XCL1

Fig1. Working model of XCL1 CC3-XCR1 binding and receptor activation. (Jamie C Fox, 2019)

What is XCL1 protein?

XCL1 (X-C motif chemokine ligand 1) gene is a protein coding gene which situated on the long arm of chromosome 1 at locus 1q24. Chemokine (C motif) ligand (XCL1), as known as lymphotactin, is the only known member of the C-chemokine family and signals through the receptor XCR1, formally known as GPR5. The expression of lymphotactin is abundant in some activated T cells such as activated CD8+ T cells and other class I MHC restricted T cells. XCL1 is a secreted protein which belongs to the intercrine gamma family. XCL1 is found in spleen with highest level, lower in peripheral leukocytes and very low levels in lung, colon and small intestine. The XCL1 protein is consisted of 114 amino acids and its molecular mass is approximately 12.5 kDa.

What is the function of XCL1 protein?

Its main function is to regulate the migration and activation of lymphocytes. By binding to its receptor XCR1, XCL1 induces the directed movement of immune cells, especially natural killer (NK) cells and specific T cell subpopulations, to sites of inflammation or infection. This chemotactic activity is essential for enhancing immune function, promoting pathogen clearance, and maintaining tissue homeostasis. In addition, XCL1 also plays a role in regulating immune response, maintaining tolerance, and inhibiting tumor growth.

XCL1 Related Signaling Pathway

By binding to its receptor XCR1, XCL1 activates downstream signaling pathways, thereby enhancing NK cell killing activity and cytokine production. XCL1 can activate the NF-κB (nuclear factor-κB) signaling pathway, promote inflammatory response and immune response, and promote the infiltration and activation of inflammatory cells. In addition, it can also regulate cell movement by participating in G protein-coupled receptor signaling pathway and PI3K-Akt signaling pathway.

XCL1 Related Diseases

XCL1-associated diseases involve multiple systems and organs, including the immune system, nervous system, cardiovascular system, and tumors. Specifically, XCL1 protein abnormalities have been linked to inflammatory diseases (such as autoimmune diseases), infectious diseases, neurodegenerative diseases, cardiovascular diseases, and cancer. The occurrence and development of these diseases may be related to the imbalance of expression level, activity or signaling pathway of XCL1 protein.

Bioapplications of XCL1

XCL1 is an important chemokine in the immune system, and researchers use the XCL1 protein to explore how immune cells are recruited to sites of inflammation or infection. XCL1 is able to enhance the migration of immune cells to the lymph nodes, so it is also being considered in vaccine design as a potential adjuvant to enhance the vaccine-induced immune response.

Case study 1: Ha Thi Thu Do, 2020

Chemokine-receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of XCR1, a specific receptor for XCL1, stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. In this study, siCtr and siXCR1 were transfected into MDA-MB-231 cells and cell migration assays were evaluated. Furthermore, Western Blotting and Immunocytochemistry were made to assess the expression and the intracellular localization of related proteins.

Finally, they found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial-mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2.

Fig1. Representative immunofluorescence images from the immunocytochemical studies are provided. Ctr, control. The arrows indicate β-catenin subcellular localization.

Fig2. Activation of the Extracellular signal-regulated kinase (ERK)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway by XCL1 in MDA-MB-231 cells.

Case study 2: Yeon Duk Woo, 2018

The chemokine X-C motif chemokine ligand 1 (XCL1)-X-C motif chemokine receptor 1 (XCR1) axis has been reported to play a role in immune homeostasis and inflammation. However, it is not known whether this axis has a critical function in patients with allergic asthma.

So Ovalbumin (OVA)- or house dust mite-induced asthma was developed in XCL1 or XCR1 knockout (KO) mice to explore whether the invariant natural killer T (iNKT) cell-mediated XCL1-XCR1 axis regulated allergic asthma. XCL1 or XCR1 KO mice showed attenuation in airway hyperresponsiveness (AHR), numbers of CD103+ dendritic cells (DCs), and TH2 responses in the lungs compared with wild-type (WT) mice during OVA- or house dust mite-induced asthma. Moreover, iNKT cells highly expressed XCL1 both in vitro and in vivo. In human patients, percentages and XCL1 production capacity of iNKT cells from PBMCs were greater in patients with asthma than in healthy control subjects.

Fig3. XCL1 deficiency reduces recruitment of CD103¬+, but not CD11b+ DCs into the lungs during OVA-induced allengic asthma.

Fig4. XCL1 deficiency reduces a-GalCer-mediated recruitment of CD103+ DCs into the lung.

XCL1 has several biochemical functions, for example, CCR chemokine receptor binding,chemokine activity,chemokine receptor binding. Some of the functions are cooperated with other proteins, some of the functions could acted by XCL1 itself. We selected most functions XCL1 had, and list some proteins which have the same functions with XCL1. You can find most of the proteins on our site.

XCL1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with XCL1 here. Most of them are supplied by our site. Hope this information will be useful for your research of XCL1.