CCL5 explained

Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the CCL5 gene.[1] The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome.[2]

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.[3]

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.[4] 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.[5] It is also an HIV-suppressive factor released from CD8+ T cells [6]

The chemokine CCL5 is mainly expressed by T-cells and monocytes,[7] and it has not been shown to be expressed by B-cells.[8] 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).[9] [10] [11] [12] 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.[13] 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.[14]

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.[6] 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.[15]

Interactions

CCL5 has been shown to interact with CCR3,[16] [17] CCR5[17] [18] [19] [20] and CCR1.[17]

CCL5 also activates the G-protein coupled receptor GPR75.[21]

CCL5 has two mechanisms of action according to its concentration.

Clinical significance

CCL5 is involved in transplantations,[8] anti-viral immunity, tumor development [24] and numerous human diseases and disorders, for instance viral hepatitis or COVID-19.

For instance, CCL5 level is higher during rejection of renal transplant.[8]

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.[25]

Increased levels of CCL5 was discovered in lots of cancers. For instance in breast cancer, hepatocellular carcinoma, stomach cancer, prostate cancer and pancreatic cancer.[7]

CCL5 plays an important role in various human disorders, such as atherosclerosis, COVID-19, SARS,[7] atopic dermatitis, asthma, glomerulonephritis, alcohol liver disease, acute liver failure and viral hepatitis.

