CX3CL1 (chemokine (C-X3-C motif) ligand 1)

2013-09-01   Philippe Deterre 

Immunite et Infection, UMR-S 945 INSERM UPMC, Paris, France


Atlas Image
Chromosome 16; NC_000016.9.



CX3CL1 gene is located on the long arm of chromosome 16 at position 13 and contains three exons. This gene encodes for a protein of 397 aa. The first 24 aa represents the peptide signal.
Atlas Image
The CX3CL1 gene comprises 3 exons. The first codes for the peptide signal.


Only one type of transcript has been described. The 1194-nucleotide transcript encodes a protein of 397 amino acid residues. The primary structure of human CX3CL1 consists of an N-terminal 24-amino acid signal sequence followed by the chemokine domain of CX3CL1, a mucin-like stalk, a transmembrane domain and an intracellular part.


None described so far.


Atlas Image
Secondary structure of the membrane form of CX3CL1 (Bazan et al., 1997; Fong et al., 2000).


CX3CL1 is synthesized as a membrane protein consisting of the chemokine domain, a highly glycosylated mucin-like stalk, a transmembrane domain and an intracellular part. Cleavage by some metalloproteinases like ADAM-10 (Hundhausen et al., 2003), ADAM-17 (Garton et al., 2001; Tsou et al., 2001), MMP-2 (Bourd-Boittin et al., 2009) and cathepsin-S (Clark et al., 2009) gives raise to the soluble form of CX3CL1 consisting of the chemokine domain and the glycosylated mucin-like stalk (Bazan et al., 1997; Schulte et al., 2007). The C-terminal part contains two putative adaptor protein-2 (AP-2)-binding motifs, that control the constitutive endocytosis of the whole protein (Huang et al., 2009) mediated by clathrin and dynamin-1 (Robinson et al., 2002).


The chemokine CX3CL1 is constituvely expressed in microglial cells (Cross and Woodroofe, 1999), astrocytes (Hatori et al., 2002) and some neurons (Harrison et al., 1998; Cross and Woodroofe, 1999; Maciejewski-Lenoir et al., 1999; Deiva et al., 2004). Its expression is stimulated by inflammatory ligands in vascular endothelial cells (Fong et al., 1998; Imaizumi et al., 2000; Fraticelli et al., 2001; Schäfer et al., 2007), renal endothelial (Cross and Woodroofe, 1999) and epithelial cells (Chakravorty et al., 2002), in aortic (Ludwig et al., 2002; Ollivier et al., 2003) and pulmonary (Sukkar et al., 2004) smooth muscle cells and in dendritic cells (Papadopoulos et al., 1999; Dichmann et al., 2001; Pallandre et al., 2008).


The chemokine CX3CL1 is mainly localized at the plasma membrane (Bazan et al., 1997; Fong et al., 2000). Its biosynthesis in the Golgi and/or ER organelles starts as an non glycosylated and intracellular.


The function of CX3CL1 relies on both of its forms: the soluble form, released by metalloproteinases, is chemoattractant while the membrane form mediates stable adhesion of leukocytes such as integrins (Fong et al., 1998; Haskell et al., 1999).

Implicated in

Entity name
Both CX3CL1 and CX3CR1 are expressed in human surgical glioma samples. The expression of CX3CL1 was inversely correlated with patient overall survival (Erreni et al., 2010). The presence of the rare variant CX3CR1 was shown to be associate with a longer mean survival (Rodero et al., 2008).
Entity name
The CX3CL1 molecule, with its unique CX3CR1 receptor (Imai et al., 1997), has been shown to be central in cellular processes leading to atherosclerosis. In animal models, the deletion of CX3CR1 genes lead to decreased disease (Combadière et al., 2003; Lesnik et al., 2003). In human, the presence of the rare variant CX3CR1 I249 is an independent genetic risk factor for coronary artery disease (Moatti et al., 2001).
Entity name
By binding to its receptor CX3CR1, the CX3CL1 molecule decreases the microglial neurotoxicity mediated by inflammatory molecules (reactive species, matrix metalloproteinase, inflammatory cytokines) (Cardona et al., 2006). CX3CL1 acts by binding to CX3CR1 present on microglia to modulate microglial activation (Cho et al., 2011). However converse data also exist. During focal cerebral ischemia, elimination of CX3CL1 signaling was associated with smaller infarct and enhanced recovery (Dénes et al., 2008).


