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A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins

Nature Immunology volume 2, pages 493–500 (2001)Cite this article

Abstract

Apoptosis-inducing tumor necrosis factor (TNF) family receptors recruit the proforms of caspase family cell death proteases to ligand-receptor complexes through interactions with intracellular adapter proteins. We have found that the GTP-binding protein DAP3 binds directly (with high affinity) to the death domain of TNF-related apoptosis-inducing ligand (TRAIL) receptors, and is required for TRAIL-induced apoptosis. DAP3 also associates with the pro-caspase-8–binding adapter protein Fas-associated death domain (FADD), and links FADD to the TRAIL receptors DR4 and DR5. We have also found that binding of DAP3 to FADD and activation of pro-caspase-8 in an in vitro reconstituted system is GTP-dependent. Elucidation of this mechanism suggests GTP-binding proteins as potential targets for pharmacological intervention in TRAIL-induced apoptosis.

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Figure 1: DAP3 directly binds cytosolic domain of DR4.
Figure 2: Mapping of region in DAP3 required for binding DR4.
Figure 3: DAP3 associates with FADD.
Figure 4: DAP3 is required for recruitment of FADD to TRAIL receptors.
Figure 5: DAP3 modulates apoptosis induction by TRAIL receptors.
Figure 6: DAP3 binds GTP and stimulates activation of pro-caspase-8 in vitro in a GTP-dependent manner.
Figure 7: DAP3 association with FADD is GTP-dependent.

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Acknowledgements

We thank E. Golemis, R. Brent, D. Buckholtz, S. Torii, S. Matsuzawa, A. Kimchi, J. L. Kissil, J. Tschopp, D. Wallach and V. Dixit for plasmids and G. Salvesen, S. Frisch, T. Mustelin and E. Ruoslahti for helpful comments. Supported by the NIH (GM61694) and Human Frontiers Science Program (LT0407).

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    Tadaaki Miyazaki & John C. Reed

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Correspondence to John C. Reed.

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Miyazaki, T., Reed, J. A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins. Nat Immunol 2, 493–500 (2001). https://doi.org/10.1038/88684

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