Department of Pathology
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
Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences | Pathology
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.
Proceedings of the National Academy of Sciences of the United States of America
Clancy, Lauren; Mruk, Karen; Archer, Kristina A.; Woelfel, Melissa A.; Mongkolsapaya, Juthathip; Screaton, Gavin R.; Lenardo, Michael J.; and Chan, Francis Ka-Ming, "Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis" (2005). Open Access Articles. 1754.