CX3CL1 explained

Fractalkine, also known as chemokine (C-X3-C motif) ligand 1, is a protein that in humans is encoded by the CX3CL1 gene.

Function

Fractalkine is a large cytokine protein of 373 amino acids that contains multiple domains and is the only known member of the CX₃C chemokine family. It is also commonly known under the names fractalkine (in humans) and neurotactin (in mice).^{[1] [2]} The polypeptide structure of CX3CL1 differs from the typical structure of other chemokines. For example, the spacing of the characteristic N-terminal cysteines differs; there are three amino acids separating the initial pair of cysteines in CX3CL1, with none in CC chemokines and only one intervening amino acid in CXC chemokines. CX3CL1 is produced as a long protein (with 373-amino acid in humans) with an extended mucin-like stalk and a chemokine domain on top. The mucin-like stalk permits it to bind to the surface of certain cells. However a soluble (90 kD) version of this chemokine has also been observed. Soluble CX3CL1 potently chemoattracts T cells and monocytes, while the cell-bound chemokine promotes strong adhesion of leukocytes to activated endothelial cells, where it is primarily expressed.^[2] CX3CL1 elicits its adhesive and migratory functions by interacting with the chemokine receptor CX3CR1.^[3] Its gene is located on human chromosome 16 along with some CC chemokines known as CCL17 and CCL22.^{[2] [4]}

Fractalkine is found commonly throughout the brain, particularly in neural cells, and its receptor is known to be present on microglial cells. It has also been found to be essential for microglial cell migration.^[5] CX3CL1 is also up-regulated in the hippocampus during a brief temporal window following spatial learning, the purpose of which may be to regulate glutamate-mediated neurotransmission tone. This indicates a possible role for the chemokine in the protective plasticity process of synaptic scaling.^[6]

References

Further reading

• Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ . A new class of membrane-bound chemokine with a CX3C motif . Nature . 385 . 6617 . 640–4 . 1997 . 9024663 . 10.1038/385640a0 . 1997Natur.385..640B . 4322166 .
• Combadiere C, Salzwedel K, Smith ED, Tiffany HL, Berger EA, Murphy PM . Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1 . J. Biol. Chem. . 273 . 37 . 23799–804 . 1998 . 9726990 . 10.1074/jbc.273.37.23799 . free .
• Meucci O, Fatatis A, Simen AA, Bushell TJ, Gray PW, Miller RJ . Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity . Proc. Natl. Acad. Sci. U.S.A. . 95 . 24 . 14500–5 . 1998 . 9826729 . 24402 . 10.1073/pnas.95.24.14500 . 1998PNAS...9514500M . free .
• Mizoue LS, Bazan JF, Johnson EC, Handel TM . Solution structure and dynamics of the CX3C chemokine domain of fractalkine and its interaction with an N-terminal fragment of CX3CR1 . Biochemistry . 38 . 5 . 1402–14 . 1999 . 9931005 . 10.1021/bi9820614 .
• Papadopoulos EJ, Sassetti C, Saeki H, Yamada N, Kawamura T, Fitzhugh DJ, Saraf MA, Schall T, Blauvelt A, Rosen SD, Hwang ST . Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation . Eur. J. Immunol. . 29 . 8 . 2551–9 . 1999 . 10458770 . 10.1002/(SICI)1521-4141(199908)29:08<2551::AID-IMMU2551>3.0.CO;2-T . free .
• Loftus BJ, Kim UJ, Sneddon VP, Kalush F, Brandon R, Fuhrmann J, Mason T, Crosby ML, Barnstead M, Cronin L, Deslattes Mays A, Cao Y, Xu RX, Kang HL, Mitchell S, Eichler EE, Harris PC, Venter JC, Adams MD . Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q . Genomics . 60 . 3 . 295–308 . 1999 . 10493829 . 10.1006/geno.1999.5927 .
• Howard E. Gendelman . Tong N, Perry SW, Zhang Q, James HJ, Guo H, Brooks A, Bal H, Kinnear SA, Fine S, Epstein LG, Dairaghi D, Schall TJ, Gendelman HE, Dewhurst S, Sharer LR, Gelbard HA . Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system . J. Immunol. . 164 . 3 . 1333–9 . 2000 . 10640747 . 10.4049/jimmunol.164.3.1333 . 20616076 . free .
• Faure S, Meyer L, Costagliola D, Vaneensberghe C, Genin E, Autran B, Delfraissy JF, McDermott DH, Murphy PM, Debré P, Théodorou I, Combadière C . Rapid progression to AIDS in HIV+ individuals with a structural variant of the chemokine receptor CX3CR1 . Science . 287 . 5461 . 2274–7 . 2000 . 10731151 . 10.1126/science.287.5461.2274 . 2000Sci...287.2274F .
• Hoover DM, Mizoue LS, Handel TM, Lubkowski J . The crystal structure of the chemokine domain of fractalkine shows a novel quaternary arrangement . J. Biol. Chem. . 275 . 30 . 23187–93 . 2000 . 10770945 . 10.1074/jbc.M002584200 . 38835823 . free .
• Meucci O, Fatatis A, Simen AA, Miller RJ . Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival . Proc. Natl. Acad. Sci. U.S.A. . 97 . 14 . 8075–80 . 2000 . 10869418 . 16672 . 10.1073/pnas.090017497 . 2000PNAS...97.8075M . free .
• Papadopoulos EJ, Fitzhugh DJ, Tkaczyk C, Gilfillan AM, Sassetti C, Metcalfe DD, Hwang ST . Mast cells migrate, but do not degranulate, in response to fractalkine, a membrane-bound chemokine expressed constitutively in diverse cells of the skin . Eur. J. Immunol. . 30 . 8 . 2355–61 . 2000 . 10940926 . 10.1002/1521-4141(2000)30:8<2355::AID-IMMU2355>3.0.CO;2-# . 196597758 .
• Lucas AD, Chadwick N, Warren BF, Jewell DP, Gordon S, Powrie F, Greaves DR . The transmembrane form of the CX3CL1 chemokine fractalkine is expressed predominantly by epithelial cells in vivo . Am. J. Pathol. . 158 . 3 . 855–66 . 2001 . 11238035 . 1850344 . 10.1016/S0002-9440(10)64034-5 .
• Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ, Raines EW . Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1) . J. Biol. Chem. . 276 . 41 . 37993–8001 . 2001 . 11495925 . 10.1074/jbc.M106434200 . free .
• Umehara H, Bloom ET, Okazaki T, Nagano Y, Yoshie O, Imai T . Fractalkine in vascular biology: from basic research to clinical disease . Arterioscler. Thromb. Vasc. Biol. . 24 . 1 . 34–40 . 2004 . 12969992 . 10.1161/01.ATV.0000095360.62479.1F . 6183022 . free .
• Umehara H, Tanaka M, Sawaki T, Jin ZX, Huang CR, Dong L, Kawanami T, Karasawa H, Masaki Y, Fukushima T, Hirose Y, Okazaki T . Fractalkine in rheumatoid arthritis and allied conditions . Mod Rheumatol . 16 . 3 . 124–30 . 2006 . 16767549 . 10.1007/s10165-006-0471-9 . 10199059 .

