Newcastle Disease virus infection activates PI3K/Akt/mTOR and p38 MAPK/Mnk1 pathways to benefit viral mRNA translation via interaction of the viral NP protein and host eIF4E.

Yuan Zhan,Lei Tan,Shen Yang,Yingjie Sun,Chunchun Meng,Cuiping Song,Weiwei Liu,Chan Ding,Xusheng Qiu,Ying Liao,Shengqing Yu,Daniel R Perez

doi:10.1371/journal.ppat.1008610

Abstract

Newcastle disease virus (NDV), a member of the Paramyxoviridae family, can activate PKR/eIF2α signaling cascade to shutoff host and facilitate viral mRNA translation during infection, however, the mechanism remains unclear. In this study, we revealed that NDV infection up-regulated host cap-dependent translation machinery by activating PI3K/Akt/mTOR and p38 MAPK/Mnk1 pathways. In addition, NDV infection induced p38 MAPK/Mnk1 signaling participated 4E-BP1 hyperphosphorylation for efficient viral protein synthesis when mTOR signaling is inhibited. Furthermore, NDV NP protein was found to be important for selective cap-dependent translation of viral mRNAs through binding to eIF4E during NDV infection. Taken together, NDV infection activated multiple signaling pathways for selective viral protein synthesis in infected cells, via interaction between viral NP protein and host translation machinery. Our results may help to design novel targets for therapeutic intervention against NDV infection and to understand the NDV anti-oncolytic mechanism.

Highlights

Viruses remain exclusively dependent on the translation machinery of their host to ensure viral protein synthesis and progeny virion production during infection
We previous reported that Newcastle disease virus (NDV) shutoff host and facilitate viral mRNA translation by activating PKR/eIF2α signaling cascade
We demonstrated that NDV infection up-regulated host cap-dependent translation machinery by activating PI3K/Akt/ mammalian target of rapamycin (mTOR) and p38 MAPK/MAP kinase-interacting serine/threonine-protein kinase 1 (Mnk1) pathways

Summary

Introduction

Viruses remain exclusively dependent on the translation machinery of their host to ensure viral protein synthesis and progeny virion production during infection. Hyperphosphorylation of the 4E-BPs by the mammalian target of rapamycin (mTOR) results in the release of eIF4E, allowing eIF4G to bind eIF4E to assemble an active eIF4F complex and stimulate cap-dependent translation [10, 11]. In addition to hyperphosphorylation of 4E-BP1, mTOR regulates translation via the activation of p70S6K and the subsequent phosphorylation of rpS6 correlates with an increase in translation of mRNA transcripts that contain an oligopyrimidine tract in their 5’ untranslated regions [12]. Another pathway that regulates translation initiation is p38 MAP kinase-interacting serine/threonine-protein kinase 1 (Mnk1), which catalyzes eIF4E Ser209 phosphorylation [13]. Since eIF2B is present in limiting quantities, slight changes in eIF2α phosphorylation can result in the drastic suppression of global protein synthesis [18]

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