Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses

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 t...

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Autores principales:	Hanna Roth, Vera Magg, Fabian Uch, Pascal Mutz, Philipp Klein, Katharina Haneke, Volker Lohmann, Ralf Bartenschlager, Oliver T. Fackler, Nicolas Locker, Georg Stoecklin, Alessia Ruggieri
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1036acbd199245a0983b384cb9627fb3
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spelling	oai:doaj.org-article:1036acbd199245a0983b384cb9627fb32021-11-15T15:51:07ZFlavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses10.1128/mBio.02150-162150-7511https://doaj.org/article/1036acbd199245a0983b384cb9627fb32017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02150-16https://doaj.org/toc/2150-7511ABSTRACT 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 (α subunit of eukaryotic initiation factor 2). 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. IMPORTANCE For efficient production of new progeny, viruses need to balance their dependency on the host cell translation machinery with potentially adverse effects of antiviral proteins produced by the infected cell. To achieve this, many viruses evolved mechanisms to manipulate host cell translation. Here we find that infection of human cells with two major human pathogens, dengue virus (DENV) and Zika virus (ZIKV), leads to the potent repression of host cell translation initiation, while the synthesis of viral protein remains unaffected. Unlike other RNA viruses, these flaviviruses concomitantly suppress host cell stress responses, thereby uncoupling translation suppression from stress granule formation. We identified that the p38-Mnk1 cascade regulating phosphorylation of eIF4E is a target of DENV infection and plays an important role in virus production. Our results define several molecular interfaces by which flaviviruses hijack host cell translation and interfere with stress responses to optimize the production of new virus particles.Hanna RothVera MaggFabian UchPascal MutzPhilipp KleinKatharina HanekeVolker LohmannRalf BartenschlagerOliver T. FacklerNicolas LockerGeorg StoecklinAlessia RuggieriAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Hanna Roth Vera Magg Fabian Uch Pascal Mutz Philipp Klein Katharina Haneke Volker Lohmann Ralf Bartenschlager Oliver T. Fackler Nicolas Locker Georg Stoecklin Alessia Ruggieri Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses
description	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 (α subunit of eukaryotic initiation factor 2). 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. IMPORTANCE For efficient production of new progeny, viruses need to balance their dependency on the host cell translation machinery with potentially adverse effects of antiviral proteins produced by the infected cell. To achieve this, many viruses evolved mechanisms to manipulate host cell translation. Here we find that infection of human cells with two major human pathogens, dengue virus (DENV) and Zika virus (ZIKV), leads to the potent repression of host cell translation initiation, while the synthesis of viral protein remains unaffected. Unlike other RNA viruses, these flaviviruses concomitantly suppress host cell stress responses, thereby uncoupling translation suppression from stress granule formation. We identified that the p38-Mnk1 cascade regulating phosphorylation of eIF4E is a target of DENV infection and plays an important role in virus production. Our results define several molecular interfaces by which flaviviruses hijack host cell translation and interfere with stress responses to optimize the production of new virus particles.
format	article
author	Hanna Roth Vera Magg Fabian Uch Pascal Mutz Philipp Klein Katharina Haneke Volker Lohmann Ralf Bartenschlager Oliver T. Fackler Nicolas Locker Georg Stoecklin Alessia Ruggieri
author_facet	Hanna Roth Vera Magg Fabian Uch Pascal Mutz Philipp Klein Katharina Haneke Volker Lohmann Ralf Bartenschlager Oliver T. Fackler Nicolas Locker Georg Stoecklin Alessia Ruggieri
author_sort	Hanna Roth
title	Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses
title_short	Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses
title_full	Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses
title_fullStr	Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses
title_full_unstemmed	Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses
title_sort	flavivirus infection uncouples translation suppression from cellular stress responses
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/1036acbd199245a0983b384cb9627fb3
work_keys_str_mv	AT hannaroth flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT veramagg flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT fabianuch flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT pascalmutz flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT philippklein flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT katharinahaneke flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT volkerlohmann flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT ralfbartenschlager flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT olivertfackler flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT nicolaslocker flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT georgstoecklin flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses AT alessiaruggieri flavivirusinfectionuncouplestranslationsuppressionfromcellularstressresponses
_version_	1718427381605072896

Flavivirus Infection Uncouples Translation Suppression from Cellular Stress Responses

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