CXCR7 Functions as a Scavenger for CXCL12 and CXCL11 Ulrike Naumann1, Elisabetta Cameroni1, Monika Pruenster2, Harsha Mahabaleshwar3, Erez Raz3, Hans- Gu¨ nter Zerwes4, Antal Rot5, Marcus Thelen1* 1 Institute for Research in Biomedicine, Bellinzona, Switzerland, 2 Walter-Brendel-Center for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany, 3 Institute of Cell Biology, University of Mu¨ nster, Mu¨ nster, Germany, 4 Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland, 5 Medical Research Council, Center for Immune Regulation, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom Abstract Background: CXCR7 (RDC1), the recently discovered second receptor for CXCL12, is phylogenetically closely related to chemokine receptors, but fails to couple to G-proteins and to induce typical chemokine receptor mediated cellular responses. The function of CXCR7 is controversial. Some studies suggest a signaling activity in mammalian cells and zebrafish embryos, while others indicate a decoy activity in fish. Here we investigated the two propositions in human tissues. Methodology/Principal Findings: We provide evidence and mechanistic insight that CXCR7 acts as specific scavenger for CXCL12 and CXCL11 mediating effective ligand internalization and targeting of the chemokine cargo for degradation. Consistently, CXCR7 continuously cycles between the plasma membrane and intracellular compartments in the absence and presence of ligand, both in mammalian cells and in zebrafish. In accordance with the proposed activity as a scavenger receptor CXCR7-dependent chemokine degradation does not become saturated with increasing ligand concentrations. Active CXCL12 sequestration by CXCR7 is demonstrated in adult mouse heart valves and human umbilical vein endothelium. Conclusions/Significance: The finding that CXCR7 specifically scavenges CXCL12 suggests a critical function of the receptor in modulating the activity of the ubiquitously expressed CXCR4 in development and tumor formation. Scavenger activity of CXCR7 might also be important for the fine tuning of the mobility of hematopoietic cells in the bone marrow and lymphoid organs. Citation: Naumann U, Cameroni E, Pruenster M, Mahabaleshwar H, Raz E, et al. (2010) CXCR7 Functions as a Scavenger for CXCL12 and CXCL11. PLoS ONE 5(2): e9175. doi:10.1371/journal.pone.0009175 Editor: Graham Pockley, University of Sheffield, United Kingdom Received November 10, 2009; Accepted January 25, 2010; Published February 11, 2010 Copyright: 2010 Naumann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Helmut Horten Foundation, the Swiss National Science Foundation (M.T.), and the European Community Framework Program 6-Network of Excellence Grant LSHG-CT-2003-502935. E.C. was supported by the Novartis Foundation and the Roche Research Foundation, and the Fondazione Ticinese per la Ricerca sul Cancro. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: marcus.thelen@irb.unisi.ch Introduction The chemokine system is indispensable for leukocyte trafficking. Chemokines attract immune cells via their cognate G-protein coupled receptors (GPCRs) to sites of inflammation and mediate homing to lymphoid organs [1]. Among the various constituents of the chemokine system CXCL12 (SDF-1) and its receptor CXCR4 possess exceptional properties as they control processes outside of the hematopoietic system. Genetic deletion of either molecule leads to a similar phenotype in mouse embryos [2–4] that is characterized by defective lymphopoiesis and myelopoiesis, imperfect vasculature, abnormal brain and heart development leading to perinatal death. These findings led to the assumption that CXCR4 and CXCL12 represent a monogamous receptor- chemokine pair. Recently RDC1 (CXCR7) was described as second receptor for CXCL12 [5]. CXCR7, a heptahelical receptor with strong phylogenetic similarity to GPCRs [6], was shown to bind CXCL12 and CXCL11 with high affinity, but fails to induce typical chemokine responses, such as cell migration and associated intracellular signal transduction [7,8]. Nonetheless, mice lacking CXCR7 die perinatally due to heart valve malformation, a phenotype that is recapitulated in mice conditionally deficient for CXCR7 in the endothelium [9]. In humans, CXCR7 is expressed in embryonic neuronal and heart tissue, in hematopoietic cells and activated endothelium [7,8,10]. Elevated levels of CXCR7 correlate with the aggressiveness of human prostate cancer and promote growth and metastasis of various mouse tumor models [11–13]. Some studies suggest active signaling through the receptor [13,14] or modulation of CXCR4-signaling through heterodimerization with CXCR7 [9,15]. However, the biochem- ical mechanisms behind these effects are not well understood. Additional evidence for a critical role of CXCR7 in embryo- genesis arose from investigations on zebrafish development. The receptor is required for efficient migration of different cells such as the posterior lateral line primordium [16,17], motoneurons in the hindbrain [18] and the primordial germ cells [19]. Interestingly, the zebrafish genome contains two genes coding for CXCR7a and b and also two genes coding for CXCL12a and CXCL12b. However, expression patterns and functional studies suggest that PLoS ONE | www.plosone.org 1 February 2010 | Volume 5 | Issue 2 | e9175