Functional non-coding RNAs derived from the flavivirus 3′ untranslated region

•3′UTR of flaviviruses is processed into the ncRNAs: sfRNA, KUN-miR-1 and vsRNA5.•sfRNA is generated by XRN1 that stalls at 3′UTR RNA structures upstream of sfRNA.•sfRNA inhibits XRN1 and Dicer.•sfRNA inhibits type I interferon response.•KUN-mir-1 is a miRNA which is important for WNV replication in mosquito cells.

Flaviviruses are single-stranded positive sense RNA enveloped viruses. The flavivirus genus includes important human pathogens such as dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and Murray Valley encephalitis virus (MVEV). In addition to the viral proteins and viral genomic RNA, flaviviruses produce at least two functional non-coding RNAs derived from the 3′ untranslated region (3′UTR), the subgenomic flavivirus RNA (sfRNA) and a putative WNV miRNA (KUN-miR-1). In this review we summarize published data from studies with WNV, YFV, DENV, JEV, and MVEV on sfRNA production following incomplete degradation of the viral genomic RNA by the cellular 5′-3′ exoribonuclease 1 (XRN1), RNA structural elements involved in stalling XRN1 to generate sfRNA, and functions of sfRNA in modulating cellular mRNA decay and RNAi pathways as well as in modulating anti-viral type I interferon response. In addition, we also summarize data on the mechanisms of biogenesis of 3′UTR-derived KUN-miR-1 and its function in WNV replication in mosquito host, along with recent findings on a discovery of a second potential flaviviral miRNA vsRNA5, derived from the 3′UTR of DENV. This review thus summarizes the known mechanisms of generation and the functions of flaviviral 3′UTR-derived non-coding RNAs.