Impaired recruitment of Grk6 and β-arrestin2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor

McCormick, Peter J., Segarra, Marta, Gasperini, Paola, Gulino, A. Virginia and Tosato, Giovanna (2009) Impaired recruitment of Grk6 and β-arrestin2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor. PLoS One, 4 (12). ISSN 1932-6203

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Abstract

WHIM (warts, hypogammaglobulinemia, infections, and myelokatexis) syndrome is a rare immunodeficiency syndrome linked to heterozygous mutations of the chemokine receptor CXCR4 resulting in truncations of its cytoplasmic tail. Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. Here, we investigated the biochemical mechanisms underlying CXCR4 deficiency in WHIM syndrome. We report that after ligand activation, WHIM-associated mutant CXCR4 receptors lacking the carboxy-terminal 19 residues internalize and activate Erk 1/2 slower than wild-type (WT) receptors, while utilizing the same trafficking endocytic pathway. Recruitment of β-Arrestin 2, but not β-Arrestin 1, to the active WHIM-mutant receptor is delayed compared to the WT CXCR4 receptor. In addition, while both kinases Grk3 and Grk6 bind to WT CXCR4 and are critical to its trafficking to the lysosomes, Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates normally. Since β-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome.

Item Type:	Article
Additional Information:	This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Pure Connector
Date Deposited:	13 Jan 2014 13:48
Last Modified:	24 Oct 2022 05:57
URI:	https://ueaeprints.uea.ac.uk/id/eprint/47170
DOI:	10.1371/journal.pone.0008102

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