CX3C motif chemokine receptor 1

Last updated
CX3CR1
Identifiers
Aliases CX3CR1 , CCRL1, CMKBRL1, CMKDR1, GPR13, GPRV28, V28, C-X3-C motif chemokine receptor 1
External IDs OMIM: 601470 MGI: 1333815 HomoloGene: 20350 GeneCards: CX3CR1
Orthologs
SpeciesHumanMouse
Entrez

1524

13051

Ensembl

ENSG00000168329

ENSMUSG00000052336

UniProt

P49238

Q9Z0D9

RefSeq (mRNA)

NM_001337
NM_001171171
NM_001171172
NM_001171174

NM_009987

RefSeq (protein)

NP_001164642
NP_001164643
NP_001164645
NP_001328

NP_034117

Location (UCSC) Chr 3: 39.26 – 39.28 Mb Chr 9: 119.73 – 119.9 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

CX3C motif chemokine receptor 1 (CX3CR1), also known as the fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a transmembrane protein of the G protein-coupled receptor 1 (GPCR1) family and the only known member of the CX3C chemokine receptor subfamily. [5] [6] [7]

Contents

As the name suggests, this receptor binds the inflammatory chemokine CX3CL1 (also called neurotactin in mice or fractalkine in humans). This endogenous ligand solely binds to CX3CR1 receptor. Interaction of CX3CR1 with CX3CL1 can mediate migration, adhesion and retention of leukocytes, because Fractalkine exists as membrane-anchored protein (mCX3CL1) as well as cleaved soluble molecule (sCX3CL1) due to proteolysis by metalloproteinases (MPPs). The shedded form carries out typical function of conventional chemokines, the chemotaxis, while the membrane-bound protein behaves as adhesion molecule for facilitation of diapedesis. [7] [8]

Both partners of CX3CL1-CX3CR1 axis are present on numerous cell types from hematopoietic and nonhematopoietic cells throughout the body. Moreover, their distinct cell expression is dependent on specific tissues and organs, which provides broad sphere of biological activity. Hence, considering their various functional activity, they are also linked with multiple neurodegenerative and inflammatory disorders as well as with tumorigenesis. [7] [8] [9]

Genetics

The coding gene for CX3CR1 is now officially called identically to its protein: CX3CR1 gene, [5] [6] but may be still referred to by other older names such as V28; CCRL1; GPR13; CMKDR1; GPRV28; CMKBRL1. A genome location of the gene in humans is on the short arm of the chromosome 3p22.2. It is composed of four exons (only one contains coding region) and three intronic elements. Expression of the genomic sequence is regulated via three promoters. [10] [11]

Two missense mutations in CX3CR1 gene, variants of single nucleotide polymorphism (SNP) of the receptor, are responsible for functional change of the protein. Names of these variants are derived from given substitution and its position: valine to isoleucine (V249I) and threonine to methionine (T280M). Polymorphism of CX3CR1 has been linked to diseases relating to cardiovascular system (e.g. Atherosclerosis), nervous system (e.g. Alzheimer's disease, Sclerosis) or infections (e.g. systemic candidiasis. [12] [13] [14]

Orthologs of CX3CR1 gene are found among animals, especially in mammals with high functional similarity, namely chimpanzee, dog, cat, mouse and rat. Orthologs are located on chromosome 9qF4 in the mouse genome and in the rat 8th chromosome on position 8q32. [15] [16]

Expression

CX3CR1 is expressed constitutively or in inflammatory response in various cells from hematopoietic lineage: T lymphocytes, natural killer (NK) cells, dendritic cells, B lymphocytes, mast cells, monocytes, macrophages, neutrophils, microglia, osteoclasts and thrombocytes. Furthermore, this receptor can be also found in nonhematopoietic tissues such as endothelial cells, epithelial cells, myocytes and astrocytes. Considering the CX3CR1 abundance in the body, it was also found to be expressed by some types of malignant cells. [9] [10] [12] [17]

Function

The CX3CR1 receptor is part of the G-protein chemokine receptor family with the metabotropic function. Its intracellular signalling cascades are responsible for modulating cell activity rather towards higher active state as in survival, migration and proliferation. [7] [18]

In the recognition of immune cells during inflammation, the function of CX3CL1-CX3CR1 axis in the bloodstream is mainly recruitment of immune cells by migration through chemotaxis and diapedesis. Of course, as a part of the inflammatory immune response against pathogens this role considered as protective. However, as with most immune cells and proteins, in inflammatory or autoimmune diseases, CX3CR1 signalling is associated with some disease's pathophysiology. [7]

Expression of this receptor appears to be associated with lymphocytes. [19] CX3CR1 is also expressed by monocytes and plays a major role in the survival of monocytes. [20] Communication in blood vessels through the CX3CL1-CX3CR1 axis between endothelial cells and monocytes is responsible for formation of extracellular matrix and angiogenesis. It has been shown that CX3CR1 can influence monocytes already in bone marrow by means of retention and release. Moreover in bone marrow, CX3CR1 influences bone remodeling through role in differentiation of osteoclasts and osteoblasts. [9]

