ACKR3 explained

Atypical chemokine receptor 3 also known as C-X-C chemokine receptor type 7 (CXCR-7) and G-protein coupled receptor 159 (GPR159) is a protein that in humans is encoded by the ACKR3 gene.^{[1] [2]}

This gene encodes a G protein-coupled receptor family member. It belongs to the chemokine receptor family of GPCRs. Within this family, ACKR3 is classified as a class A GPCR.^[3] This GPCR protein was earlier thought to be a receptor for vasoactive intestinal peptide (VIP) and was considered to be an orphan receptor. It is now classified as a chemokine receptor able to bind the chemokines CXCL12/SDF-1 and CXCL11. The protein is also a coreceptor for human immunodeficiency viruses (HIV). Translocations involving this gene and HMGA2 on chromosome 12 have been observed in lipomas. Alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. Whereas some reports claim that the receptor induces signaling following ligand binding, recent findings in zebrafish suggest that CXCR7 functions primarily by sequestering the chemokine CXCL12.^[2]

Another study has provided evidence that ligand binding to CXCR7 activates MAP kinases through Beta-arrestins, and thus has functions beyond ligand sequestration.^[4]

ACKR3 has also been shown to sequester endogenous opioid peptides and is thought to modulate their activity.

Nomenclature

In 2013, the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology subcommittee for chemokine receptors reevaluated C-X-C chemokine receptor type 7 (CXCR7) and classified it as an atypical chemokine receptor, leading to its renaming as atypical chemokine receptor 3 (ACKR3). Additional names that have been mentioned in the literature, albeit less frequently, include GPR159 and Orphan receptor RDC1, the latter being a term primarily found in older literature.^[5]

Function

ACKR3 stands out as an atypical receptor due to its β-arrestin-biased signaling nature. In the case of a β-arrestin-biased receptor like ACKR3, when it is treated with an unbiased ligand, it triggers signaling pathways solely mediated by β-arrestin. What sets ACKR3 apart is its absence of G-protein involvement, which distinguishes it from typical GPCRs.^[6]

Despite being considered atypical, the functions of ACKR3 do not imply that it acts as a completely inactive receptor for CXCL12. On the contrary, extensive literature supports the notion of ACKR3 engaging in active signaling, which is believed to rely on arrestin-mediated mechanisms. Nevertheless, its role as a decoy receptor for CXCL12/SDF1 is well-established. This is evident by the significantly higher affinity of CXCL12 binding to ACKR3/CXCR7 compared to CXCR4, along with its constant internalization facilitated by the recruitment of β-arrestin, without known downstream signaling events.^{[7] [8]}

Ligands

In addition to CXCL12, ACKR3 engages with multiple ligands, encompassing CXCL11, macrophage inhibitory factor (MIF), adrenomedullin (ADM), opioid peptides such as nociceptin, dynorphin, and enkephalin, as well as the viral chemokine vCCL2/viral macrophage inflammatory protein-II. ^[9]

Inhibition of ACKR3 by ligands such as the peptide LIH383 (FGGFMRRK-NH₂) and the small molecules conolidine, RTI-5152-12, and VUF15485 increases opioid peptide activity and produces analgesic and antidepressant effects in animal studies.^{[10] [11] [12]}

Interactions

ACKR3 and CXCR4 have been shown to interact, different possibilities regarding the involvement of ACKR3 and CXCR4 in CXCL12 signaling:

A) ACKR3 can attenuate CXCR4 signaling by forming heterodimers with CXCR4. While this interaction was initially observed in cells with CXCR7 overexpression, it has rarely been observed with endogenous CXCR7.

B) Multiple cell types demonstrate that either ACKR3 or CXCR4 controls specific cell functions (e.g., migration, proliferation). The distinct regulation of these functions occurs through one of the receptors.

C) Synergistic effects between CXCR4 and ACKR3 have been observed in many cases, suggesting that cellular responses to CXCL12 require the presence of both receptors. Whether receptor heterodimerization is responsible for these synergistic effects remains uncertain.

D) In addition to synergistic effects, a few studies have shown additive effects of ACKR3 and CXCR4 on specific cell functions. However, it has not been experimentally tested whether receptor heterodimerization is necessary for these additive effects.E) Within specific cell types, CXCR4, ACKR3, and CXCR4/ACKR3 heterodimers control distinct cell functions. This pattern appears to be a common arrangement of the CXCL12 system in various types of stem and progenitor cells.

