Universal RNA Secondary Structure Insight Into Mosquito-Borne Flavivirus (MBFV) cis-Acting RNA Biology

Abstract

Mosquito-borne flaviviruses (MBFVs) spread between vertebrate (mammals and birds) and invertebrate (mosquitoes) hosts. The cis-acting RNAs of MBFV share common evolutionary origins and contain frequent alterations, which control the balance of linear and circular genome conformations and allow effective replication. Importantly, multiple cis-acting RNAs interact with transacting regulatory RNA-binding proteins (RBPs) and affect the MBFV lifecycle process, including viral replicase binding, viral RNA translation-cyclisation-synthesis and nucleocapsid assembly. Considering that extensive structural probing analyses have been performed on MBFV cis-acting RNAs, herein the homologous RNA structures are online folded and consensus structures are constructed by sort. The specific traits and underlying biology of MBFV cis-acting RNA are illuminated accordingly in a review of RNA structure. These findings deepen our understanding of MBFV cis-acting RNA biology and serve as a resource for designing therapeutics in targeting protein-viral RNA interaction or viral RNA secondary structures.

Information Encoded by the Flavivirus Genomes beyond the Nucleotide Sequence

“…(ii) Domain II shows moderate variations in its structural organization, not only between different ecological groups but also among different clades of the same group [ 28 ]. For example, in members of the JEV and DENV clades within the MBFV group, domain II shows two dumbbell (DB)-like structures, the 5′ and 3′DBs [ 29 ], with a linker sequence varying in sequence and length ( Figure 2 a) [ 28 ].…”

“…(ii) Domain II shows moderate variations in its structural organization, not only between different ecological groups but also among different clades of the same group [ 28 ]. For example, in members of the JEV and DENV clades within the MBFV group, domain II shows two dumbbell (DB)-like structures, the 5′ and 3′DBs [ 29 ], with a linker sequence varying in sequence and length ( Figure 2 a) [ 28 ]. In contrast, YFV bears a single pseudo-DB element, ψDB, the sequence of which seems to be a combination of the duplicated 5′ and 3′DB elements present in other MBFV members ( Figure 2 a) [ 17 , 20 , 24 ].…”

“…Thus, the DAR interaction is subject to differential selection pressure and contributes to host adaptation [ 21 , 69 ]. Interestingly, with the exception of the clades YFV, SPOV and DENV, the remaining MBFV members contain two pairs of DAR sequences, DARI and DARII ( Figure 3 ) [ 28 ]. In addition, while 3′DAR motifs seem to be conserved across flaviviruses, the 5′DAR sequences are only conserved across DENV serotypes [ 78 ].…”

Inter- and Intramolecular RNA–RNA Interactions Modulate the Regulation of Translation Mediated by the 3′ UTR in West Nile Virus

“…The last two participate in the formation of functionally important tertiary structures, such as the pseudoknots PK3 and PK4 ( Figure 1 ) [ 6 ]. The initiation of replication also requires the intact 3′ UTR to generate a cyclized genome dependent on the establishment of direct RNA–RNA interactions between the 5′ and the 3′ ends [ 10 , 11 , 12 ], which are sensed by the pseudoknots of the 3 ’UTR [ 5 , 6 ]. Such a dual regulatory role for the 3′ UTR may mean that it manages the switches between the different stages of the viral cycle.…”

The 5′ and 3′ Untranslated Regions of the Japanese Encephalitis Virus (JEV): Molecular Genetics and Higher Order Structures

“…The 5 and 3 UTRs of the Flavivirus have been shown to be crucial for virus replication, immune regulation and pathogenicity (Brinton et al, 1986;Moon et al, 2012;Chang et al, 2013;Kieft et al, 2015). However, the studies of cis-acting elements in the UTRs have been mainly focused on Dengue virus (DENV), Yellow fever virus (YFV), West Nile virus (WNV), Tick-borne encephalitis virus (TBEV), and Zika virus (ZIKV) (Zeng et al, 2020). Although Japanese encephalitis virus (JEV) is arguably the most significant pathogen causing viral encephalitis within the Flaviviruses, few studies have been conducted to explore the functions and features of JEV UTRs.…”