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Apoptotic caspase inhibits innate immune signaling by cleaving NF-κBs in both Mammals and Flies

Di Wu1, Zhaowei Wang2, Jing Zhang3,4

  • 1State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.

Cell Death & Disease
|August 24, 2022
PubMed

Insights

Apoptotic effector caspases, like caspase-3, suppress innate immune responses by degrading key NF-κB signaling proteins. Inhibiting apoptosis enhances immune signaling, revealing caspases as crucial regulators of immune balance.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Innate immunity relies on controlled signaling pathways for effective defense.
  • Dysregulation of immune responses can lead to disease.
  • Caspases are key regulators of apoptosis, but their role in immune signaling is complex.

Purpose of the Study:

  • To investigate the role of apoptotic effector caspases in regulating innate immune signaling.
  • To determine if caspases directly impact NF-κB pathway components.
  • To explore the conservation of this regulatory mechanism across species.

Main Methods:

  • Induction of apoptosis and caspase-3 overexpression in human and murine cells.
  • Analysis of cytokine signaling pathways.
  • Site-directed mutagenesis to create caspase-resistant NF-κB mutants.
  • Investigation of Toll signaling in Drosophila melanogaster.

Main Results:

  • Apoptosis induction or caspase-3 overexpression significantly reduced cytokine signaling.
  • Loss of caspase-3 or apoptosis inhibition enhanced immune signaling.
  • Caspase-3 directly cleaved NF-κB members (p65/RelA, RelB, c-Rel).
  • Caspase-3-resistant NF-κB mutants partially restored signaling.
  • Apoptotic pathways in Drosophila also inhibited Toll signaling via effector caspases.

Conclusions:

  • Mammalian caspase-3 and Drosophila effector caspases (drICE, DCP-1) act as repressors of NF-κB-mediated innate immunity.
  • Caspase activity is critical for controlling immune signaling balance.
  • Effector caspases represent a conserved mechanism for regulating innate immune responses.

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