Further reading

• Nagata S, Ishihara T, Robberecht P, Libert F, Parmentier M, Christophe J, Vassart G . RDC1 may not be VIP receptor . Trends in Pharmacological Sciences . 13 . 3 . 102–103 . March 1992 . 1315461 . 10.1016/0165-6147(92)90037-7 .
• Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG . Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor . Genomics . 11 . 1 . 225–227 . September 1991 . 1662665 . 10.1016/0888-7543(91)90125-X .
• Sreedharan SP, Robichon A, Peterson KE, Goetzl EJ . Cloning and expression of the human vasoactive intestinal peptide receptor . Proceedings of the National Academy of Sciences of the United States of America . 88 . 11 . 4986–4990 . June 1991 . 1675791 . 51792 . 10.1073/pnas.88.11.4986 . free . 1991PNAS...88.4986S .
• Law NM, Rosenzweig SA . Characterization of the G-protein linked orphan receptor GPRN1/RDC1 . Biochemical and Biophysical Research Communications . 201 . 1 . 458–465 . May 1994 . 8198609 . 10.1006/bbrc.1994.1723 .
• Shimizu N, Soda Y, Kanbe K, Liu HY, Mukai R, Kitamura T, Hoshino H . A putative G protein-coupled receptor, RDC1, is a novel coreceptor for human and simian immunodeficiency viruses . Journal of Virology . 74 . 2 . 619–626 . January 2000 . 10623723 . 111581 . 10.1128/JVI.74.2.619-626.2000 .
• Broberg K, Zhang M, Strömbeck B, Isaksson M, Nilsson M, Mertens F, Mandahl N, Panagopoulos I . 6 . Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15 . International Journal of Oncology . 21 . 2 . 321–326 . August 2002 . 12118328 . 10.3892/ijo.21.2.321 .
• Infantino S, Moepps B, Thelen M . Expression and regulation of the orphan receptor RDC1 and its putative ligand in human dendritic and B cells . Journal of Immunology . 176 . 4 . 2197–2207 . February 2006 . 16455976 . 10.4049/jimmunol.176.4.2197 . free .
• Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, Penfold ME, Sunshine MJ, Littman DR, Kuo CJ, Wei K, McMaster BE, Wright K, Howard MC, Schall TJ . 6 . A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development . The Journal of Experimental Medicine . 203 . 9 . 2201–2213 . September 2006 . 16940167 . 2118398 . 10.1084/jem.20052144 .
• Proost P, Mortier A, Loos T, Vandercappellen J, Gouwy M, Ronsse I, Schutyser E, Put W, Parmentier M, Struyf S, Van Damme J . 6 . Proteolytic processing of CXCL11 by CD13/aminopeptidase N impairs CXCR3 and CXCR7 binding and signaling and reduces lymphocyte and endothelial cell migration . Blood . 110 . 1 . 37–44 . July 2007 . 17363734 . 10.1182/blood-2006-10-049072 . free .
• Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, Kleer CG, Essner JJ, Nasevicius A, Luker GD, Howard MC, Schall TJ . 6 . CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature . Proceedings of the National Academy of Sciences of the United States of America . 104 . 40 . 15735–15740 . October 2007 . 17898181 . 1994579 . 10.1073/pnas.0610444104 . free . 2007PNAS..10415735M .
• Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S, Wilson D, Xu Q, Raz E . 6 . Control of chemokine-guided cell migration by ligand sequestration . Cell . 132 . 3 . 463–473 . February 2008 . 18267076 . 10.1016/j.cell.2007.12.034 . free . 11858/00-001M-0000-0012-DDE5-7 . free .
• Takaya K, Asou T, Kishi K . Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3 . International Journal of Molecular Sciences . 23 . 12 . 6531 . June 2022 . 35742971 . 9223754 . 10.3390/ijms23126531 . free .

