Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells

ABSTRACT The cellular mRNA decay protein AUF1 acts as a restriction factor during infection by picornaviruses, including poliovirus, coxsackievirus, and human rhinovirus. AUF1 relocalizes from the nucleus to the cytoplasm during infection by these viruses due to the disruption of nucleocytoplasmic t...

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Autores principales:	Wendy Ullmer, Bert L. Semler
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	AUF1 IRES-mediated translation RNA replication coxsackievirus enterovirus host restriction Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6c7621b27168473297bba5bd02485a4a
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spelling	oai:doaj.org-article:6c7621b27168473297bba5bd02485a4a2021-11-15T15:58:20ZDirect and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells10.1128/mBio.01669-182150-7511https://doaj.org/article/6c7621b27168473297bba5bd02485a4a2018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01669-18https://doaj.org/toc/2150-7511ABSTRACT The cellular mRNA decay protein AUF1 acts as a restriction factor during infection by picornaviruses, including poliovirus, coxsackievirus, and human rhinovirus. AUF1 relocalizes from the nucleus to the cytoplasm during infection by these viruses due to the disruption of nucleocytoplasmic trafficking by viral proteinases. Previous studies have demonstrated that AUF1 binds to poliovirus and coxsackievirus B3 (CVB3) RNA during infection, with binding shown to occur within the internal ribosome entry site (IRES) of the 5′ noncoding region (NCR) or the 3′ NCR, respectively. Binding to different sites within the viral RNA suggests that AUF1 may negatively regulate infection by these viruses using different mechanisms. The work presented here addresses the mechanism of AUF1 inhibition of the replication of poliovirus and CVB3. We demonstrate that AUF1 knockdown in human cells results in increased viral translation, RNA synthesis, and virus production. AUF1 is shown to negatively regulate translation of a poliovirus and CVB3 IRES reporter RNA during infection but not in uninfected cells. We found that this inhibitory activity is not mediated through destabilization of viral genomic RNA; however, it does require virus-induced relocalization of AUF1 from the nucleus to the cytoplasm during the early phases of infection. Our findings suggest that AUF1 restriction of poliovirus and CVB3 replication uses a common mechanism through the viral IRES, which is distinct from the canonical role that AUF1 plays in regulated mRNA decay in uninfected host cells. IMPORTANCE Picornaviruses primarily infect the gastrointestinal or upper respiratory tracts of humans and animals and may disseminate to tissues of the central nervous system, heart, skin, liver, or pancreas. Many common human pathogens belong to the Picornaviridae family, which includes viruses known to cause paralytic poliomyelitis (poliovirus); myocarditis (coxsackievirus B3 [CVB3]); the common cold (human rhinovirus [HRV]); and hand, foot, and mouth disease (enterovirus 71 [EV71]), among other illnesses. There are no specific treatments for infection, and vaccines exist for only two picornaviruses: poliovirus and hepatitis A virus. Given the worldwide distribution and prevalence of picornaviruses, it is important to gain insight into the host mechanisms used to restrict infection. Other than proteins involved in the innate immune response, few host factors have been identified that restrict picornavirus replication. The work presented here seeks to define the mechanism of action for the host restriction factor AUF1 during infection by poliovirus and CVB3.Wendy UllmerBert L. SemlerAmerican Society for MicrobiologyarticleAUF1IRES-mediated translationRNA replicationcoxsackievirusenterovirushost restrictionMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	AUF1 IRES-mediated translation RNA replication coxsackievirus enterovirus host restriction Microbiology QR1-502
spellingShingle	AUF1 IRES-mediated translation RNA replication coxsackievirus enterovirus host restriction Microbiology QR1-502 Wendy Ullmer Bert L. Semler Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells
description	ABSTRACT The cellular mRNA decay protein AUF1 acts as a restriction factor during infection by picornaviruses, including poliovirus, coxsackievirus, and human rhinovirus. AUF1 relocalizes from the nucleus to the cytoplasm during infection by these viruses due to the disruption of nucleocytoplasmic trafficking by viral proteinases. Previous studies have demonstrated that AUF1 binds to poliovirus and coxsackievirus B3 (CVB3) RNA during infection, with binding shown to occur within the internal ribosome entry site (IRES) of the 5′ noncoding region (NCR) or the 3′ NCR, respectively. Binding to different sites within the viral RNA suggests that AUF1 may negatively regulate infection by these viruses using different mechanisms. The work presented here addresses the mechanism of AUF1 inhibition of the replication of poliovirus and CVB3. We demonstrate that AUF1 knockdown in human cells results in increased viral translation, RNA synthesis, and virus production. AUF1 is shown to negatively regulate translation of a poliovirus and CVB3 IRES reporter RNA during infection but not in uninfected cells. We found that this inhibitory activity is not mediated through destabilization of viral genomic RNA; however, it does require virus-induced relocalization of AUF1 from the nucleus to the cytoplasm during the early phases of infection. Our findings suggest that AUF1 restriction of poliovirus and CVB3 replication uses a common mechanism through the viral IRES, which is distinct from the canonical role that AUF1 plays in regulated mRNA decay in uninfected host cells. IMPORTANCE Picornaviruses primarily infect the gastrointestinal or upper respiratory tracts of humans and animals and may disseminate to tissues of the central nervous system, heart, skin, liver, or pancreas. Many common human pathogens belong to the Picornaviridae family, which includes viruses known to cause paralytic poliomyelitis (poliovirus); myocarditis (coxsackievirus B3 [CVB3]); the common cold (human rhinovirus [HRV]); and hand, foot, and mouth disease (enterovirus 71 [EV71]), among other illnesses. There are no specific treatments for infection, and vaccines exist for only two picornaviruses: poliovirus and hepatitis A virus. Given the worldwide distribution and prevalence of picornaviruses, it is important to gain insight into the host mechanisms used to restrict infection. Other than proteins involved in the innate immune response, few host factors have been identified that restrict picornavirus replication. The work presented here seeks to define the mechanism of action for the host restriction factor AUF1 during infection by poliovirus and CVB3.
format	article
author	Wendy Ullmer Bert L. Semler
author_facet	Wendy Ullmer Bert L. Semler
author_sort	Wendy Ullmer
title	Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells
title_short	Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells
title_full	Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells
title_fullStr	Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells
title_full_unstemmed	Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells
title_sort	direct and indirect effects on viral translation and rna replication are required for auf1 restriction of enterovirus infections in human cells
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/6c7621b27168473297bba5bd02485a4a
work_keys_str_mv	AT wendyullmer directandindirecteffectsonviraltranslationandrnareplicationarerequiredforauf1restrictionofenterovirusinfectionsinhumancells AT bertlsemler directandindirecteffectsonviraltranslationandrnareplicationarerequiredforauf1restrictionofenterovirusinfectionsinhumancells
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Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells

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