Pubmed IDLast YearTitleAuthors
90246631997A new class of membrane-bound chemokine with a CX3C motif.Bazan JF et al
194328092009CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver.Bourd-Boittin K et al
167322732006Control of microglial neurotoxicity by the fractalkine receptor.Cardona AE et al
121000352002Fractalkine expression on human renal tubular epithelial cells: potential role in mononuclear cell adhesion.Chakravorty SJ et al
217717912011CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease.Cho SH et al
194743212009The liberation of fractalkine in the dorsal horn requires microglial cathepsin S.Clark AK et al
126009152003Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice.Combadière C et al
105597771999Chemokine modulation of matrix metalloproteinase and TIMP production in adult rat brain microglia and a human microglial cell line in vitro.Cross AK et al
156101552004Fractalkine reduces N-methyl-d-aspartate-induced calcium flux and apoptosis in human neurons through extracellular signal-regulated kinase activation.Deiva K et al
185754572008Role of CX3CR1 (fractalkine receptor) in brain damage and inflammation induced by focal cerebral ischemia in mouse.Dénes A et al
117669922001Fractalkine induces chemotaxis and actin polymerization in human dendritic cells.Dichmann S et al
207283442010Human glioblastoma tumours and neural cancer stem cells express the chemokine CX3CL1 and its receptor CX3CR1.Erreni M et al
106605272000Ultrastructure and function of the fractalkine mucin domain in CX(3)C chemokine domain presentation.Fong AM et al
97821181998Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow.Fong AM et al
113425812001Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses.Fraticelli P et al
114959252001Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1).Garton KJ et al
97248011998Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia.Harrison JK et al
101877841999Molecular uncoupling of fractalkine-mediated cell adhesion and signal transduction. Rapid flow arrest of CX3CR1-expressing cells is independent of G-protein activation.Haskell CA et al
121250822002Fractalkine and fractalkine receptors in human neurons and glial cells.Hatori K et al
197236362009Constitutive endocytosis of the chemokine CX3CL1 prevents its degradation by cell surface metalloproteases.Huang YW et al
127145082003The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion.Hundhausen C et al
93905611997Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion.Imai T et al
112113122000Interferon-gamma stimulates the expression of CX3CL1/fractalkine in cultured human endothelial cells.Imaizumi T et al
125691582003Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis.Lesnik P et al
117779522002Fractalkine is expressed by smooth muscle cells in response to IFN-gamma and TNF-alpha and is modulated by metalloproteinase activity.Ludwig A et al
104150681999Characterization of fractalkine in rat brain cells: migratory and activation signals for CX3CR-1-expressing microglia.Maciejewski-Lenoir D et al
112641532001Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease.Moatti D et al
128240042003Fractalkine/CX3CL1 production by human aortic smooth muscle cells impairs monocyte procoagulant and inflammatory responses.Ollivier V et al
186826002008Dendritic cell and natural killer cell cross-talk: a pivotal role of CX3CL1 in NK cytoskeleton organization and activation.Pallandre JR et al
104587701999Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation.Papadopoulos EJ et al
118131592002Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-alpha.Robinson SC et al
190013282008Polymorphism in the microglial cell-mobilizing CX3CR1 gene is associated with survival in patients with glioblastoma.Rodero M et al
170824822007The CX3C chemokine fractalkine induces vascular dysfunction by generation of superoxide anions.Schäfer A et al
174676662007Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases.Schulte A et al
153217872004Fractalkine/CX3CL1 production by human airway smooth muscle cells: induction by IFN-gamma and TNF-alpha and regulation by TGF-beta and corticosteroids.Sukkar MB et al
115713002001Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine.Tsou CL et al

Other Information

Locus ID:

NCBI: 6376
MIM: 601880
HGNC: 10647
Ensembl: ENSG00000006210


dbSNP: 6376
ClinVar: 6376
TCGA: ENSG00000006210


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class A/1 (Rhodopsin-like receptors)REACTOMER-HSA-373076
Peptide ligand-binding receptorsREACTOMER-HSA-375276
Chemokine receptors bind chemokinesREACTOMER-HSA-380108

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
128106882003Fractalkine preferentially mediates arrest and migration of CD16+ monocytes.159
187997222008CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis.124
257451662015Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor.93
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
243527392013Neuron-glia crosstalk in health and disease: fractalkine and CX3CR1 take centre stage.83
129699922004Fractalkine in vascular biology: from basic research to clinical disease.72
120552302002Dual functions of fractalkine/CX3C ligand 1 in trafficking of perforin+/granzyme B+ cytotoxic effector lymphocytes that are defined by CX3CR1 expression.66
191553112009Membrane microvesicles as actors in the establishment of a favorable prostatic tumoral niche: a role for activated fibroblasts and CX3CL1-CX3CR1 axis.64
121250822002Fractalkine and fractalkine receptors in human neurons and glial cells.63
120161062002CX(3)C chemokine fractalkine in pulmonary arterial hypertension.61


Philippe Deterre

CX3CL1 (chemokine (C-X3-C motif) ligand 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-09-01

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