title: Human herpesvirus 8-encoded chemokine vCCL2/vMIP-II is an agonist of the atypical chemokine receptor ACKR3/CXCR7.
abstract: The atypical chemokine receptor CXCR7/ACKR3 binds two endogenous chemokines, CXCL12 and CXCL11, and is upregulated in many cancers or following infection by several cancer-inducing viruses, including HHV-8. ACKR3 is a ligand-scavenging receptor and does not activate the canonical G protein pathways but was proposed to trigger β-arrestin-dependent signaling. Here, we identified the human herpesvirus 8-encoded CC chemokine vCCL2/vMIP-II as a third high-affinity ligand for ACKR3. vCCL2 acted as partial ACKR3 agonist, inducing β-arrestin recruitment to the receptor, subsequent reduction of its surface levels and its delivery to endosomes. In addition, ACKR3 reduced vCCL2-triggered MAP kinase and PI3K/Akt signaling through other chemokine receptors. Our data suggest that ACKR3 acts as a scavenger receptor for vCCL2, regulating its availability and activity toward human receptors, thereby likely controlling its function in HHV-8 infection. Our study provides new insights into the complex crosstalk between viral chemokines and host receptors as well as into the biology of ACKR3, this atypical and still enigmatic receptor.
authors.affiliation: Department of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: martyna.szpakowska@lih.lu.
authors.forename: Martyna
authors.initials: M
authors.lastname: Szpakowska
authors.affiliation: Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, GIGA B34, University of Liège, 11 Allée de l'Hôpital, B-4000 Liège, Belgium. Electronic address: ndupuis@ulg.ac.be.
authors.forename: Nadine
authors.initials: N
authors.lastname: Dupuis
authors.affiliation: Department of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: alessandra.baragli@lih.lu.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baragli
authors.affiliation: Department of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: manuel.counson@lih.lu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Counson
authors.affiliation: Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, GIGA B34, University of Liège, 11 Allée de l'Hôpital, B-4000 Liège, Belgium. Electronic address: j.hanson@ulg.ac.be.
authors.forename: Julien
authors.initials: J
authors.lastname: Hanson
authors.affiliation: Laboratory of Virology and Immunology, GIGA-Infammation, Infection & Immunity, GIGA B34, University of Liège, 11 Allée de l'Hôpital, B-4000 Liège, Belgium. Electronic address: jpiette@ulg.ac.be.
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.affiliation: Department of Infection and Immunity, Luxembourg Institute of Health, 29 rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: andy.chevigne@lih.lu.
authors.forename: Andy
authors.initials: A
authors.lastname: Chevigné
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D003412:Cricetulus; D011992:Endosomes / Q000378:metabolism; D005434:Flow Cytometry; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D020239:Receptor Cross-Talk; D054387:Receptors, CXCR / Q000819:agonists* / Q000235:genetics; D014162:Transfection; D000071560:beta-Arrestin 2 / Q000378:metabolism
chemical_list: C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; D018925:Chemokines; D008024:Ligands; D054387:Receptors, CXCR; D000071560:beta-Arrestin 2; C108059:vMIP-II
keywords: ACKR3; CXCR7; HHV-8; Kaposi’s sarcoma; vCCL2; vMIP-II