Subgenomic flaviviral RNAs: What do we know after the first decade of research

• Published in: Antiviral research Vol. 159; pp. 13 - 25
• Main Authors: Slonchak, Andrii, Khromykh, Alexander A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2018
• Subjects: Flavivirus; Noncoding RNA; sfRNA; Subgenomic flaviviral RNA; XRN-1 resistance; Subgenomic flaviviral RNA; Noncoding RNA; Flavivirus; sfRNA; XRN-1 resistance
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2018.09.006

The common feature of flaviviral infection is the accumulation of abundant virus-derived noncoding RNA, named flaviviral subgenomic RNA (sfRNA) in infected cells. This RNA represents a product of incomplete degradation of viral genomic RNA by the cellular 5′-3′ exoribonuclease XRN1 that stalls at the conserved highly structured elements in the 3′ untranslated region (UTR). This mechanism of sfRNA generation was discovered a decade ago and since then sfRNA has been a focus of intense research. The ability of flaviviruses to produce sfRNA was shown to be evolutionary conserved in all members of Flavivirus genus. Mutations in the 3′UTR that affect production of sfRNAs and their interactions with host factors showed that sfRNAs are responsible for viral pathogenicity, host adaptation, and emergence of new pathogenic strains. RNA structural elements required for XRN1 stalling have been elucidated and the role of sfRNAs in inhibiting host antiviral responses in arthropod and vertebrate hosts has been demonstrated. Some molecular mechanisms determining these properties of sfRNA have been recently characterized, while other aspects of sfRNA functions remain an open avenue for future research. In this review we summarise the current state of knowledge on the mechanisms of generation and functional roles of sfRNAs in the life cycle of flaviviruses and highlight the gaps in our knowledge to be addressed in the future. •sfRNAa are produced via incomplete digestion of flaviviral genomic RNA by XRN-1.•RNA elements in 3′UTRs that form a 3-way junctions (xrRNAs) and pseudoknots are required to stall XRN-1 and produce sfRNAs.•Generation of sfRNAs is highly conserved amongst all flaviviruses, whereas the structure of xrRNAs varies.•Different sfRNA species may be required for adaptation of some flaviviruses to replication in arthropod or vertebrate hosts.•sfRNA inhibits RNAi response and Toll pathway in arthropods and type I interferon IFN response in vertebrates.