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Molecular and Cellular Biology, September 2004, p. 7748-7757, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7748-7757.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Stabilization of the E3 Ubiquitin Ligase Nrdp1 by the Deubiquitinating Enzyme USP8

Xiuli Wu, Lily Yen, Lisa Irwin, Colleen Sweeney, and Kermit L. Carraway III*

UC Davis Cancer Center, Sacramento, California

Received 15 February 2004/ Returned for modification 30 March 2004/ Accepted 7 June 2004

Nrdp1 is a RING finger-containing E3 ubiquitin ligase that physically interacts with and regulates steady-state cellular levels of the ErbB3 and ErbB4 receptor tyrosine kinases and has been implicated in the degradation of the inhibitor-of-apoptosis protein BRUCE. Here we demonstrate that the Nrdp1 protein undergoes efficient proteasome-dependent degradation and that mutations in its RING finger domain that disrupt ubiquitin ligase activity enhance stability. These observations suggest that Nrdp1 self-ubiquitination and stability could play an important role in regulating the activity of this protein. Using affinity chromatography, we identified the deubiquitinating enzyme USP8 (also called Ubpy) as a protein that physically interacts with Nrdp1. Nrdp1 and USP8 could be coimmunoprecipitated, and in transfected cells USP8 specifically bound to Nrdp1 but not cbl, a RING finger E3 ligase involved in ligand-stimulated epidermal growth factor receptor down-regulation. The USP8 rhodanese and catalytic domains mediated Nrdp1 binding. USP8 markedly enhanced the stability of Nrdp1, and a point mutant that disrupts USP8 catalytic activity destabilized endogenous Nrdp1. Our results indicate that Nrdp1 is a specific target for the USP8 deubiquitinating enzyme and are consistent with a model where USP8 augments Nrdp1 activity by mediating its stabilization.

* Corresponding author. Mailing address: UC Davis Cancer Center, Research Building III, Room 1400, 4645 2nd Ave., Sacramento, CA 95817. Phone: (916) 734-3114. Fax: (916) 734-0190. E-mail: klcarraway{at}ucdavis.edu.

Molecular and Cellular Biology, September 2004, p. 7748-7757, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7748-7757.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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