title: Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis.
abstract: 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.
authors.affiliation: Department of Pathology, Immunology and Virology Program, University of Massachusetts Medical School, Worcester, 01655, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Clancy
authors.forename: Karen
authors.initials: K
authors.lastname: Mruk
authors.forename: Kristina
authors.initials: K
authors.lastname: Archer
authors.forename: Melissa
authors.initials: M
authors.lastname: Woelfel
authors.forename: Juthathip
authors.initials: J
authors.lastname: Mongkolsapaya
authors.forename: Gavin
authors.initials: G
authors.lastname: Screaton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.forename: Francis Ka-Ming
authors.initials: FK
authors.lastname: Chan
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism*; D001667:Binding, Competitive / Q000276:immunology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D013755:Tetradecanoylphorbol Acetate; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C451501:TNFRSF10D protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate