title: CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome.
abstract: WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is an immune deficiency linked in many cases to heterozygous mutations causing truncations in the cytoplasmic tail of CXC chemokine receptor 4 (CXCR4). Leukocytes expressing truncated CXCR4 display enhanced responses to the receptor ligand CXCL12, including chemotaxis, which likely impair their trafficking and contribute to the immunohematologic clinical manifestations of the syndrome. CXCR4 desensitization and endocytosis are dependent on beta-arrestin (betaarr) 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 betaarr2-dependent signaling downstream of the truncated CXCR4 receptor. Indeed, the WHIM-associated receptor CXCR4(1013) maintains association with betaarr2 and triggers augmented and prolonged betaarr2-dependent signaling, as revealed by ERK1/2 phosphorylation kinetics. Evidence is also provided that CXCR4(1013)-mediated chemotaxis critically requires betaarr2, and disrupting the SHSK motif in the third intracellular loop of CXCR4(1013) abrogates betaarr2-mediated signaling, but not coupling to G proteins, and normalizes chemotaxis. We also demonstrate that CXCR4(1013) spontaneously forms heterodimers with wild-type CXCR4. Accordingly, we propose a model where enhanced functional interactions between betaarr2 and receptor dimers account for the altered responsiveness of WHIM leukocytes to CXCL12.
authors.affiliation: Unité de Pathogénie Virale Moléculaire, Institut Pasteur, Paris, France. lagane@pasteur.fr
authors.forename: Bernard
authors.initials: B
authors.lastname: Lagane
authors.forename: Ken Y C
authors.initials: KY
authors.lastname: Chow
authors.forename: Karl
authors.initials: K
authors.lastname: Balabanian
authors.forename: Angélique
authors.initials: A
authors.lastname: Levoye
authors.forename: Julie
authors.initials: J
authors.lastname: Harriague
authors.forename: Thierry
authors.initials: T
authors.lastname: Planchenault
authors.forename: Françoise
authors.initials: F
authors.lastname: Baleux
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gunera-Saad
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020816:Amino Acid Motifs; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte; D019281:Dimerization; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007239:Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D009503:Neutropenia / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014860:Warts / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D000071557:beta-Arrestins