The CX3CL1/CX3CR1 axis role in the nervous system is to mediate communication between microglia, neuroglia and neurons for regulation of microglia activity, hence this axis plays a neurodegenerative and neuroprotective function based on the physiological state. [7] [9]

Fractalkine signaling has also recently been discovered to play a developmental role in the migration of microglia in the central nervous system to their synaptic targets, where phagocytosis and synaptic refinement occur. CX3CR1 knockout mice had more synapses on hippocampal neurons than wild-type mice. [21]

Structure

CX3CR1 is integral membrane protein formed by 355 amino acids with molecular weight around 40 kDa, which consist of three distinguishable segments: extracellular, transmembrane and intracellular part. [7] [8] As a member of the biggest class of GPCR family the rhodopsin-like receptors, the intracellular part of receptor, C-terminus of the polypeptide and three intracellular loops, is a bounding place with conserved DRYLAIV motif for the heterotrimeric G protein. This family is also known as T-transmembrane receptors (7-TM) by reason of 7 α-helices of transmembrane protein, which are alternately located in the cell's cytoplasmic membrane. [12] [16] Extracellular side of CX3CR1 consists of N-terminus of the polypeptide chain and three extracellular loops, forming a binding place for its main ligand CX3CL1, but also CCL26 (Eotaxin-3): has lower binding affinity when compared to fractalkine), immunoglobulins or infectious agents. [9] [10]

Signalling cascade

CX3CL1-CX3CR1 axis' signalling commences via activation of the receptor by its agonist's binding. It is followed by conformational change and component's dissociation of the heterotrimeric G complex, which consists of three subunits: α (alpha), β (beta) and γ (gamma). Several important signalling pathways are triggered by separated parts of G protein (Gα and Gβγ) such as the PLC/PKC pathway, the PI3K/AKT/NFκB pathway, the Ras/Raf/MEK/ERK (MAPK) pathway (or p38 and JNK) and the CREB pathway. All of those signalling cascades are responsible for diverse cellular behaviours and regulations, in terms of increased proliferation, survival and cell growth, metabolic regulation, induction of migration, apoptosis resistance and secretion of hormones and inflammatory cytokines. Products of CX3CR1 signalling cascades possess importance in the immune response of CX3CR1 positive hematopoietic cells. [9] [10] [18]

Clinical significance

CX3CR1 and immune cells are strongly connected due to its abundant cell surface expression. Therefore, clinical meaning of CX3CR1 can be found in diseases connected with immunity. CX3CR1 is able to increase accumulation of immune cells in the affected body part, which results in disease aggravation. Few examples: allergies, Rheumatoid arthritis, Renal diseases, Chronic liver disease or Crohn's disease. [10] [18] [22]

CX3CR1 is also a coreceptor for HIV-1, and some variations in this gene lead to increased susceptibility to HIV-1 infection and rapid progression to AIDS. [23]

Since CX3CR1 plays a major role for interaction between endothelial cells and immune cells, it can aid vascular build up on the artery walls (plaque), thus it has been associated with Atherosclerosis. In addition, this may lead to thrombosis, other cardiovascular diseases or even cerebral ischemia. [10] [18] [17]

CX3CL1-CX3CR1 axis has an ability to control neurological inflammation through activation of microglia. Its role in brain pathologies can be therefore protective but also detrimental. There are connections between microglia and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease or even with neurocognitive HIV-dementia. [10] [24] Moreover, CX3CR1 variants have been described to modify the survival time and the progression rate of patients with amyotrophic lateral sclerosis. [25]

Mutations in CX3CR1 are associated to dysplasia of the hip. [26] Homozygous CX3CR1-M280 mutation impairs human monocyte survival and deteriorates outcome of human systemic candiasis. [27]

As mentioned before, this receptor and its ligand are important for the metabolism of the bone tissue in terms of differentiation of osteoclasts and osteoblasts. Overactivation of osteoclasts as well as accumulation of other immune cells has been linked to Osteoporosis. [9] [17] [8]

CX3CR1 with Fractalkine have a meaningful place also in many various types of cancer (e.g. Neuroblastoma, Prostate cancer, Gastric adenocarcinoma or B cell lymphomas) where CX3CL1-CX3CR1 axis is a double agent, providing antitumoral effects (stimulating and recruiting immune cells to target neoplasm) and protumoral effects (stimulating important activity in malignant cells like: invasion, proliferation and apoptosis resistance, for facilitating metastasis). Therefore, it has a lot of potential as therapeutical target in cancer. [9] [10] [18]

Related Research Articles

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 10-15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia originate in the yolk sac under a tightly regulated molecular process. These cells are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.