Notes and References

1. Pan Y, Lloyd C, Zhou H, Dolich S, Deeds J, Gonzalo JA, Vath J, Gosselin M, Ma J, Dussault B, Woolf E, Alperin G, Culpepper J, Gutierrez-Ramos JC, Gearing D . Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation . Nature . 387 . 6633 . 611–617 . 1997 . 9177350 . 10.1038/42491 . 1997Natur.387..611P . 4307876 .
2. Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ . A new class of membrane-bound chemokine with a CX3C motif . Nature . 385 . 6617 . 640–644 . 1997 . 9024663 . 10.1038/385640a0 . 1997Natur.385..640B . 4322166 .
3. Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, Kakizaki M, Takagi S, Nomiyama H, Schall TJ, Yoshie O . Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion . Cell . 91 . 4 . 521–530 . 1997 . 9390561 . 10.1016/S0092-8674(00)80438-9 . 17281691 . free .
4. Nomiyama H, Imai T, Kusuda J, Miura R, Callen DF, Yoshie O . Human chemokines fractalkine (SCYD1), MDC (SCYA22) and TARC (SCYA17) are clustered on chromosome 16q13 . Cytogenet. Cell Genet. . 81 . 1 . 10–11 . 1998 . 9691168 . 10.1159/000015000 . 2024-07-29 . 46851784 .
5. Characterization of fractalkine in rat brain cells: migratory and activation signals for CX3CR-1-expressing microglia. Journal of Immunology. 1999-08-01. 0022-1767. 10415068. 1628–1635. 163. 3. D.. Maciejewski-Lenoir. S.. Chen. L.. Feng. R.. Maki. K. B.. Bacon. 10.4049/jimmunol.163.3.1628 . free.
6. Sheridan GK, Wdowicz A, Pickering M, Watters O, Halley P, O'Sullivan NC, Mooney C, O'Connell DJ, O'Connor JJ, Murphy KJ . CX3CL1 is up-regulated in the rat hippocampus during memory-associated synaptic plasticity . Front Cell Neurosci . 8 . 233 . 2014 . 25161610 . 4130185 . 10.3389/fncel.2014.00233 . free .