Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.

Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We...

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Autores principales:	Hendrik Jan Thibaut, Lonneke van der Linden, Ping Jiang, Bert Thys, María-Dolores Canela, Leire Aguado, Bart Rombaut, Eckard Wimmer, Aniko Paul, María-Jesús Pérez-Pérez, Frank J M van Kuppeveld, Johan Neyts
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3a31551959154d10b2a8714b46cf2715
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spelling	oai:doaj.org-article:3a31551959154d10b2a8714b46cf27152021-11-18T06:06:42ZBinding of glutathione to enterovirus capsids is essential for virion morphogenesis.1553-73661553-737410.1371/journal.ppat.1004039https://doaj.org/article/3a31551959154d10b2a8714b46cf27152014-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24722756/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH), thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis.Hendrik Jan ThibautLonneke van der LindenPing JiangBert ThysMaría-Dolores CanelaLeire AguadoBart RombautEckard WimmerAniko PaulMaría-Jesús Pérez-PérezFrank J M van KuppeveldJohan NeytsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 4, p e1004039 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Hendrik Jan Thibaut Lonneke van der Linden Ping Jiang Bert Thys María-Dolores Canela Leire Aguado Bart Rombaut Eckard Wimmer Aniko Paul María-Jesús Pérez-Pérez Frank J M van Kuppeveld Johan Neyts Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.
description	Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH), thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis.
format	article
author	Hendrik Jan Thibaut Lonneke van der Linden Ping Jiang Bert Thys María-Dolores Canela Leire Aguado Bart Rombaut Eckard Wimmer Aniko Paul María-Jesús Pérez-Pérez Frank J M van Kuppeveld Johan Neyts
author_facet	Hendrik Jan Thibaut Lonneke van der Linden Ping Jiang Bert Thys María-Dolores Canela Leire Aguado Bart Rombaut Eckard Wimmer Aniko Paul María-Jesús Pérez-Pérez Frank J M van Kuppeveld Johan Neyts
author_sort	Hendrik Jan Thibaut
title	Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.
title_short	Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.
title_full	Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.
title_fullStr	Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.
title_full_unstemmed	Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.
title_sort	binding of glutathione to enterovirus capsids is essential for virion morphogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/3a31551959154d10b2a8714b46cf2715
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Binding of glutathione to enterovirus capsids is essential for virion morphogenesis.

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