CCL5

Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the CCL5 gene.{{cite journal | vauthors = Donlon TA, Krensky AM, Wallace MR, Collins FS, Lovett M, Clayberger C | title = Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12 | journal = Genomics | volume = 6 | issue = 3 | pages = 548–553 | date = March 1990 | pmid = 1691736 | doi = 10.1016/0888-7543(90)90485-D | hdl-access = free | hdl = 2027.42/28717 }} The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome.{{Cite journal| vauthors = Chen L, Zhang Q, Yu C, Wang F, Kong X |date=2020-03-01|title=Functional roles of CCL5/RANTES in liver disease |journal=Liver Research |volume=4|issue=1|pages=28–34 |doi=10.1016/j.livres.2020.01.002 |s2cid=212858919 |doi-access=free }}

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.{{cite web | vauthors = Cohen P | date = 14 December 1996 | title = 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 | publisher = Copyright New Scientist Ltd. | url = https://www.newscientist.com/article/mg15220603-700-hooked-on-hiv-whats-the-connection-between-a-1980s-film-character-and-the-cutting-edge-of-aids-research-philip-cohen-reports-on-a-protein-thats-unlocking-hivs-mysteries/#ixzz768mxV32v }}

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.{{Cite journal |vauthors=Appay V, Rowland-Jones SL |date=January 2001 |title=RANTES: a versatile and controversial chemokine |journal=Trends in Immunology |language=en |volume=22 |issue=2 |pages=83–87 |doi=10.1016/S1471-4906(00)01812-3|pmid=11286708 }} 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.{{cite journal | vauthors = Maghazachi AA, Al-Aoukaty A, Schall TJ | title = CC chemokines induce the generation of killer cells from CD56+ cells | journal = European Journal of Immunology | volume = 26 | issue = 2 | pages = 315–319 | date = February 1996 | pmid = 8617297 | doi = 10.1002/eji.1830260207 | s2cid = 25389419 }} It is also an HIV-suppressive factor released from CD8+ T cells {{cite journal | vauthors = Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P | title = Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells | journal = Science | volume = 270 | issue = 5243 | pages = 1811–1815 | date = December 1995 | pmid = 8525373 | doi = 10.1126/science.270.5243.1811 | bibcode = 1995Sci...270.1811C | s2cid = 84062618 | url = https://zenodo.org/record/1231052 }}

The chemokine CCL5 is mainly expressed by T-cells and monocytes,{{cite journal | vauthors = Zeng Z, Lan T, Wei Y, Wei X | title = CCL5/CCR5 axis in human diseases and related treatments | journal = Genes & Diseases | volume = 9 | issue = 1 | pages = 12–27 | date = January 2022 | pmid = 34514075 | pmc = 8423937 | doi = 10.1016/j.gendis.2021.08.004 }} and it has not been shown to be expressed by B-cells.{{cite journal | vauthors = Krensky AM, Ahn YT | title = Mechanisms of disease: regulation of RANTES (CCL5) in renal disease | journal = Nature Clinical Practice. Nephrology | volume = 3 | issue = 3 | pages = 164–170 | date = March 2007 | pmid = 17322928 | pmc = 2702760 | doi = 10.1038/ncpneph0418 }} 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, 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.

