CD95/Fas ligand induced toxicity

Abstract

The role of CD95/Fas ligand (CD95L/FasL) in the induction of CD95-mediated extrinsic apoptosis is well characterized. Trimerized, membrane-bound CD95L ligates the CD95 receptor activating downstream signaling resulting in the execution of cells by caspase proteins. However, the expression of CD95L has been reported to induce cell death in contexts in which this pathway is unlikely to be activated, such as in cell autonomous activation induced cell death (AICD) and in CD95-resistant cancer cell lines. Recent data suggests that the CD95L mRNA exerts toxicity through death induced by survival gene elimination (DISE). DISE results from the targeting of networks of survival genes by toxic short RNA (sRNA)s in the RNA-induced silencing complex (RISC). CD95L mRNA contributes to this death directly, through the processing of its mRNA into toxic sRNAs that are loaded into the RISC, and indirectly, by promoting the loading of other toxic sRNAs. Interestingly, CD95L is not the only mRNA that is processed and loaded into the RISC. Protein-coding mRNAs involved in protein translation are also selectively loaded. We propose a model in which networks of mRNA-derived sRNAs modulate DISE, with networks of genes providing non-toxic RISC substrate sRNAs that protect against DISE, and opposing networks of stress-activated genes that produce toxic RISC substrate sRNAs that promote DISE.

Keywords: DISE; FasL; RISC; RNA toxicity; RNAi; cell death.

Figure 1:

Model of the contribution of CD95L to cell fate. (A) The canonical activity of membrane bound CD95L is to induce apoptosis through binding to CD95 on the surface of susceptible cells promoting formation of the death inducing signaling complex (DISC), leading to direct activation of caspase-3/7 in Type I cells [83]. (B) DISE occurs when a number of RISC-bound sRNAs (miRNAs and non-canonical RISC substrates such as processed mRNAs) target C-rich seed matches (red hatched boxes) in the 3’ UTR of a network of survival genes (S-genes) with a G-rich toxic 6mer seed (red boxes). (C) Particularly in conditions of low miRNA expression (i.e. in cells with low Drosha or Dicer activity) mRNAs are degraded into sRNAs by an unknown mechanism that does not include the activities of Drosha, Dicer or Ago2. Such RNAs can be CD95L (I), components of a stress induced network of genes (coding and noncoding) (II), or members of a network of protective mRNAs including ribosomal protein mRNAs (III). sRNAs from protective mRNAs mostly carry nontoxic seeds (green boxes). (D) Certain species of these sRNAs are then loaded into the RISC. The RISC acts like a central rheostat, the balance between sRNAs with toxic and nontoxic seeds decides cell fate. A shift towards loading sRNA with more toxic 6mer seeds can activate a “kill switch”, resulting in DISE.