CD95/Fas ligand induced toxicity

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.