Submitted July 18, 2007
Accepted March 27, 2008
CXCR4 dimerization and 
-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome
Bernard Lagane*, Ken Y. C. Chow, Karl Balabanian, Angelique Levoye, Julie Harriague, Thierry Planchenault, Francoise Baleux, Nathalie Gunera-saad, Fernando Arenzana-Seisdedos, and Francoise Bachelerie
Unite de Pathogenie Virale Moleculaire, INSERM U819, Institut Pasteur, Paris, France
Unite de Chimie Organique, Institut Pasteur, Paris, France
URCI-LS CH Lyon-sud, Universite Lyon 1, Lyon, France
* Corresponding author; email: lagane{at}pasteur.fr.
WHIM syndrome is an immune deficiency linked in many cases to heterozygous mutations causing truncations in the cytoplasmic tail of the chemokine receptor CXCR4. Leukocytes expressing truncated CXCR4 display enhanced responses to the receptor ligand CXCL12, including chemotaxis, which likely impair their trafficking and contribute to the immuno-hematological clinical manifestations of the syndrome. CXCR4 desensitization and endocytosis are dependent on 
-arrestin recruitment to the cytoplasmic tail, so that the truncated CXCR4 are refractory to these processes and so have enhanced G-protein-dependent signaling. Here, we show that the augmented responsiveness of WHIM leukocytes is also accounted for by enhanced -arrestin2-dependent signaling downstream of the truncated CXCR4 receptor. Indeed, the WHIM-associated receptor CXCR41013 maintains association with -arrestin2 and triggers augmented and prolonged -arrestin2-dependent signaling, as revealed by ERK1/2 phosphorylation kinetics. Evidence is also provided that CXCR41013-mediated chemotaxis critically requires -arrestin2, and disrupting the SHSK motif in the third intracellular loop of CXCR41013 abrogates -arrestin2-mediated signaling, but not coupling to G-proteins, and normalizes chemotaxis. We also demonstrate that CXCR41013 spontaneously forms heterodimers with wild-type CXCR4. Accordingly, we propose a model where enhanced functional interactions between -arrestin2 and receptor dimers account for the altered responsiveness of WHIM leukocytes to CXCL12.
