A brilliant disguise for self RNA 5′-end and internal modifications of primary transcripts suppress elements of innate immunity

Interferon inducible protein kinase PKR is a component of innate immunity and mediates antiviral actions by recognizing pathogen associated molecular patterns (PAMPs). A well-known activator of PKR is long dsRNA, which can be produced during viral replication. Our recent results indicate that PKR can also be activated by short stem-loop RNA in a 5'-triphosphate-dependent fashion. A 5'-triphosphate is present primarily in foreign RNAs such as viral and bacterial transcripts, while a non-activating 5'-cap or 5'-monophosphate is present in most cellular RNAs. Additional studies indicate that internal RNA modifications and non-Watson-Crick motifs also repress PKR activation, and do so in an RNA structure-specific fashion. Interestingly, self-RNAs have more nucleoside modifications than non-self RNAs. Internal and 5'-end RNA modifications have repressive effects on other innate immune sensors as well, including TLR3, TLR7, TLR8, and RIG-L suggesting that nucleoside modifications suppress innate immunity on a wide scale.