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NF-κB signaling and cell-fate decision induced by a fast-dissociating tumor necrosis factor mutant

Xiaoling Zhang1, Ning Yin1, Annan Guo2

  • 1Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.

Biochemical and Biophysical Research Communications
|May 31, 2017
PubMed

Insights

Tumor necrosis factor (TNF) mutants with altered binding kinetics selectively activate cell death pathways over survival pathways. This finding highlights the critical role of ligand-receptor binding dynamics in controlling cellular responses.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Tumor necrosis factor (TNF) is a key inflammatory cytokine.
  • TNF signaling can activate both pro-survival (NF-κB) and pro-apoptotic pathways.
  • Selective activation of these pathways is challenging.

Purpose of the Study:

  • To investigate how TNF receptor binding kinetics influence downstream signaling pathways.
  • To determine if altered TNF binding kinetics can selectively activate apoptosis over NF-κB survival signaling.

Main Methods:

  • Utilized TNF mutants with modified TNFR1 binding kinetics.
  • Analyzed NF-κB signaling dynamics, including response time and nuclear translocation.
  • Assessed cell apoptosis induction by TNF mutants.

Main Results:

  • A TNF mutant (R1antTNF) with faster association/dissociation rates altered NF-κB signaling dynamics.
  • R1antTNF induced shorter NF-κB response times and favored fast-response gene activation.
  • At specific concentrations, R1antTNF selectively triggered apoptosis, bypassing NF-κB activation.

Conclusions:

  • Ligand-receptor binding kinetics are crucial for selective pathway activation.
  • TNF binding kinetics can be engineered to bias cellular responses towards apoptosis.
  • This offers potential for targeted therapeutic strategies in diseases involving TNF signaling.
Keywords:
ApoptosisBiased activationGene expressionNF-κB signaling dynamicsReceptor-ligand binding kineticsTNF

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