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Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis.

Publication ,  Journal Article
Clancy, L; Mruk, K; Archer, K; Woelfel, M; Mongkolsapaya, J; Screaton, G; Lenardo, MJ; Chan, FK-M
Published in: Proc Natl Acad Sci U S A
December 13, 2005

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.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

December 13, 2005

Volume

102

Issue

50

Start / End Page

18099 / 18104

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factor Decoy Receptors
  • Tetradecanoylphorbol Acetate
  • TNF-Related Apoptosis-Inducing Ligand
  • Signal Transduction
  • Receptors, Tumor Necrosis Factor
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • RNA Interference
  • Protein Structure, Tertiary
  • Membrane Glycoproteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Clancy, L., Mruk, K., Archer, K., Woelfel, M., Mongkolsapaya, J., Screaton, G., … Chan, F.-M. (2005). Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci U S A, 102(50), 18099–18104. https://doi.org/10.1073/pnas.0507329102
Clancy, Lauren, Karen Mruk, Kristina Archer, Melissa Woelfel, Juthathip Mongkolsapaya, Gavin Screaton, Michael J. Lenardo, and Francis Ka-Ming Chan. “Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis.Proc Natl Acad Sci U S A 102, no. 50 (December 13, 2005): 18099–104. https://doi.org/10.1073/pnas.0507329102.
Clancy L, Mruk K, Archer K, Woelfel M, Mongkolsapaya J, Screaton G, et al. Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18099–104.
Clancy, Lauren, et al. “Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis.Proc Natl Acad Sci U S A, vol. 102, no. 50, Dec. 2005, pp. 18099–104. Pubmed, doi:10.1073/pnas.0507329102.
Clancy L, Mruk K, Archer K, Woelfel M, Mongkolsapaya J, Screaton G, Lenardo MJ, Chan FK-M. Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18099–18104.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

December 13, 2005

Volume

102

Issue

50

Start / End Page

18099 / 18104

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factor Decoy Receptors
  • Tetradecanoylphorbol Acetate
  • TNF-Related Apoptosis-Inducing Ligand
  • Signal Transduction
  • Receptors, Tumor Necrosis Factor
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • RNA Interference
  • Protein Structure, Tertiary
  • Membrane Glycoproteins