Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1997 Sep 1;16(17):5386–5397. doi: 10.1093/emboj/16.17.5386

TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL.

H Walczak 1, M A Degli-Esposti 1, R S Johnson 1, P J Smolak 1, J Y Waugh 1, N Boiani 1, M S Timour 1, M J Gerhart 1, K A Schooley 1, C A Smith 1, R G Goodwin 1, C T Rauch 1
PMCID: PMC1170170  PMID: 9311998

Abstract

TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines and induces apoptosis in a wide variety of cells. Based on homology searching of a private database, a receptor for TRAIL (DR4 or TRAIL-R1) was recently identified. Here we report the identification of a distinct receptor for TRAIL, TRAIL-R2, by ligand-based affinity purification and subsequent molecular cloning. TRAIL-R2 was purified independently as the only receptor for TRAIL detectable on the surface of two different human cell lines that undergo apoptosis upon stimulation with TRAIL. TRAIL-R2 contains two extracellular cysteine-rich repeats, typical for TNF receptor (TNFR) family members, and a cytoplasmic death domain. TRAIL binds to recombinant cell-surface-expressed TRAIL-R2, and TRAIL-induced apoptosis is inhibited by a TRAIL-R2-Fc fusion protein. TRAIL-R2 mRNA is widely expressed and the gene encoding TRAIL-R2 is located on human chromosome 8p22-21. Like TRAIL-R1, TRAIL-R2 engages a caspase-dependent apoptotic pathway but, in contrast to TRAIL-R1, TRAIL-R2 mediates apoptosis via the intracellular adaptor molecule FADD/MORT1. The existence of two distinct receptors for the same ligand suggests an unexpected complexity to TRAIL biology, reminiscent of dual receptors for TNF, the canonical member of this family.

