UBC9

UBC9, also known as UBE2I, is the sole ubiquitin-like modifier (SUMO)–conjugating enzyme in the SUMOylation pathway. It transfers SUMO from the E1 activating enzyme to substrate proteins, often with the help of E3 ligases, thereby influencing protein activity, interactions, stability, and subcellular localization. SUMOylation regulates a wide range of cellular processes, including transcription, DNA repair, and stress responses.

In humans, the UBE2I gene encodes a 158-amino-acid protein of about 18 kDa. The enzyme contains a conserved UBC domain and a catalytic cysteine (C93) that forms a thioester intermediate with SUMO. UBC9 can conjugate SUMO1, SUMO2, and SUMO3 to target proteins.

Mechanistically, UBC9 accepts SUMO from the E1 activating enzyme SAE1/SAE2 to form a SUMO–UBC9 thioester, then transfers SUMO to lysine residues on substrates. E3 ligases, such as members of the PIAS family, enhance substrate specificity and efficiency, though UBC9 can modify certain substrates in an E3-independent manner. UBC9 also recognizes substrates containing SUMOylation motifs, which facilitates targeted modification.

Localization is predominantly nuclear, aligning with roles in transcriptional regulation, chromatin dynamics, DNA damage response, and cell cycle control. SUMOylation mediated by UBC9 can alter substrate stability, interactions, and cellular distribution.

Dysregulation of SUMOylation, including UBC9 activity, is associated with diseases such as cancer and neurodegeneration. Because of its central role in SUMO signaling, UBC9 is a focus of research as a potential therapeutic target, with regulation occurring through post-translational modifications and protein–protein interactions.