ACKR4 Membrane Protein Introduction

Introduction of ACKR4

Atypical chemokine receptor 4 (ACKR4) is a protein that in humans is encoded by the CCRL1 gene. The protein is a member of the G protein-coupled receptor family, and is a receptor for C-C type chemokines. It has been reported to function with dendritic cell- and T cell-activated chemokines including CCL19/ELC, CCL21/SLC, and CCL25/TECK. Alternatively, spliced transcript variants encoding the same protein have been found.

Function of ACKR4 Membrane Protein

ACKR4 controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades. It is also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. ACKR4 can act as a receptor for chemokines CCL2, CCL8, CCL13, CCL19, CCL21 and CCL25. Chemokine-binding cannot activate G-protein-mediated signal transduction. However, it will induce beta-arrestin recruitment, which will lead to ligand internalization. This protein plays an important role in controlling the migration of immune and cancer cells that express chemokine receptors CCR7 and CCR9, by reducing the availability of CCL19, CCL21, and CCL25 through internalization. It also limits CXCR3-induced chemotaxis and regulates T-cell development in the thymus.

Fig.1 Models for immune and inflammatory functions of ACKRs in vivo. (Nibbs, 2013)

Application of ACKR4 Membrane Protein in Literature

1. Lucas B., et al. CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice. Eur J Immunol. 2015, 45(2): 574-83. PubMed ID: 25521433
   
   

   The authors show that CCRL1 is expressed within the thymic cortex, predominantly by MHC-II(low) CD40(-) cortical thymic epithelial cells and at the subcapsular zone by a population of podoplanin(+) thymic epithelial cells in mice. They also find that CCRL1 suppresses thymocyte progenitor entry into the thymus.

2. Bryce S.A., et al. ACKR4 on Stromal Cells Scavenges CCL19 To Enable CCR7-Dependent Trafficking of APCs from Inflamed Skin to Lymph Nodes. J Immunol. 2016, 196(8): 3341-53. PubMed ID: 26976955
   
   

   This article demonstrates that ACKR4 on stromal cells can aid the egress of APCs from mouse skin, and, during inflammation, it facilitates CCR7-dependent cell trafficking by scavenging CCL19.

3. Parsi B., et al. Transient expression of recombinant ACKR4 (CCRL1) gene, an atypical chemokine receptor in human embryonic kidney (HEK 293) cells. Mol Biol Rep. 2016, 43(7): 583-9. PubMed ID: 27168154
   
   

   In this article, the authors find ACKR4 may represent a novel molecular target in cancer therapy, which might provide a chance for a new therapeutic strategy. This can help to understand the molecular mechanisms of ACKR4 action in the generation of ACKR4-HEK293T recombinant cells.

4. Jafarnejad M., et al. A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4. J Immunol. 2017, 199(7): 2291-2304. PubMed ID: 28807994
   
   

   This article shows that magnitude is sensitive to these key parameters: chemokine production, diffusivity, matrix binding site availability, and CCR7 abundance. It also predicts that ACKR4 in LNs prevents CCL19/CCL21 accumulation in efferent lymph. Instead, it attributes the disrupted interfollicular CCL21 gradients observed in Ackr4-deficient LNs to ACKR4 loss upstream.

5. Thomson C.A., et al. Expression of the Atypical Chemokine Receptor ACKR4 Identifies a Novel Population of Intestinal Submucosal Fibroblasts That Preferentially Expresses Endothelial Cell Regulators. J Immunol. 2018, 201(1): 215-229. PubMed ID: 29760193
   
   

   The article shows that intestinal submucosal fibroblasts in mice are a distinct population of intestinal mesenchymal cells that can be identified by their expression of Ackr4 and have transcriptional and anatomical properties that strongly suggest roles in endothelial cell regulation.

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Reference

1. Nibbs R J and Graham G J., (2013). Immune regulation by atypical chemokine receptors. Nat Rev Immunol. 13(11): 815-29.

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