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Updated: Aug 2, 2025

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

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CD95/Fas ligand mRNA is toxic to cells through more than one mechanism

Ashley Haluck-Kangas1, Madelaine Fink1, Elizabeth T Bartom2,3

  • 1Department of Medicine/Division Hematology/Oncology, Feinberg School of Medicine, Chicago, IL, USA.

Molecular Biomedicine
|April 14, 2023
PubMed

Insights

CD95/Fas ligand (CD95L) mRNA triggers cell death via RNA interference (RNAi) independent of the CD95 receptor. This process, known as Death Induced by Survival Gene Elimination (DISE), involves specific RNA processing and RISC loading.

Area of Science:

  • Molecular Biology
  • Cell Death Mechanisms
  • RNA Interference

Background:

  • CD95/Fas ligand (CD95L) protein binding to the CD95 receptor induces apoptosis.
  • CD95L mRNA can also induce toxicity independently of CD95, a process termed Death Induced by Survival Gene Elimination (DISE), mediated by RNA interference (RNAi).

Purpose of the Study:

  • To investigate the mechanism by which CD95L mRNA induces toxicity and identify the RNA species involved in DISE.
  • To determine the role of microRNA biogenesis proteins and Argonaute proteins in CD95L-induced toxicity.

Main Methods:

  • Analysis of CD95L mRNA processing products.
  • Assessment of CD95L mRNA toxicity in cells with varying Argonaute protein expression.
  • Mutation of start codons in CD95L open reading frame (ORF).
  • Identification of RISC-bound small RNAs (sRNAs) and their seed sequences.

Main Results:

  • CD95L mRNA processing generates a short RNA (sRNA) similar to a known DISE-inducing shRNA.
  • DISE induction by CD95L mRNA does not require Drosha or Dicer but can depend on Ago2 in some cell lines.
  • HCT116 cells show redundant Argonaute function, with Ago1-4 knockout cells retaining CD95L mRNA toxicity.
  • Toxicity is abolished by mutating all in-frame start codons in the CD95L ORF.
  • Dying cells show enrichment of RISC-bound sRNAs with toxic 6-nucleotide seed sequences.

Conclusions:

  • CD95L mRNA processing generates toxic sRNAs that mediate DISE.
  • The dependence on Argonaute proteins for CD95L mRNA toxicity varies between cell types.
  • Alternative mechanisms may contribute to CD95L mRNA processing and its associated toxicity.
Keywords:
Cell deathFasLRISCRNA toxicityRNAi

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