UMMS Affiliation

Department of Pathology

Date

12-13-2005

Document Type

Article

Subjects

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

Disciplines

Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences | Pathology

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.

Comments

Citation: Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18099-104. Epub 2005 Nov 30. Link to article on publisher's site

Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/misc/authorfaq.shtml.

Related Resources

Link to Article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID

16319225

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