Exoribonuclease-resistant RNAs in tick-borne flaviviruses
Tick-borne flaviviruses (TBF) are a group of emerging and re-emerging pathogens that affect large geographic regions, including Europe, Asia, North America, and Africa, posing a major public health threat. A critical aspect of their molecular biology and pathology is the presence of evolutionarily conserved functional RNAs in their 3’ untranslated regions (3’UTRs). These non-coding RNAs, specifically exoribonuclease-resistant RNAs (xrRNAs), have the ability to resist degradation by host exoribonucleases such as XRN1 through the formation of a distinct three-dimensional structure that exerts mechanical anisotropy on a ring-like fold when tension is applied to the 5’-end. Here we present data from a recent computational study that uncovers notable structural distinctions of TBF xrRNAs when compared to xrRNAs from other flavivirus groups. Functionally homologous to their counterparts in mosquito-borne flaviviruses, TBF xrRNAs demonstrate a divergent structural paradigm. While most xrRNAs form a three-way junction secondary structure, we have identified several examples of TBF xrRNAs that are not reliant on a three-way junction element to adopt the canonical ring-like tertiary structure. Our data indicate that TBF xrRNAs are stabilized through at least two unique pseudoknot interactions. The TBF xrRNA architecture is further characterized by the presence of a conserved AU basepair and multiple conserved unpaired nucleotides. Our study on the complex structural organization of TBF xrRNAs allows for a deeper understanding of the pathobiology of flaviviruses and paves the way for novel therapeutic approaches. The intricate knowledge of xrRNA structures opens promising avenues for the development of novel antiviral drugs that target these resilient RNA elements. Furthermore, insights obtained from this study will allow us to design artificial xrRNAs that can act as molecular roadblocks to mediate targeted RNA degradation. This approach holds potential for decay applications, such as the fine-tuning of mRNA vaccine technologies.
