PolySUMOylation

PolySUMOylation refers to the attachment of multiple SUMO (small ubiquitin-like modifier) units to a substrate protein, forming SUMO chains. This is distinct from monoSUMOylation, where only a single SUMO moiety is added. In vertebrates, SUMO-2 and SUMO-3 readily form chains, whereas SUMO-1 is less prone to chain formation and can sometimes cap chains. The process is carried out by the SUMO machinery, including the E1 activating enzyme (a heterodimer of Aos1/UBA2), the E2 conjugating enzyme Ubc9, and various E3 ligases such as the PIAS family, Siz1/2, or RanBP2 that promote substrate specificity.

PolySUMO chains are formed through SUMO–SUMO interactions and, in many cases, require SUMO-interacting motifs (SIMs) within substrates or adaptors. Chains can be remodeled by SUMO-specific isopeptidases (SENPs) that trim or remove SUMO units, providing dynamic regulation of conjugation status.

Biological significance of polySUMOylation includes modulation of protein stability, localization, and interactions. Chains often serve as signals for downstream processing, notably by SUMO-targeted ubiquitin ligases (STUbLs) such as RNF4, which recognize polySUMO chains and can ubiquitinate the substrate to promote proteasomal degradation. PolySUMOylation also participates in DNA damage response, chromatin organization, transcriptional regulation, and cellular stress responses, and can influence protein phase behavior.

Detection and study of polySUMOylation rely on mass spectrometry and SUMO-chain–specific antibodies, as well as engineered SUMO mutants that prevent chain formation. Dysregulation of polySUMOylation has been linked to various diseases, including cancer and neurodegenerative disorders, making it a topic of ongoing research for understanding cellular regulation and potential therapeutic targeting.