Rapid Uptake and Degradation of CXCL12 Depend on CXCR7 Carboxyl-terminal Serine/Threonine Residues

Hoffmann, Frauke; Müller, Wiebke; Schütz, Dagmar; Penfold, Mark E.T.; Wong, Yung Hou; Schulz, Stefan; Stumm, Ralf

doi:10.1074/jbc.m111.335679

Cited by 85 publications

(99 citation statements)

References 43 publications

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“…The inability of ACKRs to raise G protein-dependent responses has been hypothesized to be caused by variation in the ACKR3 intracellular DRY motif (34). However, insertion of the corresponding region from CXCR4 into ACKR3 did not restore G protein signaling (4,35). It may be speculated that differences in the CRS2-CXCL12 interaction between CXCR4 and ACKR3 also contribute to the absence of G protein signaling in ACKR3.…”

Section: Discussionmentioning

confidence: 99%

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Mutational Analysis of Atypical Chemokine Receptor 3 (ACKR3/CXCR7) Interaction with Its Chemokine Ligands CXCL11 and CXCL12

Benredjem

Girard

Rhainds

et al. 2017

Journal of Biological Chemistry

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Edited by Henrik G. DohlmanAtypical chemokine receptors do not mediate chemotaxis or G protein signaling, but they recruit arrestin. They also efficiently scavenge their chemokine ligands, thereby contributing to gradient maintenance and termination. ACKR3, also known as CXCR7, binds and degrades the constitutive chemokine CXCL12, which also binds the canonical receptor CXCR4, and CXCL11, which also binds CXCR3. Here we report comprehensive mutational analysis of the ACKR3 interaction with its chemokine ligands, using 30 substitution mutants. Atypical chemokine receptors (ACKRs)4 are chemokine receptors that do not activate G protein-dependent signaling cascades upon agonist binding; they also do not mediate chemotaxis (1). Rather, chemokine binding to ACKRs leads to rapid chemokine internalization and degradation. Therefore, ACKRs act as chemokine scavengers and play a role in chemokine gradient reshaping, maintenance, and resolution.ACKR3, also known as CXCR7, is an atypical chemokine receptor for the constitutive chemokine CXCL12 (SDF-1), which also binds CXCR4 as a cognate canonical chemokine receptor (2). The second ACKR3 ligand is the highly regulated inflammatory chemokine CXCL11 (I-TAC), which also binds the canonical receptor CXCR3. Being unable to raise G protein responses in most cell types, agonist binding to ACKR3 nevertheless induces arrestin recruitment as a signaling response (3) and rapid degradation of both CXCL12 and CXCL11 (4). ACKR3 has been identified as a potentially promising drug target (2). Given the highly divergent role and regulation of its two ligands, selective interference with their ACKR3 interaction and scavenging may be of interest, warranting better understanding of ligand engagement and scavenging.The structures of chemokine receptors are beginning to be unraveled by crystallography, and the results are in line with those reported earlier from receptor mutagenesis-based approaches (5-7). The reported chemokine receptor crystals required co-crystallization in complex with receptor antagonists. CXCR4 was the first receptor crystallized in complex with an antagonistic chemokine ligand, the virally encoded vMIP-II, which has also permitted refined modeling of the putative CXCR4-CXCL12 complex (8). Overall, these structures refine an early two-step binding model that provides a conceptual framework for the interactions of chemokines with canonical chemokine receptors (for a recent critical review of this model see Kleist et al.; Ref. 9). Following this model, initial chemokine interaction with the receptor critically depends on the receptor N terminus, and some extracellular loop residues. This is then followed by secondary interaction mainly involving the chemokine N terminus with receptor binding pocket residues; this second interaction is required for receptor activation. Of note, for CXCR4 the two-step interaction model is supported by 4 The abbreviations used are: ACKR, atypical chemokine receptor; BRET, bioluminescence resonance energy transfer; CRS1, chemokine recognition...

