CXCR7 Functions as a Scavenger for CXCL12 and CXCL11

TLDR

CXCR7 is a second receptor for CXCL12 that, unlike typical chemokine receptors, does not couple to G‑proteins and its role—signaling versus decoy—remains controversial. The study aimed to determine whether CXCR7 functions as a signaling or decoy receptor in human tissues. Using cellular and zebrafish models, the authors demonstrated that CXCR7 acts as a specific scavenger for CXCL12 and CXCL11 by mediating ligand internalization and targeting the chemokines for degradation. CXCR7 continuously cycles between the plasma membrane and intracellular compartments, internalizes CXCL12 and CXCL11 without saturation, and actively degrades these chemokines in mouse heart valves and human endothelial cells, thereby modulating CXCR4 activity and potentially regulating hematopoietic cell mobility.

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.