<span class="mw-page-title-main">CCL5</span> Mammalian protein found in Homo sapiens

Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTES. RANTES was first described by Dr. Tom Schall who named the protein, the original source of the name Rantes was from the Argentine movie Man Facing Southeast about an alien who shows up in a mental ward who was named Rantés, the rather clunky acronym was only made to fit the name.

<span class="mw-page-title-main">Interleukin 1 beta</span> Mammalian protein found in Homo sapiens

Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

Chemokine ligands 4 previously known as macrophage inflammatory protein (MIP-1β), is a protein which in humans is encoded by the CCL4 gene. CCL4 belongs to a cluster of genes located on 17q11-q21 of the chromosomal region. Identification and localization of the gene on the chromosome 17 was in 1990 although the discovery of MIP-1 was initiated in 1988 with the purification of a protein doublet corresponding to inflammatory activity from supernatant of endotoxin-stimulated murine macrophages. At that time, it was also named as "macrophage inflammatory protein-1" (MIP-1) due to its inflammatory properties.

Chemokine ligand 1 (CCL1) is also known as small inducible cytokine A1 and I-309 in humans. CCL1 is a small glycoprotein that belongs to the CC chemokine family.

<span class="mw-page-title-main">CCL7</span> Mammalian protein found in Homo sapiens

Chemokine ligand 7 (CCL7) is a small cytokine that was previously called monocyte-chemotactic protein 3 (MCP3). CCL7 is a small protein that belongs to the CC chemokine family and is most closely related to CCL2.

<span class="mw-page-title-main">CCL8</span> Mammalian protein found in Homo sapiens

Chemokine ligand 8 (CCL8), also known as monocyte chemoattractant protein 2 (MCP2), is a protein that in humans is encoded by the CCL8 gene.

<span class="mw-page-title-main">CCL17</span> Mammalian protein found in Homo sapiens

CCL17 is a powerful chemokine produced in the thymus and by antigen-presenting cells like dendritic cells, macrophages, and monocytes. CCL17 plays a complex role in cancer. It attracts T-regulatory cells allowing for some cancers to evade an immune response. However, in other cancers, such as melanoma, an increase in CCL17 is linked to an improved outcome. CCL17 has also been linked to autoimmune and allergic diseases.

<span class="mw-page-title-main">CX3CL1</span> Protein-coding gene in the species Homo sapiens

Fractalkine, also known as chemokine ligand 1, is a protein that in humans is encoded by the CX3CL1 gene.

<span class="mw-page-title-main">CXCL1</span> Mammalian protein found in Homo sapiens

The chemokine ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infection and plays an important role in regulation of immune and inflammatory responses. It was previously called GRO1 oncogene, GROα, neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MGSA-α). CXCL1 was first cloned from a cDNA library of genes induced by platelet-derived growth factor (PDGF) stimulation of BALB/c-3T3 murine embryonic fibroblasts and named "KC" for its location in the nitrocellulose colony hybridization assay. This designation is sometimes erroneously believed to be an acronym and defined as "keratinocytes-derived chemokine". Rat CXCL1 was first reported when NRK-52E cells were stimulated with interleukin-1β (IL-1β) and lipopolysaccharide (LPS) to generate a cytokine that was chemotactic for rat neutrophils, cytokine-induced neutrophil chemoattractant (CINC). In humans, this protein is encoded by the gene Cxcl1 and is located on human chromosome 4 among genes for other CXC chemokines.

<span class="mw-page-title-main">CCR2</span> Mammalian protein found in Homo sapiens

C-C chemokine receptor type 2 (CCR2 or CD192 is a protein that in humans is encoded by the CCR2 gene. CCR2 is a CC chemokine receptor.

<span class="mw-page-title-main">C-C chemokine receptor type 7</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.

<span class="mw-page-title-main">CCR1</span> Protein in humans

C-C chemokine receptor type 1 is a protein that in humans is encoded by the CCR1 gene.

<span class="mw-page-title-main">CCR9</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene. This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described.

<span class="mw-page-title-main">TREM1</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 1 (TREM1) is an immunoglobulin (Ig) superfamily transmembrane protein that, in humans, is encoded by the TREM1 gene. TREM1 is constitutively expressed on the surface of peripheral blood monocytes and neutrophils, and upregulated by toll-like receptor (TLR) ligands; activation of TREM1 amplifies immune responses.

<span class="mw-page-title-main">TREM2</span> Protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 2(TREM2) is a protein that in humans is encoded by the TREM2 gene. TREM2 is expressed on macrophages, immature monocyte-derived dendritic cells, osteoclasts, and microglia, which are immune cells in the central nervous system. In the liver, TREM2 is expressed by several cell types, including macrophages, that respond to injury. In the intestine, TREM2 is expressed by myeloid-derived dendritic cells and macrophage. TREM2 is overexpressed in many tumor types and has anti-inflammatory activities. It might therefore be a good therapeutic target.

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

References

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Further reading

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