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).{{cite journal | vauthors = Schall TJ, Jongstra J, Dyer BJ, Jorgensen J, Clayberger C, Davis MM, Krensky AM | title = A human T cell-specific molecule is a member of a new gene family | journal = Journal of Immunology | volume = 141 | issue = 3 | pages = 1018–1025 | date = August 1988 | doi = 10.4049/jimmunol.141.3.1018 | pmid = 2456327 | s2cid = 41891558 | url = http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=2456327 | doi-access = free }}{{cite book | author = Alan M. Krensky | title = Biology of the Chemokine in Rantes (Molecular Biology Intelligence Unit) | publisher = R G Landes Co. | year = 1995 | isbn = 978-1-57059-253-9 }}{{cite journal | vauthors = Song A, Chen YF, Thamatrakoln K, Storm TA, Krensky AM | title = RFLAT-1: a new zinc finger transcription factor that activates RANTES gene expression in T lymphocytes | journal = Immunity | volume = 10 | issue = 1 | pages = 93–103 | date = January 1999 | pmid = 10023774 | doi = 10.1016/S1074-7613(00)80010-2 | doi-access = free }}{{cite journal | vauthors = Song A, Nikolcheva T, Krensky AM | title = Transcriptional regulation of RANTES expression in T lymphocytes | journal = Immunological Reviews | volume = 177 | pages = 236–245 | date = October 2000 | pmid = 11138780 | doi = 10.1034/j.1600-065X.2000.17610.x | s2cid = 30184294 }} 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. 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.{{cite journal | vauthors = Kumar D, Hosse J, von Toerne C, Noessner E, Nelson PJ | title = JNK MAPK pathway regulates constitutive transcription of CCL5 by human NK cells through SP1 | journal = Journal of Immunology | volume = 182 | issue = 2 | pages = 1011–1020 | date = January 2009 | pmid = 19124744 | doi = 10.4049/jimmunol.182.2.1011 | s2cid = 1190644 | doi-access = free }} 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.{{cite journal | vauthors = Swanson BJ, Murakami M, Mitchell TC, Kappler J, Marrack P | title = RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process | journal = Immunity | volume = 17 | issue = 5 | pages = 605–615 | date = November 2002 | pmid = 12433367 | doi = 10.1016/S1074-7613(02)00456-9 | doi-access = free }}

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. 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.{{cite journal | vauthors = Vangelista L, Secchi M, Liu X, Bachi A, Jia L, Xu Q, Lusso P | title = Engineering of Lactobacillus jensenii to secrete RANTES and a CCR5 antagonist analogue as live HIV-1 blockers | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 7 | pages = 2994–3001 | date = July 2010 | pmid = 20479208 | pmc = 2897324 | doi = 10.1128/AAC.01492-09 }}*{{lay source |template = cite web|vauthors = ((American Society for Microbiology))|url = https://www.sciencedaily.com/releases/2010/07/100721153305.htm|title = Microbicide containing engineered bacteria may inhibit HIV-1|date = July 24, 2010 |website = Science Daily }}

Interactions

CCL5 has been shown to interact with CCR3,{{cite journal | vauthors = Daugherty BL, Siciliano SJ, DeMartino JA, Malkowitz L, Sirotina A, Springer MS | title = Cloning, expression, and characterization of the human eosinophil eotaxin receptor | journal = The Journal of Experimental Medicine | volume = 183 | issue = 5 | pages = 2349–2354 | date = May 1996 | pmid = 8642344 | pmc = 2192548 | doi = 10.1084/jem.183.5.2349 }}{{cite journal | vauthors = Struyf S, Menten P, Lenaerts JP, Put W, D'Haese A, De Clercq E, Schols D, Proost P, Van Damme J | display-authors = 6 | title = 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 | journal = European Journal of Immunology | volume = 31 | issue = 7 | pages = 2170–2178 | date = July 2001 | pmid = 11449371 | doi = 10.1002/1521-4141(200107)31:7<2170::AID-IMMU2170>3.0.CO;2-D | doi-access = free }} CCR5{{cite journal | vauthors = Slimani H, Charnaux N, Mbemba E, Saffar L, Vassy R, Vita C, Gattegno L | title = Interaction of RANTES with syndecan-1 and syndecan-4 expressed by human primary macrophages | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1617 | issue = 1–2 | pages = 80–88 | date = October 2003 | pmid = 14637022 | doi = 10.1016/j.bbamem.2003.09.006 | doi-access = }}{{cite journal | vauthors = Proudfoot AE, Fritchley S, Borlat F, Shaw JP, Vilbois F, Zwahlen C, Trkola A, Marchant D, Clapham PR, Wells TN | display-authors = 6 | title = The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 14 | pages = 10620–10626 | date = April 2001 | pmid = 11116158 | doi = 10.1074/jbc.M010867200 | doi-access = free }}{{cite journal | vauthors = Laplana M, Fibla J | title = Distribution of functional polymorphic variants of inflammation-related genes RANTES and CCR5 in long-lived individuals | journal = Cytokine | volume = 58 | issue = 1 | pages = 10–13 | date = April 2012 | pmid = 22265023 | doi = 10.1016/j.cyto.2011.12.021 | doi-access = free | hdl = 10459.1/68002 | hdl-access = free }} and CCR1.

