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Messenger RNA translation enhancement by immune evasion proteins: a comparative study between EKB (vaccinia virus) and NS1 (influenza A virus).

ABSTRACT: In this study, we compared vaccinia virus derived monofunctional E3, K3 and B18R (also known as EKB) with influenza A virus derived multifunctional non-structural protein 1 (NS1) based on their ability to enhance mRNA translation. EKB and NS1-TX91 were all found to enhance mRNA translation and suppress interferon production, yet level of enhancement by EKB was much lower than NS1-TX91. Similarly, greater luciferase expression was mediated by co-delivery of unmodified luciferase with NS1 mRNA, compared to co-delivery of unmodified luciferase with either E3, K3 or B18R mRNA, respectively. Different combinations of E3, K3 and/or B18R mRNA were mixed with NS1-TX91 mRNA at varying ratios and co-delivered with luciferase mRNA. However, no synergism was observed as mRNA translation enhancement mediated by NS1-TX91 could not be improved by the inclusion EKB in all tested combinations. Lastly, it was found that E3 was able to rescue mRNA translation enhancement mediated by NS1 PKR knockout mutant (PR8^PKR-), suggesting that one of NS1's multiple immune evasion mechanisms overlapped with E3. Altogether, our data validated mRNA translation enhancement mediated by immune evasion proteins (EKB and NS1) and showed that the multifunctional nature of NS1 accounted for its superior performance.

SUBMITTER: Liu Y

PROVIDER: S-EPMC6700162 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Messenger RNA translation enhancement by immune evasion proteins: a comparative study between EKB (vaccinia virus) and NS1 (influenza A virus).

Liu Yi Y Chin Jas Min JM Choo En Lin EL Phua Kyle K L KKL

Scientific reports 20190819 1

In this study, we compared vaccinia virus derived monofunctional E3, K3 and B18R (also known as EKB) with influenza A virus derived multifunctional non-structural protein 1 (NS1) based on their ability to enhance mRNA translation. EKB and NS1-TX91 were all found to enhance mRNA translation and suppress interferon production, yet level of enhancement by EKB was much lower than NS1-TX91. Similarly, greater luciferase expression was mediated by co-delivery of unmodified luciferase with NS1 mRNA, co ...[more]

PMID: 31427778

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Project description:Recently, two influenza A virus (FLUAV) genomes were identified in Central and South American bats. These sequences exhibit notable divergence from classical FLUAV counterparts, and functionally, bat FLUAV glycoproteins lack canonical receptor binding and destroying activity. Nevertheless, other features that distinguish these viruses from classical FLUAVs have yet to be explored. Here, we studied the viral nonstructural protein NS1, a virulence factor that modulates host signaling to promote efficient propagation. Like all FLUAV NS1 proteins, bat FLUAV NS1s bind double-stranded RNA and act as interferon antagonists. Unexpectedly, we found that bat FLUAV NS1s are unique in being unable to bind host p85?, a regulatory subunit of the cellular metabolism-regulating enzyme, phosphoinositide 3-kinase (PI3K). Furthermore, neither bat FLUAV NS1 alone nor infection with a chimeric bat FLUAV efficiently activates Akt, a PI3K effector. Structure-guided mutagenesis revealed that the bat FLUAV NS1-p85? interaction can be reengineered (in a strain-specific manner) by changing two to four NS1 residues (96L, 99M, 100I, and 145T), thereby creating a hydrophobic patch. Notably, ameliorated p85?-binding is insufficient for bat FLUAV NS1 to activate PI3K, and a chimeric bat FLUAV expressing NS1 with engineered hydrophobic patch mutations exhibits cell-type-dependent, but species-independent, propagation phenotypes. We hypothesize that bat FLUAV hijacking of PI3K in the natural bat host has been selected against, perhaps because genes in this metabolic pathway were differentially shaped by evolution to suit the unique energy use strategies of this flying mammal. These data expand our understanding of the enigmatic functional divergence between bat FLUAVs and classical mammalian and avian FLUAVs.IMPORTANCE The potential for novel influenza A viruses to establish infections in humans from animals is a source of continuous concern due to possible severe outbreaks or pandemics. The recent discovery of influenza A-like viruses in bats has raised questions over whether these entities could be a threat to humans. Understanding unique properties of the newly described bat influenza A-like viruses, such as their mechanisms to infect cells or how they manipulate host functions, is critical to assess their likelihood of causing disease. Here, we characterized the bat influenza A-like virus NS1 protein, a key virulence factor, and found unexpected functional divergence of this protein from counterparts in other influenza A viruses. Our study dissects the molecular changes required by bat influenza A-like virus NS1 to adopt classical influenza A virus properties and suggests consequences of bat influenza A-like virus infection, potential future evolutionary trajectories, and intriguing virus-host biology in bat species.

Dataset Information

Messenger RNA translation enhancement by immune evasion proteins: a comparative study between EKB (vaccinia virus) and NS1 (influenza A virus).

Publications

Messenger RNA translation enhancement by immune evasion proteins: a comparative study between EKB (vaccinia virus) and NS1 (influenza A virus).

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