Degradation of the deubiquitinating enzyme USP33 is mediated by p97 and the ubiquitin ligase HERC2.

Abstract

Because the deubiquitinating enzyme USP33 is involved in several important cellular processes (β-adrenergic receptor recycling, centrosome amplification, RalB signaling, and cancer cell migration), its levels must be carefully regulated. Using quantitative mass spectrometry, we found that the intracellular level of USP33 is highly sensitive to the activity of p97. Knockdown or chemical inhibition of p97 causes robust accumulation of USP33 due to inhibition of its degradation. The p97 adaptor complex involved in this function is the Ufd1-Npl4 heterodimer. Furthermore, we identified HERC2, a HECT domain-containing E3 ligase, as being responsible for polyubiquitination of USP33. Inhibition of p97 causes accumulation of polyubiquitinated USP33, suggesting that p97 is required for postubiquitination processing. Thus, our study has identified several key molecules that control USP33 degradation within the ubiquitin-proteasome system.

• Authors: Nickie C Chan, Willem den Besten, Michael J Sweredoski, Sonja Hess, Raymond J Deshaies, David C Chan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 28 Pg. 19789-98 (Jul 11 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24855649 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Cell Cycle Proteins
• Guanine Nucleotide Exchange Factors
• Herc2 protein, mouse
• Ubiquitin
• HERC2 protein, human
• Ubiquitin-Protein Ligases
• USP33 protein, human
• Ubiquitin Thiolesterase
• Proteasome Endopeptidase Complex
• Adenosine Triphosphatases
• Valosin Containing Protein

Topics

• Adenosine Triphosphatases (genetics, metabolism)
• Animals
• Cell Cycle Proteins (genetics, metabolism)
• Guanine Nucleotide Exchange Factors (genetics, metabolism)
• HeLa Cells
• Humans
• Mice
• NIH 3T3 Cells
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Proteolysis
• Ubiquitin (genetics, metabolism)
• Ubiquitin Thiolesterase (genetics, metabolism)
• Ubiquitin-Protein Ligases
• Ubiquitination (physiology)
• Valosin Containing Protein