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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Transition from TNF-Induced Inflammation to Death Signaling

Swati Choksi1, Gourav Choudhary1, Zheng-Gang Liu2

  • 1Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Methods in Molecular Biology (Clifton, N.J.)
|November 13, 2020
PubMed

Insights

Tumor necrosis factor (TNF) triggers cell death pathways. RARγ protein acts as a crucial checkpoint, switching inflammatory signals to RIPK1-initiated cell death upon TNF receptor activation.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Inflammation signaling pathways

Background:

  • Tumor necrosis factor (TNF) is a key cytokine involved in inflammation, apoptosis, and necroptosis.
  • TNF initiates signaling cascades through its receptor, TNFR1, leading to cellular events.
  • The precise molecular switch controlling the transition from TNF-induced inflammation to cell death remains incompletely understood.

Purpose of the Study:

  • To identify RARγ as a downstream mediator in the TNFR1 signaling complex.
  • To elucidate the role of RARγ in regulating the switch between TNF-induced inflammation and RIPK1-initiated cell death.
  • To characterize the interactions of RARγ within cytosolic death complexes.

Main Methods:

  • Confocal imaging to visualize RARγ localization upon cell death activation.
  • Immunoprecipitation assays to identify proteins interacting with RARγ.
  • Analysis of TNFR1 signaling pathways.

Main Results:

  • RARγ is released from the nucleus to the cytosol upon TNF stimulation.
  • Cytosolic RARγ plays a pivotal role in transitioning TNF signaling from inflammation to RIPK1-dependent cell death.
  • RARγ was identified as a downstream mediator of the TNFR1 signaling complex.

Conclusions:

  • RARγ acts as a critical checkpoint protein in TNF signaling.
  • RARγ orchestrates the formation of cytosolic death complexes, directing the cell towards RIPK1-initiated death.
  • Understanding RARγ's role provides insights into controlling inflammatory and cell death responses.
Keywords:
ImmunoprecipitationRARγRIPK1TRADD

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