The response of mammalian cells to double-stranded RNA

Abstract

Double-stranded RNA (dsRNA) has long been recognized as a central component of the interferon (IFN) system. It was originally characterized as a key mediator of IFN induction in response to virus infection. Subsequently, it was identified as a prime activator of the antiviral response. In recent years the discovery of the RNA interference (RNAi) pathway in mammals has renewed interest in dsRNA-mediated cellular responses. This has coincided with the identification of key components of the IFN induction pathway. Here, we present an overview of the current knowledge of dsRNA-mediated pathways in mammalian cells and introduce a link between these pathways and application of RNAi.

Fig. 1. dsRNA-induced translation inhibition mechanisms

dsRNA promotes activation of PKR and 2'5'OAS. PKR phosphorylates eIF2α, which results in sequestration of eIF2B and inhibition of translation initiation by the ribosomal complex [29]. Activated 2'5'OAS promotes RNaseL dimerization via the formation of 2'-5'oligoadenylates [33]. RNaseL subsequently degrades RNAs non-specifically. These two events fortify the antiviral state by stopping protein synthesis.

Fig. 2. Sensing of ssRNA/dsRNA by the immune system

The detection by viral ss/dsRNA products by the cell is cell-type dependent. On the left of the diagram, sensing in non-immune cell types is represented. This relies on RIG-I (for RNAs with 5'-triphosphate) and MDA-5 (for dsRNAs), and is negatively regulated by LGP2 [11,12,59,65,97]. CARDIF transduces the activation of RIG-I, resulting in activation of transcription factors [60]. On the right of the schematic, innate immune sensing of ss/dsRNAs by endosomal TLRs in immune cells is represented. Through activation and recruitement of adaptors (TRIF and MyD88), TRL3, 7 and 8 activate IRFs and NF-κB transcription factors [98]. These transcription factors induce expression of IFNs and pro-inflammatory cytokines. This further results in the induction of ISGs such as PKR/2'5'OAS and confers a general antiviral state by affecting cell growth and ultimately provoking cell death. In parallel, endogenous cytoplasmic dsRNAs such as pre-miRNAs are specifically recognised by DICER because of their protruding 3'-end, preventing potential recognition by RIG-I [25].