Full Text

The Full Text of this article is available as a PDF (891.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alderson M. R., Tough T. W., Davis-Smith T., Braddy S., Falk B., Schooley K. A., Goodwin R. G., Smith C. A., Ramsdell F., Lynch D. H. Fas ligand mediates activation-induced cell death in human T lymphocytes. J Exp Med. 1995 Jan 1;181(1):71–77. doi: 10.1084/jem.181.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ameisen J. C., Estaquier J., Idziorek T. From AIDS to parasite infection: pathogen-mediated subversion of programmed cell death as a mechanism for immune dysregulation. Immunol Rev. 1994 Dec;142:9–51. doi: 10.1111/j.1600-065x.1994.tb00882.x. [DOI] [PubMed] [Google Scholar]
  3. Badley A. D., Dockrell D., Simpson M., Schut R., Lynch D. H., Leibson P., Paya C. V. Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor. J Exp Med. 1997 Jan 6;185(1):55–64. doi: 10.1084/jem.185.1.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Badley A. D., McElhinny J. A., Leibson P. J., Lynch D. H., Alderson M. R., Paya C. V. Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes. J Virol. 1996 Jan;70(1):199–206. doi: 10.1128/jvi.70.1.199-206.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bellgrau D., Gold D., Selawry H., Moore J., Franzusoff A., Duke R. C. A role for CD95 ligand in preventing graft rejection. Nature. 1995 Oct 19;377(6550):630–632. doi: 10.1038/377630a0. [DOI] [PubMed] [Google Scholar]
  6. Biemann K. Appendix 5. Nomenclature for peptide fragment ions (positive ions). Methods Enzymol. 1990;193:886–887. doi: 10.1016/0076-6879(90)93460-3. [DOI] [PubMed] [Google Scholar]
  7. Bodmer J. L., Burns K., Schneider P., Hofmann K., Steiner V., Thome M., Bornand T., Hahne M., Schröter M., Becker K. TRAMP, a novel apoptosis-mediating receptor with sequence homology to tumor necrosis factor receptor 1 and Fas(Apo-1/CD95). Immunity. 1997 Jan;6(1):79–88. doi: 10.1016/s1074-7613(00)80244-7. [DOI] [PubMed] [Google Scholar]
  8. Boldin M. P., Goncharov T. M., Goltsev Y. V., Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell. 1996 Jun 14;85(6):803–815. doi: 10.1016/s0092-8674(00)81265-9. [DOI] [PubMed] [Google Scholar]
  9. Brojatsch J., Naughton J., Rolls M. M., Zingler K., Young J. A. CAR1, a TNFR-related protein, is a cellular receptor for cytopathic avian leukosis-sarcoma viruses and mediates apoptosis. Cell. 1996 Nov 29;87(5):845–855. doi: 10.1016/s0092-8674(00)81992-3. [DOI] [PubMed] [Google Scholar]
  10. Bäumler C. B., Böhler T., Herr I., Benner A., Krammer P. H., Debatin K. M. Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children. Blood. 1996 Sep 1;88(5):1741–1746. [PubMed] [Google Scholar]
  11. Cerami A., Beutler B. The role of cachectin/TNF in endotoxic shock and cachexia. Immunol Today. 1988 Jan;9(1):28–31. doi: 10.1016/0167-5699(88)91353-9. [DOI] [PubMed] [Google Scholar]
  12. Chinnaiyan A. M., O'Rourke K., Tewari M., Dixit V. M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell. 1995 May 19;81(4):505–512. doi: 10.1016/0092-8674(95)90071-3. [DOI] [PubMed] [Google Scholar]
  13. Cohen J. Cytokines as mediators of graft-versus-host disease. Bone Marrow Transplant. 1988 May;3(3):193–197. [PubMed] [Google Scholar]
  14. Dhein J., Walczak H., Bäumler C., Debatin K. M., Krammer P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) Nature. 1995 Feb 2;373(6513):438–441. doi: 10.1038/373438a0. [DOI] [PubMed] [Google Scholar]
  15. French L. E., Hahne M., Viard I., Radlgruber G., Zanone R., Becker K., Müller C., Tschopp J. Fas and Fas ligand in embryos and adult mice: ligand expression in several immune-privileged tissues and coexpression in adult tissues characterized by apoptotic cell turnover. J Cell Biol. 1996 Apr;133(2):335–343. doi: 10.1083/jcb.133.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Galle P. R., Hofmann W. J., Walczak H., Schaller H., Otto G., Stremmel W., Krammer P. H., Runkel L. Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med. 1995 Nov 1;182(5):1223–1230. doi: 10.1084/jem.182.5.1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hahne M., Rimoldi D., Schröter M., Romero P., Schreier M., French L. E., Schneider P., Bornand T., Fontana A., Lienard D. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science. 1996 Nov 22;274(5291):1363–1366. doi: 10.1126/science.274.5291.1363. [DOI] [PubMed] [Google Scholar]
  18. Hsu H., Xiong J., Goeddel D. V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995 May 19;81(4):495–504. doi: 10.1016/0092-8674(95)90070-5. [DOI] [PubMed] [Google Scholar]
  19. Ju S. T., Panka D. J., Cui H., Ettinger R., el-Khatib M., Sherr D. H., Stanger B. Z., Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. doi: 10.1038/373444a0. [DOI] [PubMed] [Google Scholar]
  20. Kischkel F. C., Hellbardt S., Behrmann I., Germer M., Pawlita M., Krammer P. H., Peter M. E. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995 Nov 15;14(22):5579–5588. doi: 10.1002/j.1460-2075.1995.tb00245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kitson J., Raven T., Jiang Y. P., Goeddel D. V., Giles K. M., Pun K. T., Grinham C. J., Brown R., Farrow S. N. A death-domain-containing receptor that mediates apoptosis. Nature. 1996 Nov 28;384(6607):372–375. doi: 10.1038/384372a0. [DOI] [PubMed] [Google Scholar]
  22. Kägi D., Vignaux F., Ledermann B., Bürki K., Depraetere V., Nagata S., Hengartner H., Golstein P. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science. 1994 Jul 22;265(5171):528–530. doi: 10.1126/science.7518614. [DOI] [PubMed] [Google Scholar]
  23. Mann M., Wilm M. Error-tolerant identification of peptides in sequence databases by peptide sequence tags. Anal Chem. 1994 Dec 15;66(24):4390–4399. doi: 10.1021/ac00096a002. [DOI] [PubMed] [Google Scholar]
  24. March C. J., Mosley B., Larsen A., Cerretti D. P., Braedt G., Price V., Gillis S., Henney C. S., Kronheim S. R., Grabstein K. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature. 1985 Jun 20;315(6021):641–647. doi: 10.1038/315641a0. [DOI] [PubMed] [Google Scholar]
  25. Marsters S. A., Sheridan J. P., Donahue C. J., Pitti R. M., Gray C. L., Goddard A. D., Bauer K. D., Ashkenazi A. Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B. Curr Biol. 1996 Dec 1;6(12):1669–1676. doi: 10.1016/s0960-9822(02)70791-4. [DOI] [PubMed] [Google Scholar]
  26. Mohler K. M., Torrance D. S., Smith C. A., Goodwin R. G., Stremler K. E., Fung V. P., Madani H., Widmer M. B. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol. 1993 Aug 1;151(3):1548–1561. [PubMed] [Google Scholar]
  27. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  28. Muzio M., Chinnaiyan A. M., Kischkel F. C., O'Rourke K., Shevchenko A., Ni J., Scaffidi C., Bretz J. D., Zhang M., Gentz R. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Cell. 1996 Jun 14;85(6):817–827. doi: 10.1016/s0092-8674(00)81266-0. [DOI] [PubMed] [Google Scholar]
  29. Nicoletti I., Migliorati G., Pagliacci M. C., Grignani F., Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991 Jun 3;139(2):271–279. doi: 10.1016/0022-1759(91)90198-o. [DOI] [PubMed] [Google Scholar]
  30. Pan G., O'Rourke K., Chinnaiyan A. M., Gentz R., Ebner R., Ni J., Dixit V. M. The receptor for the cytotoxic ligand TRAIL. Science. 1997 Apr 4;276(5309):111–113. doi: 10.1126/science.276.5309.111. [DOI] [PubMed] [Google Scholar]
  31. Peter M. E., Hellbardt S., Schwartz-Albiez R., Westendorp M. O., Walczak H., Moldenhauer G., Grell M., Krammer P. H. Cell surface sialylation plays a role in modulating sensitivity towards APO-1-mediated apoptotic cell death. Cell Death Differ. 1995 Jul;2(3):163–171. [PubMed] [Google Scholar]
  32. Pitti R. M., Marsters S. A., Ruppert S., Donahue C. J., Moore A., Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996 May 31;271(22):12687–12690. doi: 10.1074/jbc.271.22.12687. [DOI] [PubMed] [Google Scholar]
  33. Revel M., Schattner A. Interferons: cytokines in autoimmunity. Ciba Found Symp. 1987;129:223–233. doi: 10.1002/9780470513484.ch15. [DOI] [PubMed] [Google Scholar]
  34. Strand S., Hofmann W. J., Hug H., Müller M., Otto G., Strand D., Mariani S. M., Stremmel W., Krammer P. H., Galle P. R. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells--a mechanism of immune evasion? Nat Med. 1996 Dec;2(12):1361–1366. doi: 10.1038/nm1296-1361. [DOI] [PubMed] [Google Scholar]
  35. Takahashi T., Tanaka M., Inazawa J., Abe T., Suda T., Nagata S. Human Fas ligand: gene structure, chromosomal location and species specificity. Int Immunol. 1994 Oct;6(10):1567–1574. doi: 10.1093/intimm/6.10.1567. [DOI] [PubMed] [Google Scholar]
  36. Tanaka K., Kikuchi-Yanoshita R., Muraoka M., Konishi M., Oshimura M., Miyaki M. Suppression of tumorigenicity and invasiveness of colon carcinoma cells by introduction of normal chromosome 8p12-pter. Oncogene. 1996 Jan 18;12(2):405–410. [PubMed] [Google Scholar]
  37. Thompson C. B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456–1462. doi: 10.1126/science.7878464. [DOI] [PubMed] [Google Scholar]
  38. Wiley S. R., Schooley K., Smolak P. J., Din W. S., Huang C. P., Nicholl J. K., Sutherland G. R., Smith T. D., Rauch C., Smith C. A. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995 Dec;3(6):673–682. doi: 10.1016/1074-7613(95)90057-8. [DOI] [PubMed] [Google Scholar]
  39. Wilm M., Mann M. Analytical properties of the nanoelectrospray ion source. Anal Chem. 1996 Jan 1;68(1):1–8. doi: 10.1021/ac9509519. [DOI] [PubMed] [Google Scholar]
  40. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  41. Zheng L., Fisher G., Miller R. E., Peschon J., Lynch D. H., Lenardo M. J. Induction of apoptosis in mature T cells by tumour necrosis factor. Nature. 1995 Sep 28;377(6547):348–351. doi: 10.1038/377348a0. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES