The dimeric form of CXCL12 binds to atypical chemokine receptor 1

Abstract

The pleiotropic chemokine CXCL12 is involved in diverse physiological and pathophysiological processes, including embryogenesis, hematopoiesis, leukocyte migration, and tumor metastasis. It is known to engage the classical receptor CXCR4 and the atypical receptor ACKR3. Differential receptor engagement can transduce distinct cellular signals and effects as well as alter the amount of free, extracellular chemokine. CXCR4 binds both monomeric and the more commonly found dimeric forms of CXCL12, whereas ACKR3 binds monomeric forms. Here, we found that CXCL12 also bound to the atypical receptor ACKR1 (previously known as Duffy antigen/receptor for chemokines or DARC). In vitro nuclear magnetic resonance spectroscopy and isothermal titration calorimetry revealed that dimeric CXCL12 bound to the extracellular N terminus of ACKR1 with low nanomolar affinity, whereas the binding affinity of monomeric CXCL12 was orders of magnitude lower. In transfected MDCK cells and primary human Duffy-positive erythrocytes, a dimeric, but not a monomeric, construct of CXCL12 efficiently bound to and internalized with ACKR1. This interaction between CXCL12 and ACKR1 provides another layer of regulation of the multiple biological functions of CXCL12. The findings also raise the possibility that ACKR1 can bind other dimeric chemokines, thus potentially further expanding the role of ACKR1 in chemokine retention and presentation.

Identification of Metabolism-Related Gene-Based Subgroup in Prostate Cancer

“…17βHSD2 decreased potent androgen production by converting testosterone or dihydrotestosterone to each of their upstream precursors ( 40 ), which might provide new strategies for clinical management. On the other hand, chemokine signaling regulates tumor metastasis ( 41 ). CXCL12, a member of the chemokine family, and its receptor, CXCR4, are key mediators of PCa bone metastasis ( 42 ).…”

Atypical CXCL12 signaling enhances neutrophil migration by modulating nuclear deformability

“…CXCL12 was initially described to bind to the receptor CXCR4; however, CXCL12 also binds to the atypical chemokine receptor 3 (ACKR3) (also known as CXCR7) ( 18 ). Dimeric CXCL12 also binds to ACKR1 in Madin-Darby canine kidney cells and erythrocytes ( 19 ). CXCL12 is constitutively expressed by many endothelial cell types and promotes the arrest and TEM of leukocytes under physiological shear flow by binding to CXCR4.…”

DPP4-Truncated CXCL12 Alters CXCR4/ACKR3 Signaling, Osteogenic Cell Differentiation, Migration, and Senescence

“…44 Although it was previously reported that CXCL12 is not a ligand for ACKR1, 45 a new study shows that ACKR1 binds preferentially to the dimeric form of CXCL12. 46 Understanding the extent to which CXCR4, ACKR3, and ACKR1 mediate the biological effects exerted by CXCL12(3−68) and its dimeric isoform will be the focus of future studies.…”

“…For example, the atypical chemokine receptor 1 (ACKR1) was not included in the PRESTO-Tango screen, and this receptor was recently found to be expressed at high levels in the nucleated erythroid cells that make up the red pulp of the bone marrow . Although it was previously reported that CXCL12 is not a ligand for ACKR1, a new study shows that ACKR1 binds preferentially to the dimeric form of CXCL12 . Understanding the extent to which CXCR4, ACKR3, and ACKR1 mediate the biological effects exerted by CXCL12(3–68) and its dimeric isoform will be the focus of future studies.…”