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

• Published in: The Journal of biological chemistry 2007-12, Vol.282 (51), p.36971-36979
• Main Authors: Bhandari, Deepali, Trejo, JoAnn, Benovic, Jeffrey L., Marchese, Adriano
• Format: Article
• Language: English
• Subjects: Arrestins - antagonists & inhibitors; Arrestins - genetics; Arrestins - metabolism; beta-Arrestins; Cell Line; Cell Membrane - genetics; Cell Membrane - metabolism; Endocytosis - drug effects; Endocytosis - physiology; Endosomes - genetics; Endosomes - metabolism; Humans; Protein Binding - drug effects; Protein Binding - physiology; Protein Structure, Tertiary - physiology; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA, Small Interfering - pharmacology; Transport Vesicles - genetics; Transport Vesicles - metabolism; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - drug effects; Ubiquitination - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M705085200

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.