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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 induced toxicity.

Ashley Haluck-Kangas1, Marcus E Peter1,2

  • 1Department of Medicine, Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, U.S.A.

Biochemical Society Transactions
|January 11, 2023
PubMed
Summary
This summary is machine-generated.

The Fas ligand (CD95L) mRNA triggers cell death by targeting survival genes via the RNA-induced silencing complex (RISC). This mechanism, known as death induced by survival gene elimination (DISE), involves toxic short RNAs derived from mRNA.

Keywords:
DISEFasLRISCRNA toxicityRNAicell death

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Area of Science:

  • Molecular Biology
  • Cell Death Pathways
  • RNA Interference

Background:

  • The CD95/Fas ligand (CD95L/FasL) pathway is known to induce extrinsic apoptosis.
  • CD95L expression can cause cell death independently of the canonical apoptotic pathway, observed in cell autonomous activation induced cell death (AICD) and CD95-resistant cells.
  • Emerging evidence points to CD95L mRNA's role in toxicity through a novel mechanism.

Purpose of the Study:

  • To elucidate the mechanism by which CD95L mRNA induces cell death outside of canonical apoptosis.
  • To investigate the role of the RNA-induced silencing complex (RISC) in CD95L-mediated toxicity.
  • To propose a model for how mRNA-derived small RNAs (sRNAs) regulate cell death via DISE.

Main Methods:

  • Analysis of CD95L mRNA processing and its incorporation into the RISC.
  • Investigating the targeting of survival gene networks by toxic sRNAs.
  • Modeling the interplay between different mRNA-derived sRNAs in regulating DISE.

Main Results:

  • CD95L mRNA is processed into toxic sRNAs that are loaded into RISC, directly causing death induced by survival gene elimination (DISE).
  • CD95L promotes the loading of other toxic sRNAs into RISC, amplifying DISE.
  • Protein-coding mRNAs, particularly those involved in translation, are selectively loaded into RISC.
  • Networks of mRNA-derived sRNAs modulate DISE; protective sRNAs from survival genes counteract toxic sRNAs from stress-activated genes.

Conclusions:

  • CD95L mRNA actively participates in cell death induction through the DISE pathway.
  • The RISC machinery, loaded with specific mRNA-derived sRNAs, is central to mediating DISE.
  • A balance between protective and toxic sRNA networks dictates cellular fate in response to stress.