XCR1

Official Full Name

X-C motif chemokine receptor 1

Organism

Homo sapiens

GeneID

2829

Background

The protein encoded by this gene is a chemokine receptor belonging to the G protein-coupled receptor superfamily. The family members are characterized by the presence of 7 transmembrane domains. The encoded protein transduces a signal by increasing the intracellular calcium ion level. The viral macrophage inflammatory protein-II is an antagonist of this receptor and blocks signaling. Some studies have implicated a cluster of genes at 3p21.31, including this gene, as associated with COVID-19 risk. The encoded protein may also play a role in cell proliferation and migration in several types of cancer. [provided by RefSeq, Jan 2023]

Synonyms

GPR5; CCXCR1;

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Detailed Information

Chemokines are a large family of structurally related polypeptides that, together with their receptors, control directional cell migration during immune surveillance, development, inflammation, angiogenesis, as well as tumor growth and metastasis. The chemokine XCL1 (also known as lymphotactin, ATAC, SCM-1) is the only member of the C chemokine subfamily in the house mouse. In human, there are two homologues, XCL1 and XCL2, with only two amino acid differences from each other. Mouse XCL1 and Human XCL1s share the 60% amino acid identity. Similar to other chemokine receptors, XCR1 is a typical seven-transmembrane protein and can couple efficiently to G-proteins. Early studies showed that XCR1 mRNA was detected in many organs and cell types. In mouse, XCR1 mRNA was detectable in spleen and lung as well as in B cells, CD8⁺ cells, NK1.1⁺ cells, CD4⁺ T cells, and neutrophils. In human, XCR1 mRNA was detected in placenta, thymus and spleen. Human XCR1 mRNA was also detected in activated CD3⁺ T cells, CD8⁺ T cells, anergized CD4⁺ T cells, and neutrophils.

The XCL1-XCR1 axis was reported to play a crucial role in the immune system, including the regulation of the dendritic-cell-mediated cytotoxic immune response, the generation of regulatory T cells and the thymic establishment of self-tolerance. Recent studies also showed that XCR1 was overexpressed in ovarian carcinoma, breast cancer and oral cancer. Activation of XCR1 by its ligand XCL1 could promote cancer cell adhesion, proliferation, migration and invasion. Moreover, the XCL1/XCR1 axis also contributes to the progression of various diseases, including rheumatoid arthritis, AIDS and Crohn's disease.

XCL1 and XCR1 in Cytotoxic Immune Response

Mouse CD8⁺ dendritic cells (DCs) efficiently process cell-associated antigens and present them to CD8⁺ T cells, which mediate cytotoxic T lymphocyte response to intracellular viral and tumor antigens. Human CD141⁺ DCs are also efficient in the presentation of soluble or cell-associated antigens to CD8⁺ T cells. Studies have suggested that ovalbumin (OVA)-specific OT-I TCR-transgenic CD8⁺ spleen T cells produce XCL1 8-36 h after encountering the OVA antigen presented by CD8⁺ DCs. Genetic ablation of XCL1 reduces the proliferation, IFN-g secretion, and OVA-specific cytotoxicity of OT-I TCR-transgenic CD8⁺ cells upon stimulation with OVA-presenting CD8⁺ DCs. XCL1-deficient mouse demonstrates decreased early CD8⁺ T cell response to Listeria monocytogenes infection, which is associated with higher bacterial loads early in the infection, suggesting that XCR1 promotes the ability of CD8⁺ DCs to activate early CD8⁺ T cell mediated defense against the intracellular pathogenic bacterium. Therefore, the XCL1-XCR1 axis is crucial for efficient cytotoxic immune response mediated by CD8⁺ T cells.

XCR1 Figure 1. XCL1 produced by activated CD8⁺ T cells attracts XCR1-expressing DCs. (Xu F, et al. 2019)

XCR1 and Non-small Cell Lung Cancer

Recently, the study showed that XCR1 was overexpressed in lung cancer bone metastasis compared with primary non-small cell lung cancer (NSCLC). Moreover, XCL1, the ligand of XCR1, was confirmed to be expressed in bone marrow cells. The mRNA level of XCL1 was relatively highly expressed in the mouse bone tissue. Besides, XCL1 significantly promoted the proliferation and migration of lung cancer cells by activating XCR1. These results indicated a possible procedure in NSCLC bone metastasis that XCL1 in bone tissue activating XCR1 in cancer cells promoted tumor progression. In addition, this study has also found the JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including JunB, PIM1, TTP, MMP2 and MMP9. These results indicate that XCR1 is a novel potential therapeutic target for the treatment of lung cancer bone metastasis.

XCR1 and Breast Cancer

Two-thirds of breast cancer overexpress estrogen receptor (ER) or progesterone receptors, which suggest a degree of estrogen dependence for growth. It has been reported that the development of estrogen independence and endocrine therapy resistance in breast cancer patients may be correlated with the insulin-like growth factor (IGF) system, SDF-1-CXCR4 signaling, IGF1 receptor (IGF1R) expression, and hyperactivation of the IGF-IR/InsR/PI3K/mTOR pathway. Recently, studies found a strong association between ER and XCR1, the further biological effects of XCR1 in breast cancer are that XCR1 can inhibit cell growth and tumorigenesis by down-regulating the activation of MAPK and PI3K/AKT/mTOR signaling pathway but promote the migration and invasion through decreasing the protein level of β-catenin. Researchers believe controlling the expression of XCR1 in different steps of tumor development that can effectively inhibit breast cancer, especially ER+ cell growth and metastasis that could be a hopeful therapeutic strategy against estrogen independence and tumor relapse, but further studies of XCR1 are still needed.

References:

Wang T, et al. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer. Biochemical and biophysical research communications, 2015, 464(2): 635-641.
Lei Y, Takahama Y. XCL1 and XCR1 in the immune system. Microbes and infection, 2012, 14(3): 262-267.
Xu F, et al. Genetic diversity of chemokine XCL1 and its receptor XCR1 in murine rodents. Developmental & Comparative Immunology, 2019, 98: 80-88.
Yang X L, et al. The role of the chemokine receptor XCR1 in breast cancer cells. Breast Cancer: Targets and Therapy, 2017, 9: 227.

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