Functions of the 3′ and 5′ genome RNA regions of members of the genus Flavivirus

Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention1,2, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests.

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“…We also found evidence for purifying selection in the ZIKV 3′ UTR (Fig. 3d, Supplementary Table 3), which is important for viral replication 22 .…”

mentioning

confidence: 58%

Zika virus evolution and spread in the Americas

Metsky

Matranga

Wohl

et al. 2017

Nature

341

314

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“…Considering their location in the viral genomes, the yet best characterized circularization elements were termed as CS, UAR, and DAR, respectively (see Fig. 1; for review, see Iglesias and Gamarnik 2011;Bidet and Garcia-Blanco 2014;Brinton and Basu 2015). Although circularization of the viral genome is essential for the initiation of RNA synthesis, the replication process nevertheless depends on a fine balance of the levels of the circular and linear forms of the flaviviral genome (Villordo et al ′ -terminal region of the core (C) protein coding region are depicted according to the experimental data reported by Dong et al (2008).…”

Section: Introductionmentioning

confidence: 99%

“…Several host factors of WNV or DV were characterized (for review, see Bidet and Garcia-Blanco 2014;Brinton and Basu 2015), among these also AUF1. Thus, a certain intracellular level of AUF1 is crucial for the efficient initiation of WNV RNA replication.…”

Section: Introductionmentioning

confidence: 99%

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Friedrich

Schmidt

Schierhorn

et al. 2016

RNA

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A prerequisite for the intracellular replication process of the Flavivirus West Nile virus (WNV) is the cyclization of the viral RNA genome, which enables the viral replicase to initiate RNA synthesis. Our earlier studies indicated that the p45 isoform of the cellular AU-rich element binding protein 1 (AUF1) has an RNA chaperone activity, which supports RNA cyclization and viral RNA synthesis by destabilizing a stem structure at the WNV RNA's 3 ′ -end. Here we show that in mammalian cells, AUF1 p45 is consistently modified by arginine methylation of its C terminus. By a combination of different experimental approaches, we can demonstrate that the methyltransferase PRMT1 is necessary and sufficient for AUF1 p45 methylation and that PRMT1 is required for efficient WNV replication. Interestingly, in comparison to the nonmethylated AUF1 p45, the methylated AUF1 p45 aDMA exhibits a significantly increased affinity to the WNV RNA termini. Further data also revealed that the RNA chaperone activity of AUF1 p45 aDMA is improved and the methylated protein stimulates viral RNA synthesis considerably more efficiently than the nonmethylated AUF1 p45. In addition to its destabilizing RNA chaperone activity, we identified an RNA annealing activity of AUF1 p45, which is not affected by methylation. Arginine methylation of AUF1 p45 thus represents a specific determinant of its RNA chaperone activity while functioning as a WNV host factor. Our data suggest that the methylation modifies the conformation of AUF1 p45 and in this way affects its RNA binding and restructuring activities.

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“…This 3′ noncoding region (NCR) of HBoV has been predicted to form two conserved hairpin structures and plays an important part in the replication of bocaviruses (39–41). The 3′ NCR could function as a binding site for miRNAs or be involved in the production of noncoding RNAs to regulate protein expression (42, 43). The sequences of this region enhanced polyadenylation at (pA)d2, but the mechanism is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

Alternative Polyadenylation of Human Bocavirus at Its 3′ End Is Regulated by Multiple Elements and Affects Capsid Expression

Hao

Zhang

Chen

et al. 2017

J Virol

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Alternative processing of human bocavirus (HBoV) P5 promoter-transcribed RNA is critical for generating the structural and nonstructural protein-encoding mRNA transcripts. The regulatory mechanism by which HBoV RNA transcripts are polyadenylated at proximal [(pA)p] or distal [(pA)d] polyadenylation sites is still unclear. We constructed a recombinant HBoV infectious clone to study the alternative polyadenylation regulation of HBoV. Surprisingly, in addition to the reported distal polyadenylation site, (pA)d, a novel distal polyadenylation site, (pA)d2, which is located in the right-end hairpin (REH), was identified during infectious clone transfection or recombinant virus infection. (pA)d2 does not contain typical hexanucleotide polyadenylation signal, upstream elements (USE), or downstream elements (DSE) according to sequence analysis. Further study showed that HBoV nonstructural protein NS1, REH, and cis elements of (pA)d were necessary and sufficient for efficient polyadenylation at (pA)d2. The distance and sequences between (pA)d and (pA)d2 also played a key role in the regulation of polyadenylation at (pA)d2. Finally, we demonstrated that efficient polyadenylation at (pA)d2 resulted in increased HBoV capsid mRNA transcripts and protein translation. Thus, our study revealed that all the bocaviruses have distal poly(A) signals on the right-end palindromic terminus, and alternative polyadenylation at the HBoV 3′ end regulates its capsid expression.IMPORTANCE The distal polyadenylation site, (pA)d, of HBoV is located about 400 nucleotides (nt) from the right-end palindromic terminus, which is different from those of bovine parvovirus (BPV) and canine minute virus (MVC) in the same genus whose distal polyadenylation is located in the right-end stem-loop structure. A novel polyadenylation site, (pA)d2, was identified in the right-end hairpin of HBoV during infectious clone transfection or recombinant virus infection. Sequence analysis showed that (pA)d2 does not contain typical polyadenylation signals, and the last 42 nt form a stem-loop structure which is almost identical to that of MVC. Further study showed that NS1, REH, and cis elements of (pA)d are required for efficient polyadenylation at (pA)d2. Polyadenylation at (pA)d2 enhances capsid expression. Our study demonstrates alternative polyadenylation at the 3′ end of HBoV and suggests an additional mechanism by which capsid expression is regulated.

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Functions of the 3′ and 5′ genome RNA regions of members of the genus Flavivirus

Cited by 73 publications

References 126 publications

Zika virus evolution and spread in the Americas

Zika virus evolution and spread in the Americas

Arginine methylation enhances the RNA chaperone activity of the West Nile virus host factor AUF1 p45

Alternative Polyadenylation of Human Bocavirus at Its 3′ End Is Regulated by Multiple Elements and Affects Capsid Expression

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