Flavivirus infection uncouples translation suppression from cellular stress responses

Roth, H, Magg, V, Uch, F, Mutz, P, Klein, P, Haneke, K, Lohmann, V, Bartenschlager, R, Fackler, OT, Locker, Nicolas et al, Stoecklin, G and Ruggieri, A (2017) Flavivirus infection uncouples translation suppression from cellular stress responses mBio, 8 (1), e02150-16.

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Abstract

As obligate parasites, viruses strictly depend on host cell translation for the production of new progeny, yet infected cells also synthesize antiviral proteins to limit virus infection. Modulation of host cell translation therefore represents a frequent strategy by which viruses optimize their replication and spread. Here we sought to define how host cell translation is regulated during infection of human cells with Dengue Virus (DENV) and Zika Virus (ZIKV), two positive-strand RNA flaviviruses. Polysome profiling and analysis of de novo protein synthesis revealed that flavivirus infection causes potent repression of host cell translation while synthesis of viral proteins remains efficient. Selective repression of host cell translation was mediated by the DENV polyprotein at the level of translation initiation. In addition, DENV and ZIKV infection suppressed host cell stress responses such as the formation of stress granules and phosphorylation of the translation initiation factor eIF2α. Mechanistic analyses revealed that translation repression was uncoupled from the disruption of stress granule formation and eIF2α signaling. Rather, DENV infection induced p38-Mnk1 signaling that resulted in the phosphorylation of the eukaryotic translation initiation factor eIF4E and was essential for the efficient production of virus particles. Together, these results identify the uncoupling of translation suppression from the cellular stress responses as a conserved strategy by which flaviviruses ensure efficient replication in human cells.

Item Type:	Article
Subjects :	Biosciences and Medicine
Divisions :	Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :	Name Email ORCID Roth, H Magg, V Uch, F Mutz, P Klein, P Haneke, K Lohmann, V Bartenschlager, R Fackler, OT Locker, Nicolas N.Locker@surrey.ac.uk Stoecklin, G Ruggieri, A
Date :	10 January 2017
DOI :	10.1128/mBio.02150-16
Copyright Disclaimer :	Copyright 2017 The Authors. Published under the Creative Commons, Attribution license, Version 4.0 (CC-BY)
Related URLs :	Publisher
Depositing User :	Symplectic Elements
Date Deposited :	17 Jan 2017 16:49
Last Modified :	16 Jan 2019 17:11
URI:	http://epubs.surrey.ac.uk/id/eprint/813307

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