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

Exp Cell Res. 2017 Jul 1;356(1):1-7. doi: 10.1016/j.yexcr.2017.05.011. Epub 2017 May 13.


Ubiquitin-mediated proteolysis regulates cellular levels of various proteins, and therefore plays important roles in controlling cell signaling and disease progression. The Skp1-Cul1-F-box ubiquitin ligase β-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 β-TrCP is able to regulate the deubiquitinase family members remains largely unexplored. Here, we found that β-TrCP downregulated cellular levels of endogenous USP33. We also revealed that β-TrCP interacted with USP33 independently of the classic binding motif for β-TrCP, and mediated USP33 degradation via the ubiquitin proteasome pathway. Furthermore, we found that the WD40 motif of β-TrCP and 201-400 amino acid motif of USP33 are required for the interaction between β-TrCP and USP33. Consequently, β-TrCP attenuated USP33-mediated inhibition of cell proliferation and cell invasion. Taken together, our study clarified that the E3 ligase β-TrCP regulates cellular USP33 levels by the ubiquitin-proteasomal proteolysis.

Keywords: E3 ligase; Protein ubiquitination; USP33; β-TrCP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation / genetics*
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Proteolysis
  • Signal Transduction / genetics
  • Ubiquitin / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination / physiology*
  • WD40 Repeats / genetics*
  • beta-Transducin Repeat-Containing Proteins / genetics
  • beta-Transducin Repeat-Containing Proteins / metabolism*


  • Ubiquitin
  • beta-Transducin Repeat-Containing Proteins
  • USP33 protein, human
  • Ubiquitin Thiolesterase