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Section: Discussionmentioning

confidence: 99%

“…Chemokine Scavenging-To determine receptor-mediated chemokine degradation, we essentially followed a protocol described in Hoffmann et al (35). Cells were transfected in 6-well plates with 1 g of coding plasmid.…”

Section: Methodsmentioning

confidence: 99%

Mutational Analysis of Atypical Chemokine Receptor 3 (ACKR3/CXCR7) Interaction with Its Chemokine Ligands CXCL11 and CXCL12

Benredjem

Girard

Rhainds

et al. 2017

Journal of Biological Chemistry

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“…Human embryonic kidney (HEK293) cells were transiently transfected as described (Hoffmann et al, 2012). Surface CXCR4 and CXCR7 receptors were immunostained in fixed non-permeabilized cells with N-terminal antibodies 2B11 (BD Biosciences) and 11G8 (Zabel et al, 2009), respectively.…”

Section: Cxcl12-565 Uptakementioning

confidence: 99%

“…The latter is also referred to as atypical chemokine receptor 3 (ACKR3) because it does not signal through G proteins and elicits no chemotaxis (Thelen and Thelen, 2008). Instead, CXCR7 sequesters CXCL12 from the extracellular environment and, thus, functions as a CXCL12 scavenger (Venkiteswaran et al, 2013;Boldajipour et al, 2008;Luker et al, 2010;Naumann et al, 2010;Hoffmann et al, 2012). Like other heptahelical receptors, including CXCR4, CXCR7 is also capable of modulating downstream pathways through β-arrestin (Cheng et al, 2000;Kalatskaya et al, 2009;Rajagopal et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

CXCR7 prevents excessive CXCL12-mediated downregulation of CXCR4 in migrating cortical interneurons

et al. 2014

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The CXCL12/CXCR4 signaling pathway is involved in the development of numerous neuronal and non-neuronal structures. Recent work established that the atypical second CXCL12 receptor, CXCR7, is essential for the proper migration of interneuron precursors in the developing cerebral cortex. Two CXCR7-mediated functions were proposed in this process: direct modulation of β-arrestin-mediated signaling cascades and CXCL12 scavenging to regulate local chemokine availability and ensure responsiveness of the CXCL12/ CXCR4 pathway in interneurons. Neither of these functions has been proven in the embryonic brain. Here, we demonstrate that migrating interneurons efficiently sequester CXCL12 through CXCR7. CXCR7 ablation causes excessive phosphorylation and downregulation of CXCR4 throughout the cortex in mice expressing CXCL12, but not in CXCL12-deficient animals. Cxcl12 −/− mice lack activated CXCR4 in embryonic brain lysates and display a similar interneuron positioning defect as Cxcr4−/− and Cxcl12 −/−;Cxcr7 −/− animals. Thus, CXCL12 is the only CXCR4-activating ligand in the embryonic brain and deletion of one of the CXCL12 receptors is sufficient to generate a migration phenotype that corresponds to the CXCL12-deficient pathway. Our findings imply that interfering with the CXCL12-scavenging activity of CXCR7 causes loss of CXCR4 function as a consequence of excessive CXCL12-mediated CXCR4 activation and degradation.

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“…Several observations support a role for CXCR7 in chemokine clearance. For example, CXCR7 does not associate with heterotrimeric G proteins, and ligand binding does not evoke calcium influx (Burns et al, 2006;Hoffmann et al, 2012). In addition, CXCR7 binds CXCL12 with a ten times higher affinity than CXCR4, and the receptor is rapidly recycled back to the plasma membrane upon ligand-induced internalization (Burns et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Chemokine signaling in development and disease

2014

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Chemokines are a group of small, secreted molecules that signal through G protein-coupled receptors to promote cell survival and proliferation and to provide directional guidance to migrating cells. CXCL12 is one of the most evolutionary conserved chemokines and signals through the chemokine receptor CXCR4 to guide cell migration during embryogenesis, immune cell trafficking and cancer metastasis. Here and in the accompanying poster, we provide an overview of chemokine signaling, focusing on CXCL12, and we highlight some of the different chemokine-dependent strategies used to guide migrating cells.

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Rapid Uptake and Degradation of CXCL12 Depend on CXCR7 Carboxyl-terminal Serine/Threonine Residues

Cited by 85 publications

References 43 publications

Mutational Analysis of Atypical Chemokine Receptor 3 (ACKR3/CXCR7) Interaction with Its Chemokine Ligands CXCL11 and CXCL12

Mutational Analysis of Atypical Chemokine Receptor 3 (ACKR3/CXCR7) Interaction with Its Chemokine Ligands CXCL11 and CXCL12

CXCR7 prevents excessive CXCL12-mediated downregulation of CXCR4 in migrating cortical interneurons

Chemokine signaling in development and disease

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