title: Epithelial chemokine CXCL14 synergizes with CXCL12viaallosteric modulation of CXCR4.
abstract: The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100-300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e.,failed to trigger chemotaxis and Ca2+mobilization, as well as signalingviaERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.-Collins, P. J., McCully, M. L., Martínez-Muñoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12viaallosteric modulation of CXCR4.
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Collins
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: McCully
authors.affiliation: Department Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez-Muñoz
authors.affiliation: Department Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Santiago
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Wheeldon
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Stephan
authors.initials: S
authors.lastname: Caucheteux
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Thelen
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cecchinato
authors.affiliation: Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland.|Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Laufer
authors.affiliation: Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland.|Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Purvanov
authors.affiliation: Institute de Biologie Structurale, Unité Mixtes de Recherche 5075, University Grenoble Alpes, Centre National de la Recherche Scientifique, Commissariat à l'Énergie Atomique, Grenoble, France.
authors.forename: Yoan R
authors.initials: YR
authors.lastname: Monneau
authors.affiliation: Institute de Biologie Structurale, Unité Mixtes de Recherche 5075, University Grenoble Alpes, Centre National de la Recherche Scientifique, Commissariat à l'Énergie Atomique, Grenoble, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.affiliation: Biotechnology Institute Thurgau at the University of Konstanz, Kreuzlingen, Switzerland.|Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Legler
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.|Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Uguccioni
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Vincent
authors.initials: V
authors.lastname: Piguet
authors.affiliation: Department Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Mellado
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom; moserb@cardiff.ac.uk.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Moser
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D005786:Gene Expression Regulation / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D012333:RNA, Messenger; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C515255:CXCL12 protein, human; C118056:CXCL14 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D012333:RNA, Messenger; D019718:Receptors, CXCR4
keywords: CXCR4; allosteric receptor modulation; signal transduction; synergism