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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine with potential therapeutic value against cancers because of its selective cytotoxicity to many transformed, but not normal, cells. The "decoy receptors" TRAIL-R3 (TR3) and TRAIL-R4 (TR4) were believed to negatively regulate TRAIL-induced cytotoxicity by competing for ligand binding with TRAIL-R1 (TR1) and TRAIL-R2 (TR2). Here, we show that inhibition of TRAIL-induced apoptosis by TR4 critically depends on its association with TR2 via the NH(2)-terminal preligand assembly domain overlapping the first partial cysteine-rich domain of both receptors. By contrast, ligand binding by TR4 is dispensable for its apoptosis inhibitory function, thereby excluding the possibility that TR4 was a "decoy" to inhibit apoptosis by binding up TRAIL. In primary CD8(+) T cells, which express only TR2 and TR4 and are resistant to TRAIL-induced apoptosis, stimulation with phorbol myristate acetate abrogated the ligand-independent interaction between TR2 and TR4 and enhanced their sensitivity to TRAIL-induced apoptosis. Hence, whereas most TNF receptors normally form only homotrimeric complexes, the preligand assembly domains in TR2 and TR4 permit mixed complex formation as a means to regulate apoptosis induction. We propose that TR4 is a "regulatory" rather than "decoy" receptor that inhibits apoptosis signaling by TRAIL through this previously uncharacterized ligand-independent mechanism.

Original publication

DOI

10.1073/pnas.0507329102

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

13/12/2005

Volume

102

Pages

18099 - 18104

Keywords

Apoptosis, Apoptosis Regulatory Proteins, Binding, Competitive, Blotting, Western, CD8-Positive T-Lymphocytes, Humans, Immunoprecipitation, Jurkat Cells, Membrane Glycoproteins, Protein Structure, Tertiary, RNA Interference, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, Tetradecanoylphorbol Acetate, Tumor Necrosis Factor Decoy Receptors, Tumor Necrosis Factor-alpha