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Degradation of the Deubiquitinating Enzyme USP33 is Mediated by p97 and the Ubiquitin Ligase HERC2

Chan, Nickie C. and den Besten, Willem and Sweredoski, Michael J. and Hess, Sonja and Deshaies, Raymond J. and Chan, David C. (2014) Degradation of the Deubiquitinating Enzyme USP33 is Mediated by p97 and the Ubiquitin Ligase HERC2. Journal of Biological Chemistry, 289 (28). pp. 19789-19798. ISSN 0021-9258. PMCID PMC4094088. https://resolver.caltech.edu/CaltechAUTHORS:20140604-082523933

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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 responsible for polyubiquitination of USP33. Inhibition of p97 causes accumulation of polyubiquitinated USP33, suggesting that p97 is required for post-ubiquitination processing. Thus, our study has identified several key molecules that control USP33 degradation within the ubiquitin-proteasome system.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.jbc.org/content/289/28/19789PublisherArticle
http://dx.doi.org/10.1074/jbc.M114.569392DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094088/PubMed CentralArticle
ORCID:
AuthorORCID
Sweredoski, Michael J.0000-0003-0878-3831
Hess, Sonja0000-0002-5904-9816
Deshaies, Raymond J.0000-0002-3671-9354
Alternate Title:HERC2 targets USP33 for degradation via p97
Additional Information:© 2014, The American Society for Biochemistry and Molecular Biology. Received March 27, 2014. Accepted May 22, 2014. First Published on May 22, 2014. We are grateful for help from the following: Tomohiko Ohta for HERC2 constructs that helped us to reconstruct full-length HERC2; William G. Kaelin Jr. for the 786-O and RCC4 cell lines; Tsui-Fen Chou (Harbor-UCLA Medical Center) for helpful discussions and reagents during the early stage of this work; Robert Graham (currently at University of Manchester) from the PEL for technical help with the mass spectrometry experiments; Michael Walters and Lev G. Lis (University of Minnesota) for NMS-873. The PEL is supported by the Gordon and Betty Moore Foundation through grant GBMF775 and the Beckman Institute. This work was funded by the Howard Hughes Medical Institute and NIH RO1 GM062967.
Funders:
Funding AgencyGrant Number
Gordon and Betty Moore FoundationGBMF775
Caltech Beckman InstituteUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIHRO1 GM062967
Subject Keywords:Protein degradation, ubiquitin ligase, ubiquitination, deubiquitinating enzyme, proteasome, p97, HERC2, USP33
Issue or Number:28
PubMed Central ID:PMC4094088
Record Number:CaltechAUTHORS:20140604-082523933
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140604-082523933
Official Citation:Protein Synthesis and Degradation: Nickie C. Chan, Willem den Besten, Michael J. Sweredoski, Sonja Hess, Raymond J. Deshaies, and David C. Chan Degradation of the Deubiquitinating Enzyme USP33 Is Mediated by p97 and the Ubiquitin Ligase HERC2 J. Biol. Chem. 2014 289: 19789-19798. First Published on May 22, 2014, doi:10.1074/jbc.M114.569392
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:46068
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:04 Jun 2014 22:35
Last Modified:03 Oct 2019 06:40

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