CCL5

Last updated
CCL5
PDB 1eqt EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CCL5 , D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228, eoCP, C-C motif chemokine ligand 5
External IDs OMIM: 187011; MGI: 98262; HomoloGene: 2244; GeneCards: CCL5; OMA:CCL5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6352

20304

Ensembl

ENSG00000271503
ENSG00000274233

ENSMUSG00000035042

UniProt

P13501

P30882

RefSeq (mRNA)

NM_002985
NM_001278736

NM_013653

RefSeq (protein)

NP_001265665
NP_002976

NP_038681

Location (UCSC) Chr 17: 35.87 – 35.88 Mb Chr 11: 83.42 – 83.42 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the CCL5 gene. [5] The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome. [6]

It is also known as RANTES (regulated on activation, normal T-cell expressed and secreted). 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. [7]

Function

CCL5 belongs to the CC subfamily of chemokines, due to its adjacent cysteines near N terminus. It is an 8kDa protein acting as a classical chemotactic cytokine or chemokine. It consists of 68 amino acids. CCL5 is proinflammatory chemokine, recruiting leukocytes to the site of inflammation. It is chemotactic for T cells, eosinophils, and basophils, but also for monocytes, natural-killer (NK) cells, dendritic cells and mastocytes. [8] With the help of particular cytokines (i.e., IL-2 and IFN-γ) that are released by T cells, CCL5 also induces the proliferation and activation of certain NK cells to form CHAK (CC-Chemokine-activated killer) cells. [9] It is also an HIV-suppressive factor released from CD8+ T cells [10]

The chemokine CCL5 is mainly expressed by T-cells and monocytes, [11] and it has not been shown to be expressed by B-cells. [12] Moreover, it is abundantly expressed by epithelial cells, fibroblasts and thrombocytes. Although it can bind to receptors CCR1, CCR3, CCR4 and CCR5, belonging to seven transmembrane G-protein coupled receptor (GPCRs) family, [8] it has the highest affinity to the CCR5. CCR5 is presented on the surface of T-cells, smooth muscle endothelial cells, epithelial cells, parenchymal cells and other cell types. After the binding of CCL5 to CCR5, phosphoinositide 3-kinase (PI3K) is phosphorylated and subsequently, the phosphorylated PI3K phosphorylates protein kinase B (PKB; also known as Akt) on the serine 473. Then, the Akt/PKB complex phosphorylates and inactivates a serine/threonine protein kinase GSK-3. After the CCL5/CCR5 binding, some other proteins are regulated as well. Bcl2 is more expressed and it induces apoptosis. Beta-catenin is phosphorylated and degraded. An important protein in the cell cycle, Cyclin D, is inhibited by inactivated GSK-3. [11]

CCL5 was first identified in a search for genes expressed "late" (3–5 days) after T cell activation. It was subsequently determined to be a CC chemokine and expressed in more than 100 human diseases. RANTES expression is regulated in T lymphocytes by Kruppel like factor 13 (KLF13). [13] [14] [15] [16] The CCL5 gene is activated after 3–5 days after activation of T-cell via TCR. This is different from the most of other chemokines which are released almost immediately after cell stimulation. Thus, CCL5 is involved in inflammation maintaining. It also induces expression of matrix metalloproteinases which are important for migration of cells into the site of inflammation. [12] CCL5 may be also expressed by NK cells. SP1 transcription factor binds near to CCL5 gene and mediates its constitutive mRNA transcription. The transcription factor is regulated by the JNK/MAPK pathway. [17] Memory CD8+ T-cells are able to secrete CCL5 immediately after TCR stimulation, because they have a large number of preformed CCL5 mRNA in cytoplasm and its secretion is dependent only on translation. [18]

RANTES, along with the related chemokines MIP-1alpha and MIP-1beta, has been identified as a natural HIV-suppressive factor secreted by activated CD8+ T cells and other immune cells. [10] The RANTES protein has been engineered for in vivo production by Lactobacillus bacteria, and this solution is being developed into a possible HIV entry-inhibiting topical microbicide. [19]

Interactions

CCL5 has been shown to interact with CCR3, [20] [21] CCR5 [21] [22] [23] [24] and CCR1. [21] [23]

CCL5 also activates the G-protein coupled receptor GPR75. [25]

CCL5 has two mechanisms of action according to its concentration.

