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 ACKR3gene.[5][6]
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.[7] 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.[6]
Another study has provided evidence that ligand binding to CXCR7 activates MAP kinases through Beta-arrestins, and thus has functions beyond ligand sequestration.[8]
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.[10]
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.[11]
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.[12][13]
ACKR3 and CXCR4 have been shown to interact, different possibilities regarding the involvement of ACKR3 and CXCR4 in CXCL12 signaling:[12]
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.
^Bachelerie F, Graham GJ, Locati M, Mantovani A, Murphy PM, Nibbs R, et al. (March 2014). "New nomenclature for atypical chemokine receptors". Nature Immunology. 15 (3): 207–208. doi:10.1038/ni.2812. PMID24549061. S2CID205367583.
Nagata S, Ishihara T, Robberecht P, Libert F, Parmentier M, Christophe J, Vassart G (March 1992). "RDC1 may not be VIP receptor". Trends in Pharmacological Sciences. 13 (3): 102–103. doi:10.1016/0165-6147(92)90037-7. PMID1315461.
Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (September 1991). "Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor". Genomics. 11 (1): 225–227. doi:10.1016/0888-7543(91)90125-X. PMID1662665.
Law NM, Rosenzweig SA (May 1994). "Characterization of the G-protein linked orphan receptor GPRN1/RDC1". Biochemical and Biophysical Research Communications. 201 (1): 458–465. doi:10.1006/bbrc.1994.1723. PMID8198609.
Broberg K, Zhang M, Strömbeck B, Isaksson M, Nilsson M, Mertens F, et al. (August 2002). "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. doi:10.3892/ijo.21.2.321. PMID12118328.