CCL5 also activates the G-protein coupled receptor GPR75.{{cite journal | vauthors = Ignatov A, Robert J, Gregory-Evans C, Schaller HC | title = RANTES stimulates Ca2+ mobilization and inositol trisphosphate (IP3) formation in cells transfected with G protein-coupled receptor 75 | journal = British Journal of Pharmacology | volume = 149 | issue = 5 | pages = 490–497 | date = November 2006 | pmid = 17001303 | pmc = 2014681 | doi = 10.1038/sj.bjp.0706909 }}

CCL5 has two mechanisms of action according to its concentration.

The first one occurs at low concentration of the chemokine. CCL5 may act as a monomer or a dimer. Dimerization is not necessary for binding to CCR5. Thus, CCL5 in nanomolar concentration acts as classical chemokine and binds to its receptor. For the acting as classical chemokine and for the dimerization, N terminus of the molecule is important.
The second one occurs at high concentration of the chemokine. CCL5 creates self-aggregates binding to glycosaminoglycans (GAGs) on the cell surface. For that, Glu66 and Glu26 are important. These amino acids are presented on the protein surface and allows ion interactions. In the experiment where these molecules were exchanged for serine, the self-aggregation did not occur.{{cite journal | vauthors = Appay V, Brown A, Cribbes S, Randle E, Czaplewski LG | title = Aggregation of RANTES is responsible for its inflammatory properties. Characterization of nonaggregating, noninflammatory RANTES mutants | journal = The Journal of Biological Chemistry | volume = 274 | issue = 39 | pages = 27505–27512 | date = September 1999 | pmid = 10488085 | doi = 10.1074/jbc.274.39.27505 | doi-access = free }} In vitro, the self-aggregates are strong activators of leukocytes. They can act as mitogens and they are not dependent on binding to the receptor. Activated T-cells (or other cells, for instance monocytes or neutrophils) either proliferate or perform apoptosis, and they release proinflammatory cytokines, such as IL-2, IL-5 and IFN-γ. CCL5 mediated apoptosis in T-cells includes release of cytochrome c in cytoplasm and the activation of caspase-9 and caspase-3. The apoptosis is dependent on GAGs binding on cell surface and there is a requirement of at least 4 CCL5 molecules to induce the apoptosis.{{cite journal | vauthors = Murooka TT, Wong MM, Rahbar R, Majchrzak-Kita B, Proudfoot AE, Fish EN | title = CCL5-CCR5-mediated apoptosis in T cells: Requirement for glycosaminoglycan binding and CCL5 aggregation | journal = The Journal of Biological Chemistry | volume = 281 | issue = 35 | pages = 25184–25194 | date = September 2006 | pmid = 16807236 | doi = 10.1074/jbc.M603912200 | doi-access = free }}

Clinical significance

CCL5 is involved in transplantations, anti-viral immunity, tumor development {{cite journal | vauthors = Lv D, Zhang Y, Kim HJ, Zhang L, Ma X | title = CCL5 as a potential immunotherapeutic target in triple-negative breast cancer | journal = Cellular & Molecular Immunology | volume = 10 | issue = 4 | pages = 303–310 | date = July 2013 | pmid = 23376885 | pmc = 4003203 | doi = 10.1038/cmi.2012.69 }} and numerous human diseases and disorders, for instance viral hepatitis or COVID-19.

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

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. 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.{{cite journal | vauthors = Crawford A, Angelosanto JM, Nadwodny KL, Blackburn SD, Wherry EJ | title = A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection | journal = PLOS Pathogens | volume = 7 | issue = 7 | pages = e1002098 | date = July 2011 | pmid = 21814510 | pmc = 3141034 | doi = 10.1371/journal.ppat.1002098 | veditors = Douek DC | doi-access = free }}

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

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

References

External links

{{UCSC gene info|CCL5}}
{{PDBe-KB2|P13501|C-C motif chemokine 5}}