TRAIL receptor-2 signals apoptosis through FADD and caspase-8 (original) (raw)

Nature Cell Biology volume 2, pages 241–243 (2000)Cite this article

Certain cytokines of the tumour-necrosis factor (TNF) family and their cognate receptors (collectively named death receptors) are potent inducers of programmed cell death (apoptosis)1. One such protein is the cell-surface receptor Fas, which, upon ligand binding, trimerizes and recruits the adaptor protein FADD through the cytoplasmic death domain of Fas. FADD then binds and activates procaspase-8 (ref. 1). TRAIL, the most recently identified member of the TNF family of death ligands, can induce apoptosis in a wide variety of tumour cells but not in normal cells2. TRAIL induces apoptosis through two death-domain-containing receptors, TRAIL-R1 (also called death receptor (DR) 4)3 and TRAIL-R2 (or DR5)4,5,6,7,8,9. Investigation of the intracellular signalling pathways responsible for TRAIL-receptor-induced apoptosis has produced controversial results. Genetic evidence10,11 indicates the possible involvement of a FADD-like molecule and caspase-10 rather than of FADD itself and caspase-8. Here we characterize the signalling complex of TRAIL-R2 that is assembled in response to ligand binding. We provide evidence that FADD and caspase-8, but not caspase-10, are recruited to the receptor. Moreover, mutant cell lines that lack FADD or caspase-8 are resistant to TRAIL-induced death. Thus, TRAIL-R2 and Fas death signals rely on identical signalling molecules.

As the TRAIL-receptor DISC isolated from BJAB cells contains a mixture of TRAIL-R1 and TRAIL-R2, we next analysed Jurkat T cells, which have been shown previously to express TRAIL-R2, but not TRAIL-R1, cDNA14. In agreement with this, we found that only TRAIL-R2 bound to immunoprecipitated TRAIL in Jurkat cells (Fig. 1b). Recruitment of FADD and caspase-8 to activated TRAIL-R2 was slightly faster than in BJAB cells — binding was already detected 1 min after ligand addition. However, the more rapid association and activation of caspase-8 was not reflected in an earlier appearance of caspase-3 activity (Fig. 1b). As in BJAB cells, recruitment of cytoplasmic caspase-10 to TRAIL-R2 was not detected, and, in contrast to caspase-8, no processing of caspase-10 was observed in the cytoplasm 60 min after TRAIL addition (Fig. 1b) or at any later time point (data not shown). To exclude the possibility that the incorporation of FADD and caspase-8 is restricted to cells of lymphocytic origin only, we studied DISC assembly in K562 chronic myelogenous leukaemia cells and MCF-7 breast adenocarcinoma cells (Fig. 1c). Again, we found that both caspase-8 and FADD, but not caspase-10 (data not shown), were constituents of the TRAIL-R2 DISC.

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Acknowledgements

We thank S. Masina and M. Thome for critical reading of the manuscript and for discussions, and S. Aslan for editorial assistance. This work was supported by grants from the Swiss National Science Foundation (to J.T.).

Correspondence and requests for materials should be addressed to J.T.

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Authors and Affiliations

  1. Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066, Epalinges, Switzerland
    Jean-Luc Bodmer, Nils Holler, Séverine Reynard, Patrizia Vinciguerra, Pascal Schneider & Jürg Tschopp
  2. Department of Cell Biology, Harvard Medical School , Boston, Massachusetts, 02115, USA
    Peter Juo & Joe Blenis

Authors

  1. Jean-Luc Bodmer
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  2. Nils Holler
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  3. Séverine Reynard
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  4. Patrizia Vinciguerra
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  5. Pascal Schneider
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  6. Peter Juo
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  7. Joe Blenis
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  8. Jürg Tschopp
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Correspondence toJürg Tschopp.

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Bodmer, JL., Holler, N., Reynard, S. et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8.Nat Cell Biol 2, 241–243 (2000). https://doi.org/10.1038/35008667

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