Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor–Receptor Interactions

Nagamani Vunnam, Chih Hung Lo, Benjamin D. Grant, David D. Thomas, Jonathan N. Sachs

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Dysregulation of tumor necrosis factor (TNF) receptor signaling is a key feature of various inflammatory disorders. Current treatments for TNF-related diseases function either by sequestering ligand or blocking ligand–receptor interactions, which can cause dangerous side effects by inhibiting the receptors that are not involved in the disease condition. Thus, alternate strategies that target receptor–receptor interactions are needed. We hypothesized that the soluble extracellular domain (ECD) of long isoform of death receptor 5 (DR5) could block endogenous receptor assembly, mimicking the biological effect of decoy receptors that lack the death domain to trigger apoptosis. Using live-cell fluorescence resonance energy transfer studies, we demonstrated that soluble ECD disrupts endogenous DR5–DR5 interactions. Cell viability assays were used to demonstrate the complete inhibition of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by the ECD, although TRAIL is still able to bind to the receptor. Importantly, we used mutagenesis to prove that the inhibition of TRAIL-induced apoptosis by the ECD predominantly comes from the disruption of DR5 oligomerization and not ligand sequestration. Inhibition of death receptor activation should have important therapeutic applications in diseases such as nonalcoholic fatty liver disease. More generally, this approach should be generalized to enable the inhibition of other TNF receptor signaling mechanisms that are associated in a wide range of clinical conditions.

Original languageEnglish (US)
Pages (from-to)2943-2953
Number of pages11
JournalJournal of Molecular Biology
Volume429
Issue number19
DOIs
StatePublished - Sep 15 2017

Keywords

  • TNF-related apoptosis inducing ligand
  • death receptor 5
  • pre-ligand assembly domain
  • time-resolved FRET
  • tumor necrosis factor receptors

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