Dengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions

ABSTRACT The Flavivirus genus of the Flaviviridae family encompasses numerous enveloped plus-strand RNA viruses. Dengue virus (DENV), a flavivirus, is the leading cause of serious arthropod-borne disease globally. The genomes of DENV, like the genomes of yellow fever virus (YFV), West Nile fever vir...

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Autores principales:	Yutong Song, JoAnn Mugavero, Charles B. Stauft, Eckard Wimmer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Zika virus cap-dependent translation cap-independent translation dengue virus internal ribosome entry site IRES Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/225a4dbc202845aeba1944777453e50f
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spelling	oai:doaj.org-article:225a4dbc202845aeba1944777453e50f2021-11-15T15:55:25ZDengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions10.1128/mBio.00459-192150-7511https://doaj.org/article/225a4dbc202845aeba1944777453e50f2019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00459-19https://doaj.org/toc/2150-7511ABSTRACT The Flavivirus genus of the Flaviviridae family encompasses numerous enveloped plus-strand RNA viruses. Dengue virus (DENV), a flavivirus, is the leading cause of serious arthropod-borne disease globally. The genomes of DENV, like the genomes of yellow fever virus (YFV), West Nile fever virus (WNV), or Zika virus (ZIKV), control their translation by a 5′-terminal capping group. Three other genera of Flaviviridae are remarkable because their viruses use internal ribosomal entry sites (IRESs) to control translation, and they are not arthropod transmitted. In 2006, E. Harris’ group published work suggesting that DENV RNA does not stringently need a cap for translation. They proposed that instead DENV translation is controlled by an interplay between 5′ and 3′ termini. Here we present evidence that the DENV or ZIKV 5′ untranslated regions (5′-UTRs) alone have IRES competence. This conclusion is based, first, on the observation that uncapped monocistronic mRNAs 5′ terminated with the DENV or ZIKV 5′-UTRs can efficiently direct translation of a reporter gene in BHK and C6/36 cells and second, that either 5′-UTR placed between two reporter genes can efficiently induce expression of the downstream gene in BHK cells but not in C6/36 cells. These experiments followed observations that uncapped DENV/ZIKV genomic transcripts, 5′ terminated with pppAN… or GpppAN…, can initiate infections of mammalian (BHK) or mosquito (C6/36) cells. IRES competence of the 5′-UTRs of DENV/ZIKV raises many open questions regarding the biology and control, as well as the evolution, of insect-borne flaviviruses. IMPORTANCE Members of the genus Flavivirus of Flaviviridae are important human pathogens of great concern because they cause serious diseases, sometimes death, in human populations living in tropical, subtropical (dengue virus [DENV], Zika virus [ZIKV], and yellow fever virus), or moderate climates (West Nile virus). Flaviviruses are known to control their translation by a cap-dependent mechanism. We have observed, however, that the uncapped genomes of DENV or ZIKV can initiate infection of mammalian and insect cells. We provide evidence that the short 5′ untranslated region (5′-UTR) of DENV or ZIKV genomes can fulfill the function of an internal ribosomal entry site (IRES). This strategy frees these organisms from the cap-dependent mechanism of gene expression at an as yet unknown stage of proliferation. The data raise new questions about the biology and evolution of flaviviruses, possibly leading to new controls of flavivirus disease.Yutong SongJoAnn MugaveroCharles B. StauftEckard WimmerAmerican Society for MicrobiologyarticleZika viruscap-dependent translationcap-independent translationdengue virusinternal ribosome entry siteIRESMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Zika virus cap-dependent translation cap-independent translation dengue virus internal ribosome entry site IRES Microbiology QR1-502
spellingShingle	Zika virus cap-dependent translation cap-independent translation dengue virus internal ribosome entry site IRES Microbiology QR1-502 Yutong Song JoAnn Mugavero Charles B. Stauft Eckard Wimmer Dengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions
description	ABSTRACT The Flavivirus genus of the Flaviviridae family encompasses numerous enveloped plus-strand RNA viruses. Dengue virus (DENV), a flavivirus, is the leading cause of serious arthropod-borne disease globally. The genomes of DENV, like the genomes of yellow fever virus (YFV), West Nile fever virus (WNV), or Zika virus (ZIKV), control their translation by a 5′-terminal capping group. Three other genera of Flaviviridae are remarkable because their viruses use internal ribosomal entry sites (IRESs) to control translation, and they are not arthropod transmitted. In 2006, E. Harris’ group published work suggesting that DENV RNA does not stringently need a cap for translation. They proposed that instead DENV translation is controlled by an interplay between 5′ and 3′ termini. Here we present evidence that the DENV or ZIKV 5′ untranslated regions (5′-UTRs) alone have IRES competence. This conclusion is based, first, on the observation that uncapped monocistronic mRNAs 5′ terminated with the DENV or ZIKV 5′-UTRs can efficiently direct translation of a reporter gene in BHK and C6/36 cells and second, that either 5′-UTR placed between two reporter genes can efficiently induce expression of the downstream gene in BHK cells but not in C6/36 cells. These experiments followed observations that uncapped DENV/ZIKV genomic transcripts, 5′ terminated with pppAN… or GpppAN…, can initiate infections of mammalian (BHK) or mosquito (C6/36) cells. IRES competence of the 5′-UTRs of DENV/ZIKV raises many open questions regarding the biology and control, as well as the evolution, of insect-borne flaviviruses. IMPORTANCE Members of the genus Flavivirus of Flaviviridae are important human pathogens of great concern because they cause serious diseases, sometimes death, in human populations living in tropical, subtropical (dengue virus [DENV], Zika virus [ZIKV], and yellow fever virus), or moderate climates (West Nile virus). Flaviviruses are known to control their translation by a cap-dependent mechanism. We have observed, however, that the uncapped genomes of DENV or ZIKV can initiate infection of mammalian and insect cells. We provide evidence that the short 5′ untranslated region (5′-UTR) of DENV or ZIKV genomes can fulfill the function of an internal ribosomal entry site (IRES). This strategy frees these organisms from the cap-dependent mechanism of gene expression at an as yet unknown stage of proliferation. The data raise new questions about the biology and evolution of flaviviruses, possibly leading to new controls of flavivirus disease.
format	article
author	Yutong Song JoAnn Mugavero Charles B. Stauft Eckard Wimmer
author_facet	Yutong Song JoAnn Mugavero Charles B. Stauft Eckard Wimmer
author_sort	Yutong Song
title	Dengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions
title_short	Dengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions
title_full	Dengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions
title_fullStr	Dengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions
title_full_unstemmed	Dengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions
title_sort	dengue and zika virus 5′ untranslated regions harbor internal ribosomal entry site functions
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/225a4dbc202845aeba1944777453e50f
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Dengue and Zika Virus 5′ Untranslated Regions Harbor Internal Ribosomal Entry Site Functions

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