Clinical significance

CCL5 is involved in transplantations, [12] anti-viral immunity, [8] tumor development [28] and numerous human diseases and disorders, for instance viral hepatitis or COVID-19. [6] [11]

For instance, CCL5 level is higher during rejection of renal transplant. [12]

Importance of CCL5 is proved by various microbial strategies to avoid the activity of chemokine. For instance, human cytomegalovirus (HCMV) express a viral chemokine receptor analogue US28, which sequesters CCL5. The chemokine is released by virus-specific activated CD8+ T-cells together with perforin and granzyme A. In cytotoxic T-cells (CTL) killing other cells via Fas/FasL interaction, CCL5 increases HIV-specific T-cell cytotoxicity. Moreover, it is considered that CCL5 in low concentration might inhibit HIV replication. It binds to CCR5 (as well as 2 other chemokines) on the surface of CD4+ T-cells. CCR5 is used by HIV as an entrance molecule to a cell. On the contrary, CCL5 in high concentration might increase HIV replication. [8] The chemokine is involved also in antiviral response against other viruses. For instance, it has been shown that CCL5 is highly expressed in mice infected by lymphocytic choriomeningitis virus. In CCL5 knock-out mice, virus-specific CD8+ T cells had reduced cytotoxic ability, reduced cytokines production and enhanced production of inhibitory molecules. It underscores the importance of CCL5 during chronic viral infection. [29]

Increased levels of CCL5 was discovered in lots of cancers. For instance in breast cancer, [28] hepatocellular carcinoma, [6] stomach cancer, prostate cancer and pancreatic cancer. [11]

CCL5 plays an important role in various human disorders, such as atherosclerosis, COVID-19, SARS, [11] atopic dermatitis, asthma, glomerulonephritis, [8] alcohol liver disease, acute liver failure and viral hepatitis. [6]

See also

Related Research Articles

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<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">CCR5</span> Immune system protein

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.

<span class="mw-page-title-main">CD4</span> Marker on immune cells

In molecular biology, CD4 is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene.

Following infection with HIV-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics and immune function, health care and co-infections as well as viral genetic variability may affect the rate of progression to the point of needing to take medication in order not to develop AIDS.

A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.

<span class="mw-page-title-main">Chemokine receptor</span> Cytokine receptor

Chemokine receptors are cytokine receptors found on the surface of certain cells that interact with a type of cytokine called a chemokine. There have been 20 distinct chemokine receptors discovered in humans. Each has a rhodopsin-like 7-transmembrane (7TM) structure and couples to G-protein for signal transduction within a cell, making them members of a large protein family of G protein-coupled receptors. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium (Ca2+) ions (calcium signaling). This causes cell responses, including the onset of a process known as chemotaxis that traffics the cell to a desired location within the organism. Chemokine receptors are divided into different families, CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors and XC chemokine receptors that correspond to the 4 distinct subfamilies of chemokines they bind. The four subfamilies of chemokines differ in the spacing of structurally important cysteine residues near the N-terminal of the chemokine.

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">XCR1</span> Protein-coding gene in the species Homo sapiens

The "C" sub-family of chemokine receptors contains only one member: XCR1, the receptor for XCL1 and XCL2.

CC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. To date, ten true members of the CC chemokine receptor subfamily have been described. These are named CCR1 to CCR10 according to the IUIS/WHO Subcommittee on Chemokine Nomenclature.

CD4 immunoadhesin is a recombinant fusion protein consisting of a combination of CD4 and the fragment crystallizable region, similarly known as immunoglobulin. It belongs to the antibody (Ig) gene family. CD4 is a surface receptor for human immunodeficiency virus (HIV). The CD4 immunoadhesin molecular fusion allow the protein to possess key functions from each independent subunit. The CD4 specific properties include the gp120-binding and HIV-blocking capabilities. Properties specific to immunoglobulin are the long plasma half-life and Fc receptor binding. The properties of the protein means that it has potential to be used in AIDS therapy as of 2017. Specifically, CD4 immunoadhesin plays a role in antibody-dependent cell-mediated cytotoxicity (ADCC) towards HIV-infected cells. While natural anti-gp120 antibodies exhibit a response towards uninfected CD4-expressing cells that have a soluble gp120 bound to the CD4 on the cell surface, CD4 immunoadhesin, however, will not exhibit a response. One of the most relevant of these possibilities is its ability to cross the placenta.

<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">CCR3 (gene)</span> Protein-coding gene in humans

C-C chemokine receptor type 3 is a protein that in humans is encoded by the CCR3 gene.

