Noncoding Flavivirus RNA Displays RNA Interference Suppressor Activity in Insect and Mammalian Cells
Esther Schnettler,Mark G. Sterken,Jason Y. Leung,Stefan W. Metz,Corrine Geertsema,Rob Goldbach,Just M. Vlak,Alaine Kohl,Alaine Kohl,Alexander A. Khromykh,Gorben P. Pijlman +10 more
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TLDR
The results of the present study suggest a novel role for sfRNA, i.e., as a nucleic acid-based regulator of RNAi pathways, a strategy that may be conserved among flaviviruses.Abstract:
West Nile virus (WNV) and dengue virus (DENV) are highly pathogenic, mosquito-borne flaviviruses (family Flaviviridae) that cause severe disease and death in humans. WNV and DENV actively replicate in mosquitoes and human hosts and thus encounter different host immune responses. RNA interference (RNAi) is the predominant antiviral response against invading RNA viruses in insects and plants. As a countermeasure, plant and insect RNA viruses encode RNA silencing suppressor (RSS) proteins to block the generation/activity of small interfering RNA (siRNA). Enhanced flavivirus replication in mosquitoes depleted for RNAi factors suggests an important biological role for RNAi in restricting virus replication, but it has remained unclear whether or not flaviviruses counteract RNAi via expression of an RSS. First, we established that flaviviral RNA replication suppressed siRNA-induced gene silencing in WNV and DENV replicon-expressing cells. Next, we showed that none of the WNV encoded proteins displayed RSS activity in mammalian and insect cells and in plants by using robust RNAi suppressor assays. In contrast, we found that the 3'-untranslated region-derived RNA molecule known as subgenomic flavivirus RNA (sfRNA) efficiently suppressed siRNA- and miRNA-induced RNAi pathways in both mammalian and insect cells. We also showed that WNV sfRNA inhibits in vitro cleavage of double-stranded RNA by Dicer. The results of the present study suggest a novel role for sfRNA, i.e., as a nucleic acid-based regulator of RNAi pathways, a strategy that may be conserved among flaviviruses.read more
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Towards the elements of successful insect RNAi.
Jeffrey G. Scott,Kristin Michel,Lyric C. Bartholomay,Blair D. Siegfried,Wayne B. Hunter,Guy Smagghe,Kun Yan Zhu,Angela E. Douglas +7 more
TL;DR: An enhanced conceptual understanding ofRNAi function in insects will facilitate the application of RNAi for dissection of gene function, and to fast-track the application to both control pests and develop effective methods to protect beneficial insects and non-insect arthropods from viral and parasitic diseases.
Journal ArticleDOI
Insect antiviral innate immunity: pathways, effectors, and connections.
TL;DR: An overview of the current understanding of the main insect antiviral pathways is provided and recent findings that further understand the roles of these pathways in facilitating a systemic and specific response to infecting viruses are examined.
Journal ArticleDOI
Zika virus produces noncoding RNAs using a multi-pseudoknot structure that confounds a cellular exonuclease
Benjamin M. Akiyama,Hannah Laurence,Hannah Laurence,Aaron R Massey,David A. Costantino,Xuping Xie,Yujiao Yang,Pei Yong Shi,Jay C. Nix,J. David Beckham,Jeffrey S. Kieft +10 more
TL;DR: The authors solved the structure of one of ZIKV's sfRNAs by x-ray crystallography and found that the multi-pseudoknot structure that it adopts underlies its exonuclease resistance, clarifying the mechanism of exonuclelease resistance and identifies features that may modulate function in diverse flaviviruses.
Journal ArticleDOI
The structural basis of pathogenic subgenomic flavivirus RNA (sfRNA) production
Erich G. Chapman,David A. Costantino,David A. Costantino,Jennifer L. Rabe,Stephanie L. Moon,Jeffrey Wilusz,Jay C. Nix,Jeffrey S. Kieft,Jeffrey S. Kieft +8 more
TL;DR: The crystal structure of a complete Xrn1-resistant flaviviral RNA is presented, which contains interwoven pseudoknots within a compact structure that depends on highly conserved nucleotides.
Journal ArticleDOI
The long and short of antiviral defense: small RNA-based immunity in insects.
TL;DR: Recent insights into the mechanism of antiviral RNAi, viral small RNA profiles, and viral counter-defense mechanisms in insects are reviewed.
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