ACKR3 gene

The ACKR3 gene (ACKR3 stands for: Atypical Chemokine Receptor 3) is a protein-coding gene. The ACKR3 gene encodes a member of the G protein-coupled receptor family. Although this protein was previously considered a receptor for vasoactive intestinal peptide (VIP), it is now considered an orphan receptor because its endogenous ligand has not been identified. The protein is also a co-receptor for human immunodeficiency viruses (HIV). Translocations involving this gene and HMGA2 on chromosome 12 have been observed in lipomas. An important paralog of this gene is CXCR2.

The ACKR3 gene encodes an atypical chemokine receptor that controls chemokine levels and localization via a high-affinity chemokine binding that is uncoupled from the classical ligand-dependent signal transduction cascades and instead leads to sequestration, degradation or transcytosis of chemokines. The receptor protein is also known as an interceptor (internalizing receptor) or chemokine scavenging receptor or chemokine decoy receptor. Acts as a receptor for the chemokines CXCL11 and CXCL12/SDF1 (Balabanian K et al. 2005; Ray P et al. 2012).

Binding of chemokines does not activate G protein-mediated signal transduction but instead induces recruitment of beta-arrestin, leading to internalization of the ligand and activation of the MAPK pathway (Hattermann K et al. 2010). Required for the regulation of CXCR4 protein levels in migrating interneurons, thereby adjusting their chemokine responsiveness. In glioma cells, it transmits signals via the MEK/ERK signaling pathway, mediating resistance to apoptosis. Promotes cell growth and survival. Not involved in cell migration, adhesion or proliferation of normal hematopoietic progenitor cells, but is activated by CXCL11 in malignant hematopoietic cells, leading to phosphorylation of ERK1/2 (MAPK3/MAPK1) and increased cell adhesion and migration. Plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12. Required for heart valve development. Regulates axon guidance in the oculomotor system by regulating CXCL12 levels (Whitman MC et al. 2019).

The receptor protein acts as a coreceptor with CXCR4 for a limited number of HIV isolates.

Mutations or alterations in this gene may be associated with various diseases, including immunological disorders.

Diseases associated with ACKR3 include:

• oculomotor abducens synkinesia

and

• XFE progeroid syndrome (XFE progeroid syndrome is a disorder characterized by an aged, bird-like face, lack of subcutaneous fat, short stature, cachexia and microcephaly. Other features include sun sensitivity from birth, learning difficulties, hearing loss and visual impairment. Mutations in the ACKR3 gene are one of the genetic factors associated with the disease. These mutations are thought to impair the function of the ACKR3 receptor, which contributes to the clinical manifestations of the syndrome. A total of 21 genes have been found to be associated with Xfe progeroid syndrome, one gene with high evidence - ERCC4 gene on chromosome 16p13 (elite gene associations) and 20 non-elite and text-based gene associations). This also includes the ACKR3 gene.

1. Balabanian K et al. (2005) The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem 280:35760-35766.
2. Hattermann K et al. (2010) The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res 70:3299-3308).
3. Ray P et al. (2012) Carboxy-terminus of CXCR7 regulates receptor localization and function. Int J Biochem Cell Biol 44:669-678.
4. Whitman MC et al. (2019) Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans. Hum Mol Genet 28:3113-3125.