Zika viruses encode multiple upstream open reading frames in the 5′ viral region with a role in neurotropism

Abstract

14 Zika virus is a single-stranded, positive-sense RNA virus of the family Flaviviridae, which has 15 recently undergone a rapid expansion among humans in the Western Hemisphere. Here, we report 16 a high-resolution map of ribosomal occupancy of the Zika virus genome during infection of 17 mammalian and insect cells, obtained by ribosome profiling. In contrast to some other flaviviruses 18 such as West Nile, we find no evidence for substantial frameshift-induced ribosomal drop-off 19 during translation of the viral polyprotein, indicating that Zika virus must use alternative 20 mechanisms to downregulate levels of catalytically active viral polymerase. We also show that 21 high levels of ribosome-protected fragments map in-frame to two previously overlooked upstream 22 open reading frames (uORFs) initiating at CUG and UUG codons, with likely consequences for 23 the efficiency of polyprotein expression. Curiously, in African isolates of Zika virus, the two 24 uORFs are fused in-frame into a single uORF. A parallel RNA-Seq analysis reveals the 5' end 25 . CC-BY 4.0 International license is made available under a

Translation regulation of Japanese encephalitis virus revealed by ribosome profiling

“…While the functional significance of the putative peptide remains unknown, a close overlap of uORF stop codon (100 th nt) with main ORF's start codon (96 th nt, Fig.4C) could directly impact ribosome loading and usage rates-key parameters in regulating protein synthesis [50]. Although a canonical structure of 5 UTR is shared amongst flaviviruses [51], this strategy of translation initiation might suggest the enhanced translational efficiency of JEV and ZIKV [13] over DENV [9]. This site exhibits high conservation across JEV strains with the exception of vaccine strain (SA14-14-2) harbouring a silent mutation.…”

“…The putative uORF would generate a 22 a.a long peptide (LRRIERLVQFKQFFRTEDNHD) with a termination codon immediately downstream of canonical start codon (Fig.4C). A recent study on riboprofile of ZIKV also showed ribosomal initiation scanning from out-of-frame non-canonical start codons present in the 5 UTR -CUG (uORF1) and UUG (uORF2) [13].…”

“…The method, popularly known as ribosome profiling, has provided promising insights into translational regulation by RNA viruses ranging from temporal regulation of host gene expression upon Dengue virus (DENV) [9] and Hepatitis C virus (HCV) [10] infection to previously uncharacterised alternate ORFs in Coronaviruses like Mouse Hepatitis virus (MHV) [11] and SARS-CoV-2 [12]. Few RNA viruses like MHV [11], Zika virus (ZIKV) [13] and Echovirus 7 [14] also display upstream ORFs with physiological implications of the encoded peptide in virus release [14]. Additionally, the method's accuracy at single-nucleotide resolution identifies the translation frame and has been applied to estimate actual in cellulo ribosomal frameshifting efficiencies during RNA-virus infections [11,12,15].…”

Virtual Screening, Design, Synthesis and Biological Activity of Zika Virus Inhibitors

“…寨卡病毒属黄病毒属、黄病毒科 [19,20] , 是一种单链 核糖核酸(RNA)虫媒病毒, 并具有十二面体结构 [21,22] . 由甲基转移酶和 RNA 聚合酶组成的多功能蛋白(NS5) 是一种在寨卡病毒复制过程中起重要作用的蛋白组分, 它由甲基转移酶(5M5B)和 C-末端 RNA 依赖性 RNA 聚 合酶(RDRP)组成 [23] .…”