See also

Further reading

Notes and References

  1. Donlon TA, Krensky AM, Wallace MR, Collins FS, Lovett M, Clayberger C . Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12 . Genomics . 6 . 3 . 548–553 . March 1990 . 1691736 . 10.1016/0888-7543(90)90485-D . free . 2027.42/28717 .
  2. 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 . 10.1016/j.livres.2020.01.002 . 212858919 . free .
  3. Web site: 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. .
  4. Appay V, Rowland-Jones SL . January 2001 . RANTES: a versatile and controversial chemokine . Trends in Immunology . en . 22 . 2 . 83–87 . 10.1016/S1471-4906(00)01812-3. 11286708 .
  5. Maghazachi AA, Al-Aoukaty A, Schall TJ . CC chemokines induce the generation of killer cells from CD56+ cells . European Journal of Immunology . 26 . 2 . 315–319 . February 1996 . 8617297 . 10.1002/eji.1830260207 . 25389419 .
  6. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P . 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 . December 1995 . 8525373 . 10.1126/science.270.5243.1811 . 1995Sci...270.1811C . 84062618 .
  7. Zeng Z, Lan T, Wei Y, Wei X . CCL5/CCR5 axis in human diseases and related treatments . Genes & Diseases . 9 . 1 . 12–27 . January 2022 . 34514075 . 8423937 . 10.1016/j.gendis.2021.08.004 .
  8. Krensky AM, Ahn YT . Mechanisms of disease: regulation of RANTES (CCL5) in renal disease . Nature Clinical Practice. Nephrology . 3 . 3 . 164–170 . March 2007 . 17322928 . 2702760 . 10.1038/ncpneph0418 .
  9. Schall TJ, Jongstra J, Dyer BJ, Jorgensen J, Clayberger C, Davis MM, Krensky AM . A human T cell-specific molecule is a member of a new gene family . Journal of Immunology . 141 . 3 . 1018–1025 . August 1988 . 10.4049/jimmunol.141.3.1018 . 2456327 . 41891558 . free .
  10. Book: Alan M. Krensky . Biology of the Chemokine in Rantes (Molecular Biology Intelligence Unit) . R G Landes Co. . 1995 . 978-1-57059-253-9 .
  11. Song A, Chen YF, Thamatrakoln K, Storm TA, Krensky AM . RFLAT-1: a new zinc finger transcription factor that activates RANTES gene expression in T lymphocytes . Immunity . 10 . 1 . 93–103 . January 1999 . 10023774 . 10.1016/S1074-7613(00)80010-2 . free .
  12. Song A, Nikolcheva T, Krensky AM . Transcriptional regulation of RANTES expression in T lymphocytes . Immunological Reviews . 177 . 236–245 . October 2000 . 11138780 . 10.1034/j.1600-065X.2000.17610.x . 30184294 .
  13. Kumar D, Hosse J, von Toerne C, Noessner E, Nelson PJ . JNK MAPK pathway regulates constitutive transcription of CCL5 by human NK cells through SP1 . Journal of Immunology . 182 . 2 . 1011–1020 . January 2009 . 19124744 . 10.4049/jimmunol.182.2.1011 . 1190644 . free .
  14. Swanson BJ, Murakami M, Mitchell TC, Kappler J, Marrack P . RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process . Immunity . 17 . 5 . 605–615 . November 2002 . 12433367 . 10.1016/S1074-7613(02)00456-9 . free .
  15. Vangelista L, Secchi M, Liu X, Bachi A, Jia L, Xu Q, Lusso P . 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 . July 2010 . 20479208 . 2897324 . 10.1128/AAC.01492-09 .
  16. Daugherty BL, Siciliano SJ, DeMartino JA, Malkowitz L, Sirotina A, Springer MS . Cloning, expression, and characterization of the human eosinophil eotaxin receptor . The Journal of Experimental Medicine . 183 . 5 . 2349–2354 . May 1996 . 8642344 . 2192548 . 10.1084/jem.183.5.2349 .
  17. Struyf S, Menten P, Lenaerts JP, Put W, D'Haese A, De Clercq E, Schols D, Proost P, Van Damme J . 6 . 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 . July 2001 . 11449371 . 10.1002/1521-4141(200107)31:7<2170::AID-IMMU2170>3.0.CO;2-D . free .
  18. Slimani H, Charnaux N, Mbemba E, Saffar L, Vassy R, Vita C, Gattegno L . 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 . October 2003 . 14637022 . 10.1016/j.bbamem.2003.09.006 .
  19. Proudfoot AE, Fritchley S, Borlat F, Shaw JP, Vilbois F, Zwahlen C, Trkola A, Marchant D, Clapham PR, Wells TN . 6 . 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 . April 2001 . 11116158 . 10.1074/jbc.M010867200 . free .
  20. Laplana M, Fibla J . Distribution of functional polymorphic variants of inflammation-related genes RANTES and CCR5 in long-lived individuals . Cytokine . 58 . 1 . 10–13 . April 2012 . 22265023 . 10.1016/j.cyto.2011.12.021 . free . 10459.1/68002 . free .
  21. Ignatov A, Robert J, Gregory-Evans C, Schaller HC . 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 . November 2006 . 17001303 . 2014681 . 10.1038/sj.bjp.0706909 .
  22. Appay V, Brown A, Cribbes S, Randle E, Czaplewski LG . Aggregation of RANTES is responsible for its inflammatory properties. Characterization of nonaggregating, noninflammatory RANTES mutants . The Journal of Biological Chemistry . 274 . 39 . 27505–27512 . September 1999 . 10488085 . 10.1074/jbc.274.39.27505 . free .
  23. Murooka TT, Wong MM, Rahbar R, Majchrzak-Kita B, Proudfoot AE, Fish EN . CCL5-CCR5-mediated apoptosis in T cells: Requirement for glycosaminoglycan binding and CCL5 aggregation . The Journal of Biological Chemistry . 281 . 35 . 25184–25194 . September 2006 . 16807236 . 10.1074/jbc.M603912200 . free .
  24. Lv D, Zhang Y, Kim HJ, Zhang L, Ma X . CCL5 as a potential immunotherapeutic target in triple-negative breast cancer . Cellular & Molecular Immunology . 10 . 4 . 303–310 . July 2013 . 23376885 . 4003203 . 10.1038/cmi.2012.69 .
  25. Crawford A, Angelosanto JM, Nadwodny KL, Blackburn SD, Wherry EJ . A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection . PLOS Pathogens . 7 . 7 . e1002098 . July 2011 . 21814510 . 3141034 . 10.1371/journal.ppat.1002098 . Douek DC . free .

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