and chain length and branching influence recognition by ubiquitin receptors and downstream pathways.

Polyubiquitination is dynamic and highly regulated. DUBs reverse ubiquitination and edit chain topology, balancing synthesis and removal. Proper control of ubiquitination is essential for cell cycle progression, stress responses, and protein quality control. Dysregulation is associated with cancers, neurodegenerative diseases, and immune disorders. The polyubiquitin system remains a focus of basic research and therapeutic development.