Deubiquitinase USP33 is negatively regulated by P-TrCP through ubiquitin-dependent proteolysis

Ubiquitin-mediated proteolysis regulates cellular levels of various proteins, and therefore plays important roles in controlling cell signaling and disease progression. The Skpl-Cull-F-box ubiquitin ligase beta-TrCP is recognized as an important negative regulator for numerous key signaling proteins. Recently, the deubiquitinases (DUBs) have turned out to be essential to regulate signaling pathways related to human diseases. However, whether beta-TrCP is able to regulate the deubiquitinase family members remains largely unexplored. Here, we found that beta-TrCP downregulated cellular levels of endogenous USP33. We also revealed that beta-TrCP interacted with USP33 independently of the classic binding motif for beta-TrCP, and mediated USP33 degradation via the ubiquitin proteasome pathway. Furthermore, we found that the WD40 motif of beta-TrCP and 201-400 amino acid motif of USP33 are required for the interaction between beta-TrCP and USP33. Consequently, beta-TrCP attenuated USP33-mediated inhibition of cell proliferation and cell invasion. Taken together, our study clarified that the E3 ligase beta-TrCP regulates cellular USP33 levels by the ubiquitin-proteasomal proteolysis.