<span class="mw-page-title-main">CD244</span> Protein found in humans

CD244 also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.

<span class="mw-page-title-main">KLF13</span> Protein found in humans

Kruppel-like factor 13, also known as KLF13, is a protein that in humans is encoded by the KLF13 gene.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

<span class="mw-page-title-main">CD28 family receptor</span> Group of regulatory cell surface receptors

CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.

References

  1. 1 2 3 ENSG00000274233 GRCh38: Ensembl release 89: ENSG00000271503, ENSG00000274233 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000035042 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Donlon TA, Krensky AM, Wallace MR, Collins FS, Lovett M, Clayberger C (March 1990). "Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12". Genomics. 6 (3): 548–553. doi:10.1016/0888-7543(90)90485-D. hdl: 2027.42/28717 . PMID   1691736.
  6. 1 2 3 4 Chen L, Zhang Q, Yu C, Wang F, Kong X (2020-03-01). "Functional roles of CCL5/RANTES in liver disease". Liver Research. 4 (1): 28–34. doi: 10.1016/j.livres.2020.01.002 . S2CID   212858919.
  7. ↑ Cohen P (14 December 1996). "Hooked on HIV - What's the connection between a 1980s film character and the cutting edge of AIDS research? Philip Cohen reports on a protein that's unlocking HIV's mysteries". Copyright New Scientist Ltd.
  8. 1 2 3 4 5 6 Appay V, Rowland-Jones SL (January 2001). "RANTES: a versatile and controversial chemokine". Trends in Immunology. 22 (2): 83–87. doi:10.1016/S1471-4906(00)01812-3. PMID   11286708.
  9. ↑ Maghazachi AA, Al-Aoukaty A, Schall TJ (February 1996). "CC chemokines induce the generation of killer cells from CD56+ cells". European Journal of Immunology. 26 (2): 315–319. doi:10.1002/eji.1830260207. PMID   8617297. S2CID   25389419.
  10. 1 2 Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P (December 1995). "Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells". Science. 270 (5243): 1811–1815. Bibcode:1995Sci...270.1811C. doi:10.1126/science.270.5243.1811. PMID   8525373. S2CID   84062618.
  11. 1 2 3 4 5 Zeng Z, Lan T, Wei Y, Wei X (January 2022). "CCL5/CCR5 axis in human diseases and related treatments". Genes & Diseases. 9 (1): 12–27. doi:10.1016/j.gendis.2021.08.004. PMC   8423937 . PMID   34514075.
  12. 1 2 3 4 Krensky AM, Ahn YT (March 2007). "Mechanisms of disease: regulation of RANTES (CCL5) in renal disease". Nature Clinical Practice. Nephrology. 3 (3): 164–170. doi:10.1038/ncpneph0418. PMC   2702760 . PMID   17322928.
  13. ↑ Schall TJ, Jongstra J, Dyer BJ, Jorgensen J, Clayberger C, Davis MM, Krensky AM (August 1988). "A human T cell-specific molecule is a member of a new gene family". Journal of Immunology. 141 (3): 1018–1025. doi: 10.4049/jimmunol.141.3.1018 . PMID   2456327. S2CID   41891558.
  14. ↑ Alan M. Krensky (1995). Biology of the Chemokine in Rantes (Molecular Biology Intelligence Unit). R G Landes Co. ISBN   978-1-57059-253-9.
  15. ↑ Song A, Chen YF, Thamatrakoln K, Storm TA, Krensky AM (January 1999). "RFLAT-1: a new zinc finger transcription factor that activates RANTES gene expression in T lymphocytes". Immunity. 10 (1): 93–103. doi: 10.1016/S1074-7613(00)80010-2 . PMID   10023774.
  16. ↑ Song A, Nikolcheva T, Krensky AM (October 2000). "Transcriptional regulation of RANTES expression in T lymphocytes". Immunological Reviews. 177: 236–245. doi:10.1034/j.1600-065X.2000.17610.x. PMID   11138780. S2CID   30184294.
  17. ↑ Kumar D, Hosse J, von Toerne C, Noessner E, Nelson PJ (January 2009). "JNK MAPK pathway regulates constitutive transcription of CCL5 by human NK cells through SP1". Journal of Immunology. 182 (2): 1011–1020. doi: 10.4049/jimmunol.182.2.1011 . PMID   19124744. S2CID   1190644.
