XCL1

XCL1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1J8I, 1J9O, 2HDM, 2JP1, 2NYZ, 2N54
Identifiers
Aliases	XCL1, ATAC, LPTN, LTN, SCM-1, SCM-1a, SCM1, SCM1A, SCYC1, X-C motif chemokine ligand 1
External IDs	OMIM: 600250 MGI: 104593 HomoloGene: 2250 GeneCards: XCL1
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q24.2 Start 168,576,605 bp[1] End 168,582,069 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 H2.2|1 72.26 cM Start 164,759,213 bp[2] End 164,763,096 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in spleen lymph node gallbladder rectum right lobe of liver appendix right uterine tube blood left uterine tube smooth muscle tissue Top expressed in thymus spleen blood secondary oocyte jejunum uterus zone of skin white adipose tissue skin of abdomen bone marrow More reference expression data BioGPS n/a
Gene ontology Molecular function chemokine receptor binding cytokine activity protein homodimerization activity chemokine activity CCR chemokine receptor binding protein binding Cellular component extracellular region extracellular space Biological process cellular response to transforming growth factor beta stimulus cellular response to interleukin-4 release of sequestered calcium ion into cytosol negative regulation of interferon-gamma production positive regulation of T-helper 1 cell cytokine production monocyte chemotaxis positive regulation of interleukin-10 production positive regulation of natural killer cell chemotaxis chemokine-mediated signaling pathway positive regulation of CD4-positive, alpha-beta T cell proliferation cellular response to tumor necrosis factor cell-cell signaling positive regulation of thymocyte migration response to virus positive regulation of T cell mediated cytotoxicity positive regulation of release of sequestered calcium ion into cytosol negative regulation of T-helper 1 type immune response negative regulation of DNA-binding transcription factor activity neutrophil chemotaxis chemotaxis positive regulation of leukocyte chemotaxis positive regulation of GTPase activity positive regulation of granzyme A production positive regulation of immunoglobulin production in mucosal tissue negative regulation of T cell cytokine production positive regulation of T cell cytokine production cellular response to interleukin-1 positive regulation of T cell chemotaxis mature natural killer cell chemotaxis regulation of inflammatory response positive regulation of ERK1 and ERK2 cascade positive regulation of neutrophil chemotaxis cellular response to interferon-gamma immune response positive regulation of B cell chemotaxis positive regulation of transforming growth factor beta production negative regulation of CD4-positive, alpha-beta T cell proliferation positive regulation of T-helper 2 cell cytokine production negative regulation of transcription, DNA-templated positive regulation of CD8-positive, alpha-beta T cell proliferation negative regulation of interleukin-2 production negative regulation of T-helper 1 cell activation positive regulation of granzyme B production signal transduction antimicrobial humoral immune response mediated by antimicrobial peptide regulation of signaling receptor activity G protein-coupled receptor signaling pathway inflammatory response lymphocyte chemotaxis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6375 16963 Ensembl ENSG00000143184 ENSMUSG00000026573 UniProt P47992 P47993 RefSeq (mRNA) NM_002995 NM_008510 RefSeq (protein) NP_002986 NP_032536 Location (UCSC) Chr 1: 168.58 – 168.58 Mb Chr 1: 164.76 – 164.76 Mb PubMed search [3] [4]
Wikidata
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Chemokine (C motif) ligand (XCL1) is a small cytokine belonging to the C chemokine family that is also known as lymphotactin. Chemokines are known for their function in inflammatory and immunological responses. This family C chemokines differs in structure and function from most chemokines.^[5][6] There are only two chemokines in this family and what separated them from other chemokines is that they only have two cysteines; one N-terminal cysteine and one cysteine downstream. These both are called Lymphotactin, alpha and beta form, and claim special characteristics only found between the two. Lymphotactins can go through a reversible conformational change which changes its binding shifts.^[7]

In normal tissues, XCL1 is found in high levels in spleen, thymus, small intestine and peripheral blood leukocytes, and at lower levels in lung, prostate gland and ovary. Secretion of XCL1 is responsible for the increase of intracellular calcium in peripheral blood lymphocytes.^[8] Cellular sources for XCL1 include activated thymic and peripheral blood CD8+ T cells.^[9][10][11] NK cells also secrete XCL1 along with other chemokines early in infections.^[12] XCR1 expressing dendritic cells (DC) are a major target of XCL1.^[12]

In humans, XCL1 is closely related to another chemokine called XCL2, whose gene is found at the same locus on chromosome 1.^[11] Both of these chemokines share many genetic and functional similarities; however XCL2 has only been known to be observed in humans and not in mice.^[12] XCL1 induces its chemotactic function by binding to a chemokine receptor called XCR1.^[13] XCL1 is expressed on macrophages, fibroblasts, and specific lymphocytes.^[6]

XCL1 is found in two metamorphic states: a monomer at 10°C, Ltn10, and a dimer at 40°C, Ltn40.^[14]

Genomics

XCL1's gene is found on the long arm of chromosome 1, located on cytogenetic band q24.2 as seen in the infobox. The encoding gene is made of 6,017 DNA bases to encode for the protein XCL1.^[15] This gene contains three exons and two introns as well as several transcription initiation sites.^[8] This gene encodes for the 114-amino acid protein called XCL1 which is similar to other chemokines except that it lacks the first and third cysteine characteristics. This means that XCL1 only contains one cysteine creating a disulfide bond instead of two or three like the other chemokines.^[5]

The genetic differences between XCL1 and XCL2 are very small. Both proteins are from the same family containing the C motif structure containing one disulfide bond and have almost identical tertiary structures.^[8] These C chemokines also have the same flanking regions, meaning regions of the gene including the promoter and other places of protein binging that do not contribute to the RNA transcribed gene.^[8] Gene mapping of this chemokine family shows similarities in their intron and exon locations with only one distinct difference. XCL1 has only one difference in its first intron that encodes for a large ribosomal subunit called L7a. In XCL2 have of the region encoding for L7a is cut off.^[8] The only other genetic difference between the two mature proteins is the different amino acid in positions 7 and 8.^[8][12] This amino acid difference may account for some biological differences. Some difficulties with comparing these two chemokines is that XCL2 has never been observed in a mouse.^[12]

Structure

One thing that sets XCL1 apart from other cytokines is its structure.^[7] While most chemokines have two disulfide bonds that connect the N-terminus to the core of the structure, XCL1 only has one.^[5] This simple difference in disulfide bonds changes the overall tertiary structure of XCL1 from other chemokines. There are two parts of the lymphotactin protein, structures Ltn10 and Ltn40, that folds into each other, which make it biologically active.^[7] This conformational change alters the binding structures on the chemokine. This understanding of the interfolding provides more of a basis to understanding to the lymphotactin kinetics.^[7]

Biological significance

The pair of XCL1 and XCR1 are known to be involved in cross-presentation, antigen uptake, and induction of innate as well as adaptive cytotoxic immunity.^[12] XCR1, the receptor for XCL1, is exclusively expressed in conventional dendritic cells.^[12] XCL1 is secreted by NK cells and by antigen-specific CD8+ T-cells, along with other chemokines including IFN-gamma.^[12] This process likely facilitates the cross-presentation of antigens by the dendritic cells.

XCL1 is also known to increate T cells in joints that are effected with rheumatoid arthritis.^[6] They are also expressed on RA synovial lymphocytes.^[6]

References