Notes and References

1. Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F . 6 . The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes . The Journal of Biological Chemistry . 280 . 42 . 35760–35766 . October 2005 . 16107333 . 10.1074/jbc.M508234200 . free .
2. Web site: Entrez Gene: CXCR7 chemokine (C-X-C motif) receptor 7.
3. Fumagalli A, Zarca A, Neves M, Caspar B, Hill SJ, Mayor F, Smit MJ, Marin P . 6 . CXCR4/ACKR3 Phosphorylation and Recruitment of Interacting Proteins: Key Mechanisms Regulating Their Functional Status . Molecular Pharmacology . 96 . 6 . 794–808 . December 2019 . 30837297 . 10.1124/mol.118.115360 . 73513931 . free . 10261/214032 . free .
4. • Rajagopal S, Kim J, Ahn S, Craig S, Lam CM, Gerard NP, Gerard C, Lefkowitz RJ . 6 . Beta-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7 . Proceedings of the National Academy of Sciences of the United States of America . 107 . 2 . 628–632 . January 2010 . 20018651 . 2818968 . 10.1073/pnas.0912852107 . free . 2010PNAS..107..628R .
5. Bachelerie F, Graham GJ, Locati M, Mantovani A, Murphy PM, Nibbs R, Rot A, Sozzani S, Thelen M . 6 . New nomenclature for atypical chemokine receptors . Nature Immunology . 15 . 3 . 207–208 . March 2014 . 24549061 . 10.1038/ni.2812 . 205367583 .
6. Rajagopal S, Kim J, Ahn S, Craig S, Lam CM, Gerard NP, Gerard C, Lefkowitz RJ . 6 . Beta-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7 . Proceedings of the National Academy of Sciences of the United States of America . 107 . 2 . 628–632 . January 2010 . 20018651 . 2818968 . 10.1073/pnas.0912852107 . 2010PNAS..107..628R . free .
7. Koch C, Engele J . Functions of the CXCL12 Receptor ACKR3/CXCR7-What Has Been Perceived and What Has Been Overlooked . Molecular Pharmacology . 98 . 5 . 577–585 . November 2020 . 32883765 . 10.1124/molpharm.120.000056 . 221498026 . free .
8. Pance K, Gramespacher JA, Byrnes JR, Salangsang F, Serrano JC, Cotton AD, Steri V, Wells JA . 6 . Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins . Nature Biotechnology . 41 . 2 . 273–281 . February 2023 . 36138170 . 10.1038/s41587-022-01456-2 . 9931583 .
9. Meyrath M, Szpakowska M, Zeiner J, Massotte L, Merz MP, Benkel T, Simon K, Ohnmacht J, Turner JD, Krüger R, Seutin V, Ollert M, Kostenis E, Chevigné A . 6 . The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides . Nature Communications . 11 . 1 . 3033 . June 2020 . 32561830 . 10.1038/s41467-020-16664-0 . 7305236 . 2020NatCo..11.3033M .
10. Meyrath M, Szpakowska M, Zeiner J, Massotte L, Merz MP, Benkel T, Simon K, Ohnmacht J, Turner JD, Krüger R, Seutin V, Ollert M, Kostenis E, Chevigné A . 6 . The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides . Nature Communications . 11 . 1 . 3033 . June 2020 . 32561830 . 7305236 . 10.1038/s41467-020-16664-0 . free . 2020NatCo..11.3033M .
11. Szpakowska M, Decker AM, Meyrath M, Palmer CB, Blough BE, Namjoshi OA, Chevigné A . The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7 . Signal Transduct Target Ther . 6 . 1 . 209 . June 2021 . 34075018 . 8169647 . 10.1038/s41392-021-00548-w .
12. Zarca AM, Adlere I, Viciano CP, Arimont-Segura M, Meyrath M, Simon IA, Bebelman JP, Laan D, Custers HG, Janssen E, Versteegh KL, Buzink MC, Nesheva DN, Bosma R, de Esch IJ, Vischer HF, Wijtmans M, Szpakowska M, Chevigné A, Hoffmann C, de Graaf C, Zarzycka BA, Windhorst AD, Smit MJ, Leurs R . Pharmacological Characterization and Radiolabeling of VUF15485, a High-Affinity Small-Molecule Agonist for the Atypical Chemokine Receptor ACKR3 . Mol Pharmacol . 105 . 4 . 301–312 . March 2024 . 38346795 . 10.1124/molpharm.123.000835 .