ACKR2 Membrane Protein Introduction

Introduction of ACKR2

ACKR2 gene encodes atypical chemokine receptor 2, which is predicted to be a seven transmembrane protein. This gene is mapped to chromosome 3p21.3, a region that includes a cluster of chemokine receptor genes. ACKR2 is the best-characterized member of the subfamily of chemokine receptors that are referred to as ACRs because of their inability to induce directional cell migration, in contrast to conventional chemokine receptors. ACKR2 is expressed in several different tissues, most prominently on lymphatic endothelial cells in lung and skin, and on syncytiotrophoblast cells in the placenta. This receptor appears to bind to most members of the family of beta-chemokines. However, its specific function is still unknown.

Function of ACKR2 Membrane Protein

As a chemokine decoy receptor, ACKR2 can bind and internalize chemokines without activating an intracellular response. ACKR2 binds most inflammatory CC-chemokines (CCL2, CCL5, CCL3, etc.) leading to their degradation, thereby reducing local levels of inflammatory chemokines, suggesting ACKR2 maybe a likely modulator of local inflammation. Upon active ligand stimulation, ACKR2 activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway. Activation of this pathway increases its efficiency in chemokine degradation and clearance from the extracellular space. ACKR2 is reported to play a nonredundant role in the protection against fetal loss caused by systemic inflammation and antiphospholipid antibodies by scavenging chemokines on the surfaces of lymphatic vessels and in the placenta. In addition, ACKR2 plays a negative role in the growth and metastasis of breast cancer, indicating its potential as a biomarker of this disease.

Fig.1 Model for pDC recruitment into inflamed epithelial sites. On their recruitment into lymphoid organs in a manner that involves CCR7 and CD62L, pDCs might be instructed through IL-3 released by local T cells to express CCR6 and CCR10. (Sisirak, 2011)

Application of ACKR2 Membrane Protein in Literature

1. Hansell C.A., et al. The atypical chemokine receptor ACKR2 suppresses Th17 responses to protein autoantigens. Immunology and Cell Biology. 2015, 93(2): 167-76. PubMed ID: 25348934
   
   

   This article finds that ACKR2 can regulate T-cell priming and GM-CSF-producing B cells during the induction of arthritic and neuropathic autoimmunity in mice, and its deletion leads to subtle changes in the development of the disease.

2. Teoh P.J., et al. Atypical chemokine receptor ACKR2 mediates chemokine scavenging by primary human trophoblasts and can regulate fetal growth, placental structure, and neonatal mortality in mice. Journal of Immunology. 2014,193(10): 5218-28. PubMed ID: 25297873
   
   

   This article suggests that primary human trophoblasts use ACKR2 to mediate efficient chemokine scavenging and that Ackr2 can play indispensable roles in regulating the placental structure, fetal weight, and neonatal mortality in mice. ACKR2 is a prominent player in the regulation of placental chemokine networks.

3. Zheng S., et al. Renal Protection by Genetic Deletion of the Atypical Chemokine Receptor ACKR2 in Diabetic OVE Mice. Journal of Diabetes Research. 2016, 2016: 5362506. PubMed ID: 26798651
   
   

   This article suggests that ACKR2 chemokine scavenger receptor has an unexpectedly important role in the development of diabetic kidney disease. Deletion of the ACKR2 gene in OVE diabetic mice produced a great reduction in albuminuria, accompanied by reduced severity of renal fibrosis, leucocyte infiltration, and inflammatory chemokine gene expression.

4. Hewit K.D., et al. The N-terminal region of the atypical chemokine receptor ACKR2 is a key determinant of ligand binding. Journal of Biological Chemistry. 2014, 289(18): 12330-42. PubMed ID: 24644289
   
   

   This article reveals that N-terminal tyrosine residues are essential for ligand internalization and scavenging and demonstrates the ability of a peptide derived from this region to bind inflammatory CC-chemokines.

5. Qi Z., et al. Identification and expression analysis of an atypical chemokine receptor-2 (ACKR2)/CC chemokine binding protein-2 (CCBP2) in rainbow trout (Oncorhynchus mykiss). Fish and Shellfish Immunology. 2015, 44(2): 389-98. PubMed ID: 25747793
   
   

   This article suggests that trout ACKR2 is regulated in a complex way and has an important role in the control of the chemokine network in fish as in mammals.

ACKR2 Preparation Options

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Reference

1. Sisirak V, et al. (2011). CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues. Blood. 118: 5130-5140.

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