title: 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.affiliation: From the Division of Biology and Biological Engineering, the Howard Hughes Medical Institute, and.
authors.forename: Nickie C
authors.initials: NC
authors.lastname: Chan
authors.affiliation: From the Division of Biology and Biological Engineering.
authors.forename: Willem
authors.initials: W
authors.lastname: den Besten
authors.affiliation: From the Division of Biology and Biological Engineering, the Proteome Exploration Laboratory/Beckman Institute, California Institute of Technology, Pasadena, California 91125.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sweredoski
authors.affiliation: From the Division of Biology and Biological Engineering, the Proteome Exploration Laboratory/Beckman Institute, California Institute of Technology, Pasadena, California 91125.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hess
authors.affiliation: From the Division of Biology and Biological Engineering, the Howard Hughes Medical Institute, and.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Deshaies
authors.affiliation: From the Division of Biology and Biological Engineering, the Howard Hughes Medical Institute, and dchan@caltech.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Chan
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000502:physiology*; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; C486527:Herc2 protein, mouse; D025801:Ubiquitin; C118566:HERC2 protein, human; D044767:Ubiquitin-Protein Ligases; C449799:USP33 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein
keywords: Deubiquitination; E3 Ubiquitin Ligase; HERC2; Proteasome; Protein Degradation; USP33; Ubiquitination; p97