OTUD4 Activators

OTUD4, a deubiquitinating enzyme, can have its functional activity enhanced by chemicals that increase the cellular concentration of ubiquitinated proteins. Proteasome inhibitors like MG-132, Bortezomib, and Lactacystin prevent the degradation of ubiquitinated proteins, thereby providing more substrates for OTUD4's enzymatic activity. Ubistatins, which inhibit the binding of ubiquitinated proteins to the proteasome, and Pyr-41, an inhibitor of ubiquitin-activating enzyme E1, also lead to an accumulation of ubiquitinated proteins, thus enhancing OTUD4's deubiquitination function. PR-619, a broad-spectrum DUB inhibitor, indirectly enhances the activity of OTUD4 by increasing the levels of ubiquitinated proteins.

OTUD4's deubiquitinating activity can be further enhanced by chemicals that influence the intracellular localization and stability of ubiquitinated proteins. NMS-873, an allosteric inhibitor of p97/VCP, leads to an accumulation of ubiquitinated proteins by preventing their extraction from complexes. Similarly, Chloroquine, an inhibitor of lysosomal degradation, and Bafilomycin A1, an inhibitor of V-ATPase, prevent the degradation of ubiquitinated proteins, enhancing OTUD4's function. Leptomycin B, an inhibitor of nuclear export, could potentially enhance OTUD4's activity by affecting the localization of ubiquitinated proteins. Lastly, MLN4924, a NEDD8-activating enzyme inhibitor, leads to an accumulation of neddylated proteins. Since OTUD4 can also deubiquitinate neddylated proteins, the increased concentration of these proteins can further enhance the enzymatic activity of OTUD4. In addition, IU1, a specific inhibitor of the deubiquitinating enzyme USP14, promotes the accumulation of ubiquitinated proteins, thereby potentially boosting the deubiquitination activity of OTUD4.