Biology:TRAIL

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Short description: Mammalian protein


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Generic protein structure example

In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.[1][2]

TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumor cells,[3] by binding to certain death receptors. TRAIL and its receptors have been used as the targets of several anti-cancer therapeutics since the mid-1990s, such as Mapatumumab. However, as of 2013, these have not shown significant survival benefit.[4] TRAIL has also been implicated as a pathogenic or protective factor in various pulmonary diseases, particularly pulmonary arterial hypertension.[5]

TRAIL has also been designated CD253 (cluster of differentiation 253) and TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10).[3]

Gene

In humans, the gene that encodes TRAIL is located at chromosome 3q26, which is not close to other TNF family members.[1] The genomic structure of the TRAIL gene spans approximately 20 kb and is composed of five exonic segments 222, 138, 42, 106, and 1245 nucleotides and four introns of approximately 8.2, 3.2, 2.3 and 2.3 kb.

The TRAIL gene lacks TATA and CAAT boxes and the promoter region contains putative response elements for transcription factors GATA, AP-1, C/EBP, SP-1, OCT-1, AP3, PEA3, CF-1, and ISRE.[citation needed]

The TRAIL gene as a drug target

TIC10 (which causes expression of TRAIL) was investigated in mice with various tumour types.[4]

Small molecule ONC201 causes expression of TRAIL which kills some cancer cells.[6]

Structure

TRAIL shows homology to other members of the tumor necrosis factor superfamily. It is composed of 281 amino acids and has characteristics of a type II transmembrane protein. The N-terminal cytoplasmic domain is not conserved across family members, however, the C-terminal extracellular domain is conserved and can be proteolytically cleaved from the cell surface. TRAIL forms a homotrimer that binds three receptor molecules.

Function

TRAIL binds to the death receptors DR4 (TRAIL-RI) and DR5 (TRAIL-RII). The process of apoptosis is caspase-8-dependent. Caspase-8 activates downstream effector caspases including procaspase-3, -6, and -7, leading to activation of specific kinases.[7] TRAIL also binds the receptors DcR1 and DcR2, which do not contain a cytoplasmic domain (DcR1) or contain a truncated death domain (DcR2). DcR1 functions as a TRAIL-neutralizing decoy-receptor. The cytoplasmic domain of DcR2 is functional and activates NFkappaB. In cells expressing DcR2, TRAIL binding therefore activates NFkappaB, leading to transcription of genes known to antagonize the death signaling pathway and/or to promote inflammation. Application of engineered ligands that have variable affinity for different death (DR4 and DR5) and decoy receptors (DCR1 and DCR2) may allow selective targeting of cancer cells by controlling activation of Type 1/Type 2 pathways of cell death and single cell fluctuations. Luminescent iridium complex-peptide hybrids, which mimic TRAIL, have recently been synthesized in vitro. These artificial TRAIL mimics bind to DR4/DR5 on cancer cells and induce cell death via both apoptosis and necrosis, which makes them a potential candidate for anticancer drug development.[8][9]

The TRAIL receptors as a drug target

In clinical trials only a small proportion of cancer patients responded to various drugs that targeted TRAIL death receptors. Many cancer cell lines develop resistance to TRAIL and limits the efficacy of TRAIL-based therapies.[10]

Interactions

TRAIL has been shown to interact with TNFRSF10B.[11][12][13]

See also

References

  1. ↑ 1.0 1.1 "Identification and characterization of a new member of the TNF family that induces apoptosis". Immunity 3 (6): 673–82. December 1995. doi:10.1016/1074-7613(95)90057-8. PMID 8777713. 
  2. ↑ "Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family". The Journal of Biological Chemistry 271 (22): 12687–90. May 1996. doi:10.1074/jbc.271.22.12687. PMID 8663110. 
  3. ↑ 3.0 3.1 "TNFSF10". NCBI Gene. https://www.ncbi.nlm.nih.gov/gene/8743. 
  4. ↑ 4.0 4.1 "Small-molecule drug drives cancer cells to suicide". Nature 494. February 2013. doi:10.1038/nature.2013.12385. 
  5. ↑ "Divergent Roles for TRAIL in Lung Diseases" (in en). Frontiers in Medicine 5: 212. 2018. doi:10.3389/fmed.2018.00212. PMID 30101145. 
  6. ↑ ONC201: Stressing tumors to death. Feb 2016
  7. ↑ "Differential cleavage of Mst1 by caspase-7/-3 is responsible for TRAIL-induced activation of the MAPK superfamily". Cellular Signalling 20 (5): 892–906. May 2008. doi:10.1016/j.cellsig.2008.01.001. PMID 18276109. 
  8. ↑ "Design and synthesis of a luminescent iridium complex-peptide hybrid (IPH) that detects cancer cells and induces their apoptosis". Bioorganic & Medicinal Chemistry 26 (17): 4804–4816. September 2018. doi:10.1016/j.bmc.2018.08.016. PMID 30177492. 
  9. ↑ "Luminescent Iridium Complex-Peptide Hybrids (IPHs) for Therapeutics of Cancer: Design and Synthesis of IPHs for Detection of Cancer Cells and Induction of Their Necrosis-Type Cell Death". Bioinorganic Chemistry and Applications 2018: 7578965. 2018-08-01. doi:10.1155/2018/7578965. PMID 30154833. 
  10. ↑ "On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics". Oncogene 32 (11): 1341–50. March 2013. doi:10.1038/onc.2012.164. PMID 22580613. 
  11. ↑ "Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3)". FEBS Letters 485 (2–3): 135–41. November 2000. doi:10.1016/S0014-5793(00)02219-5. PMID 11094155. 
  12. ↑ "TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL". The EMBO Journal 16 (17): 5386–97. September 1997. doi:10.1093/emboj/16.17.5386. PMID 9311998. 
  13. ↑ "Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5". Molecular Cell 4 (4): 563–71. October 1999. doi:10.1016/S1097-2765(00)80207-5. PMID 10549288. 

Further reading

  • "Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy". Cytokine & Growth Factor Reviews 14 (3–4): 337–48. 2004. doi:10.1016/S1359-6101(03)00029-7. PMID 12787570. 
  • "Specificity of molecular recognition learned from the crystal structures of TRAIL and the TRAIL:sDR5 complex". TRAIL (TNF-Related Apoptosis-Inducing Ligand). Vitamins & Hormones. 67. 2004. pp. 1–17. doi:10.1016/S0083-6729(04)67001-4. ISBN 978-0-12-709867-8. 
  • "TRAIL (CD253), a new member of the TNF superfamily". Journal of Biological Regulators and Homeostatic Agents 19 (1–2): 73–7. 2005. PMID 16178278. 
  • "APO2 ligand/tumor necrosis factor-related apoptosis-inducing ligand in prostate cancer therapy". Frontiers in Bioscience 11: 1549–68. May 2006. doi:10.2741/1903. PMID 16368536. 
  • "TRAIL agonists rescue mice from radiation-induced lung injury". bioRxiv. June 2023. doi:10.1101/2023.06.12.544681. 

External links



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