  18. ↑ Swanson BJ, Murakami M, Mitchell TC, Kappler J, Marrack P (November 2002). "RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process". Immunity. 17 (5): 605–615. doi: 10.1016/S1074-7613(02)00456-9 . PMID   12433367.
  19. ↑ Vangelista L, Secchi M, Liu X, Bachi A, Jia L, Xu Q, Lusso P (July 2010). "Engineering of Lactobacillus jensenii to secrete RANTES and a CCR5 antagonist analogue as live HIV-1 blockers". Antimicrobial Agents and Chemotherapy. 54 (7): 2994–3001. doi:10.1128/AAC.01492-09. PMC   2897324 . PMID   20479208.*Lay summary in: American Society for Microbiology (July 24, 2010). "Microbicide containing engineered bacteria may inhibit HIV-1". Science Daily.
  20. ↑ Daugherty BL, Siciliano SJ, DeMartino JA, Malkowitz L, Sirotina A, Springer MS (May 1996). "Cloning, expression, and characterization of the human eosinophil eotaxin receptor". The Journal of Experimental Medicine. 183 (5): 2349–2354. doi:10.1084/jem.183.5.2349. PMC   2192548 . PMID   8642344.
  21. 1 2 3 Struyf S, Menten P, Lenaerts JP, Put W, D'Haese A, De Clercq E, et al. (July 2001). "Diverging binding capacities of natural LD78beta isoforms of macrophage inflammatory protein-1alpha to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils". European Journal of Immunology. 31 (7): 2170–2178. doi: 10.1002/1521-4141(200107)31:7<2170::AID-IMMU2170>3.0.CO;2-D . PMID   11449371.
  22. ↑ Slimani H, Charnaux N, Mbemba E, Saffar L, Vassy R, Vita C, Gattegno L (October 2003). "Interaction of RANTES with syndecan-1 and syndecan-4 expressed by human primary macrophages". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1617 (1–2): 80–88. doi:10.1016/j.bbamem.2003.09.006. PMID   14637022.
  23. 1 2 Proudfoot AE, Fritchley S, Borlat F, Shaw JP, Vilbois F, Zwahlen C, et al. (April 2001). "The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity". The Journal of Biological Chemistry. 276 (14): 10620–10626. doi: 10.1074/jbc.M010867200 . PMID   11116158.
  24. ↑ Laplana M, Fibla J (April 2012). "Distribution of functional polymorphic variants of inflammation-related genes RANTES and CCR5 in long-lived individuals". Cytokine. 58 (1): 10–13. doi: 10.1016/j.cyto.2011.12.021 . hdl: 10459.1/68002 . PMID   22265023.
  25. ↑ Ignatov A, Robert J, Gregory-Evans C, Schaller HC (November 2006). "RANTES stimulates Ca2+ mobilization and inositol trisphosphate (IP3) formation in cells transfected with G protein-coupled receptor 75". British Journal of Pharmacology. 149 (5): 490–497. doi:10.1038/sj.bjp.0706909. PMC   2014681 . PMID   17001303.
  26. ↑ Appay V, Brown A, Cribbes S, Randle E, Czaplewski LG (September 1999). "Aggregation of RANTES is responsible for its inflammatory properties. Characterization of nonaggregating, noninflammatory RANTES mutants". The Journal of Biological Chemistry. 274 (39): 27505–27512. doi: 10.1074/jbc.274.39.27505 . PMID   10488085.
  27. ↑ Murooka TT, Wong MM, Rahbar R, Majchrzak-Kita B, Proudfoot AE, Fish EN (September 2006). "CCL5-CCR5-mediated apoptosis in T cells: Requirement for glycosaminoglycan binding and CCL5 aggregation". The Journal of Biological Chemistry. 281 (35): 25184–25194. doi: 10.1074/jbc.M603912200 . PMID   16807236.
  28. 1 2 Lv D, Zhang Y, Kim HJ, Zhang L, Ma X (July 2013). "CCL5 as a potential immunotherapeutic target in triple-negative breast cancer". Cellular & Molecular Immunology. 10 (4): 303–310. doi:10.1038/cmi.2012.69. PMC   4003203 . PMID   23376885.
  29. ↑ Crawford A, Angelosanto JM, Nadwodny KL, Blackburn SD, Wherry EJ (July 2011). Douek DC (ed.). "A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection". PLOS Pathogens. 7 (7): e1002098. doi: 10.1371/journal.ppat.1002098 . PMC   3141034 . PMID   21814510.

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