Ubiquitin specific peptidase 33 (USP33)

Ubiquitin specific peptidase 33 (USP33) is a cysteine protease and member of the ubiquitin-specific protease (USP) family, functioning as a deubiquitinating enzyme (DUB).[1][2] USP33 removes ubiquitin from target proteins, thereby protecting them from proteasomal degradation and regulating their stability and function.[1] It is involved in a variety of cellular processes, including centrosome duplication, receptor signaling and recycling (notably for β2-adrenergic receptors), axon guidance, cell migration, and hormone regulation (via deubiquitination of DIO2, which activates thyroid hormone).[1][2][3] USP33 is also upregulated in response to hypoxia in certain cancer stem cells where it stabilizes the hypoxia-induced factor HIF-2α, promoting tumor growth and vascularization.[6] Its dysregulation has been implicated in several disease areas, particularly in cancer, neurodegenerative disorders, and polycythemia.[1][4][6] Due to its multifaceted roles, USP33 is being explored as a potential therapeutic target, though no drugs currently target it directly in clinical practice.

Other names

Ubiquitin carboxyl-terminal hydrolase 33KIAA1097VDU1hVDU1Deubiquitinating enzyme 33Ubiquitin thioesterase 33Ubiquitin-specific-processing protease 33VHL-interacting deubiquitinating enzyme 1pVHL-interacting deubiquitinating enzyme 1

Proposed mechanism (for drug discovery): USP33 inhibition would likely reduce its deubiquitinating activity, resulting in destabilization of substrates such as HIF-2α, DIO2, ROBO1, and potentially sensitizing certain cancer cells to apoptosis or impairing tumor cell survival.[4][6] Related: Mechanistic effects seen with docetaxel (a chemotherapy) are potentiated when USP33 is depleted, enhancing JNK-mediated apoptosis, but this is not a direct effect on USP33 by the drug itself.[4]