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. 2022 Aug 15;13(8):707. doi: 10.1038/s41419-022-05101-3

Fig. 8. Schematic view of cell death signaling induced by 5’-ppp-RNA, cytosolic dsRNA, and extracellular dsRNA.

Fig. 8

a Cytosolic short 5’-ppp-dsRNA is sensed by RIG-I and activates signaling, leading to the induction of IFN-I and limited apoptosis with slow kinetics. This apoptosis is dependent on genes regulated by IRF-3 and IFN-I. b Cytosolic dsRNA introduced by the injection or transfection activates TLR3 through endosomal entrapment as above. In contrast to endosomal dsRNA, cytosolic dsRNA activates PKR, which results in the induction of SG and translational shutdown, leading to the downregulation of cFLIP and apoptosis through the activation of caspase 8. In addition, PKR was reported to promote the mitochondrial pathway in order to activate caspase 9; therefore, robust apoptosis was induced via caspases 8/9. c Extracellular dsRNA is incorporated by endocytosis and sensed by TLR3. TLR3 signals TRIF and activates signaling, leading to the induction of IFN-I and the expression of cFLIP in order to negatively regulate caspase 8. The TLR3 signaling complex also recruits FADD to activate DISC containing caspase 8; however, due to the effects of cFLIP, apoptosis is suppressed. When cells are treated with extracellular dsRNA and CHX, caspase 8 promotes apoptosis because of the downregulation of cFLIP.