Related Experiment Video

Updated: Jul 2, 2025

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex
07:17

Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex

Published on: August 2, 2021

2.6K

IRE1 RNase controls CD95-mediated cell death

Diana Pelizzari-Raymundo1,2, Victoria Maltret1,2, Manon Nivet1,2

  • 1Inserm U1242, University of Rennes, Rennes, France.

EMBO Reports
|February 22, 2024
PubMed

Insights

The unfolded protein response sensor IRE1 regulates CD95/Fas death receptor expression and function in cancer. Inhibiting IRE1 enhances CD95-mediated cell death in glioblastoma and triple-negative breast cancer.

Area of Science:

  • Cancer Biology
  • Molecular Cell Biology
  • Signaling Pathways

Background:

  • Unfolded Protein Response (UPR) and Death Receptor (DR) signaling are often co-opted for tumor progression.
  • IRE1 is a key sensor of the UPR, implicated in cancer cell survival and proliferation.

Purpose of the Study:

  • To investigate the regulatory role of IRE1 in controlling Death Receptor CD95/Fas expression and function.
  • To explore the therapeutic potential of targeting the IRE1-CD95 axis in glioblastoma and triple-negative breast cancer.

Main Methods:

  • Genetic and pharmacologic inhibition of IRE1 activity.
  • Analysis of CD95 mRNA expression and its regulation by Regulated IRE1-Dependent Decay of RNA (RIDD).
  • Assessment of CD95L-induced cell death in cancer cell lines and in vivo mouse models.

Main Results:

  • IRE1 inhibition increased CD95 expression and sensitized glioblastoma and triple-negative breast cancer cells to CD95L-induced death.
  • CD95 mRNA is a target of IRE1-mediated RIDD.
  • IRE1 inhibition reduced CD95-mediated hepatic toxicity in mice.
  • XBP1s overexpression increased CD95 expression and cell death sensitivity.

Conclusions:

  • IRE1 exerts dual control over CD95-dependent cell death via RIDD and XBP1s.
  • This study reveals a novel regulatory link between IRE1 and CD95 signaling in cancer.
  • Targeting IRE1 may offer a therapeutic strategy to enhance CD95-mediated anti-tumor immunity.
Keywords:
CD95Cell DeathER StressIRE1Unfolded Protein Response

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