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J. Biol. Chem., Vol. 283, Issue 32, 22166-22176, August 8, 2008

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Nedd4 Mediates Agonist-dependent Ubiquitination, Lysosomal Targeting, and Degradation of the β₂-Adrenergic Receptor^*

Sudha K. Shenoy¹, Kunhong Xiao, Vidya Venkataramanan, Peter M. Snyder^¶, Neil J. Freedman, and Allan M. Weissman^||2

From the Departments of Medicine and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, the ^¶Departments of Internal Medicine and Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52422, and the ^||Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702

Agonist-stimulated β₂-adrenergic receptor (β₂AR) ubiquitination is a major factor that governs both lysosomal trafficking and degradation of internalized receptors, but the identity of the E3 ubiquitin ligase regulating this process was unknown. Among the various catalytically inactive E3 ubiquitin ligase mutants that we tested, a dominant negative Nedd4 specifically inhibited isoproterenol-induced ubiquitination and degradation of the β₂AR in HEK-293 cells. Moreover, siRNA that down-regulates Nedd4 expression inhibited β₂AR ubiquitination and lysosomal degradation, whereas siRNA targeting the closely related E3 ligases Nedd4-2 or AIP4 did not. Interestingly, β₂AR as well as β-arrestin2, the endocytic and signaling adaptor for the β₂AR, interact robustly with Nedd4 upon agonist stimulation. However, β₂AR-Nedd4 interaction is ablated when β-arrestin2 expression is knocked down by siRNA transfection, implicating an essential E3 ubiquitin ligase adaptor role for β-arrestin2 in mediating β₂AR ubiquitination. Notably, β-arrestin2 interacts with two different E3 ubiquitin ligases, namely, Mdm2 and Nedd4 to regulate distinct steps in β₂AR trafficking. Collectively, our findings indicate that the degradative fate of the β₂AR in the lysosomal compartments is dependent upon β-arrestin2-mediated recruitment of Nedd4 to the activated receptor and Nedd4-catalyzed ubiquitination.

Received for publication, November 27, 2007 , and in revised form, May 28, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL080525. This work was also supported by the American Heart Association (0530014N) (to S. K. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4 and Table S1.

² Supported by the Center for Cancer Research, NCI, National Institutes of Health.

¹ To whom correspondence should be addressed. Tel.: 919-681-5061; Fax: 919-681-7851; E-mail: sudha{at}receptor-biol.duke.edu.

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