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J. Biol. Chem., Vol. 282, Issue 51, 36971-36979, December 21, 2007

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Arrestin-2 Interacts with the Ubiquitin-Protein Isopeptide Ligase Atrophin-interacting Protein 4 and Mediates Endosomal Sorting of the Chemokine Receptor CXCR4^*

Deepali Bhandari¹, JoAnn Trejo, Jeffrey L. Benovic^¶, and Adriano Marchese^||2

From the ^||Department of Pharmacology and Experimental Therapeutics and the Program in Molecular Biology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, the Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, and the ^¶Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The chemokine receptor CXCR4 is rapidly targeted for lysosomal degradation by the E3 ubiquitin ligase atrophin-interacting protein 4 (AIP4). Although it is known that AIP4 mediates ubiquitination and degradation of CXCR4 and that perturbations in these events contribute to disease, the mechanisms mediating AIP4-dependent regulation of CXCR4 degradation remain poorly understood. Here we show that AIP4 directly interacts with the amino-terminal half of nonvisual arrestin-2 via its WW domains. We show that depletion of arrestin-2 by small interfering RNA blocks agonist-promoted degradation of CXCR4 by preventing CXCR4 trafficking from early endosomes to lysosomes. Surprisingly, CXCR4 internalization and ubiquitination remain intact, suggesting that the interaction between arrestin-2 and AIP4 is not required for ubiquitination of the receptor at the plasma membrane but perhaps for a later post-internalization event. Accordingly, we show that activation of CXCR4 promotes the interaction between AIP4 and arrestin-2 that is consistent with a time when AIP4 co-localizes with arrestin-2 on endocytic vesicles. Taken together, our data suggest that the AIP4·arrestin-2 complex functions on endosomes to regulate sorting of CXCR4 into the degradative pathway.

Received for publication, June 20, 2007 , and in revised form, September 20, 2007.

^* This work was supported in part by a Scientist Development Grant from the American Heart Association (to A. M.) and National Institutes of Health Grants GM075159 (to A. M.) and GM47417 (to J. L. B.). 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.

¹ Supported by a predoctoral fellowship from the American Heart Association.

² To whom correspondence should be addressed: Dept. of Pharmacology, Loyola University Chicago, Stritch School of Medicine, 2160 S. 1^st Ave., Bldg.101/Rm. 2721, Maywood, IL 60153. Tel.: 708-216-3456; Fax: 708-216-6596; E-mail: amarchese{at}lumc.edu.

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