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ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication

Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection...

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Autores principales: Law, Lok Man John, Razooky, Brandon S., Li, Melody M. H., You, Shihyun, Jurado, Andrea, Rice, Charles M., MacDonald, Margaret R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548403/
https://www.ncbi.nlm.nih.gov/pubmed/31116799
http://dx.doi.org/10.1371/journal.ppat.1007798
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author Law, Lok Man John
Razooky, Brandon S.
Li, Melody M. H.
You, Shihyun
Jurado, Andrea
Rice, Charles M.
MacDonald, Margaret R.
author_facet Law, Lok Man John
Razooky, Brandon S.
Li, Melody M. H.
You, Shihyun
Jurado, Andrea
Rice, Charles M.
MacDonald, Margaret R.
author_sort Law, Lok Man John
collection PubMed
description Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection ZAP is targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP’s antiviral activity correlates with SG localization, and what molecular cues are required to induce this localization event. Here, we use Sindbis virus (SINV) as a model infection and find that ZAP’s localization to SGs can be transient. Sometimes no apparent viral infection follows ZAP SG localization but ZAP SG localization always precedes accumulation of SINV non-structural protein, suggesting virus replication processes trigger SG formation and ZAP recruitment. Data from single-molecule RNA FISH corroborates this finding as the majority of cells with ZAP localization in SGs contain low levels of viral RNA. Furthermore, ZAP recruitment to SGs occurred in ZAP-expressing cells when co-cultured with cells replicating full-length SINV, but not when co-cultured with cells replicating a SINV replicon. ZAP recruitment to SGs is functionally important as a panel of alanine ZAP mutants indicate that the anti-SINV activity is correlated with ZAP’s ability to localize to SGs. As ZAP is a central component of the cellular antiviral programs, these data provide further evidence that SGs are an important cytoplasmic antiviral hub. These findings provide insight into how antiviral components are regulated upon virus infection to inhibit virus spread.
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spelling pubmed-65484032019-06-17 ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication Law, Lok Man John Razooky, Brandon S. Li, Melody M. H. You, Shihyun Jurado, Andrea Rice, Charles M. MacDonald, Margaret R. PLoS Pathog Research Article Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection ZAP is targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP’s antiviral activity correlates with SG localization, and what molecular cues are required to induce this localization event. Here, we use Sindbis virus (SINV) as a model infection and find that ZAP’s localization to SGs can be transient. Sometimes no apparent viral infection follows ZAP SG localization but ZAP SG localization always precedes accumulation of SINV non-structural protein, suggesting virus replication processes trigger SG formation and ZAP recruitment. Data from single-molecule RNA FISH corroborates this finding as the majority of cells with ZAP localization in SGs contain low levels of viral RNA. Furthermore, ZAP recruitment to SGs occurred in ZAP-expressing cells when co-cultured with cells replicating full-length SINV, but not when co-cultured with cells replicating a SINV replicon. ZAP recruitment to SGs is functionally important as a panel of alanine ZAP mutants indicate that the anti-SINV activity is correlated with ZAP’s ability to localize to SGs. As ZAP is a central component of the cellular antiviral programs, these data provide further evidence that SGs are an important cytoplasmic antiviral hub. These findings provide insight into how antiviral components are regulated upon virus infection to inhibit virus spread. Public Library of Science 2019-05-22 /pmc/articles/PMC6548403/ /pubmed/31116799 http://dx.doi.org/10.1371/journal.ppat.1007798 Text en © 2019 Law et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Law, Lok Man John
Razooky, Brandon S.
Li, Melody M. H.
You, Shihyun
Jurado, Andrea
Rice, Charles M.
MacDonald, Margaret R.
ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication
title ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication
title_full ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication
title_fullStr ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication
title_full_unstemmed ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication
title_short ZAP’s stress granule localization is correlated with its antiviral activity and induced by virus replication
title_sort zap’s stress granule localization is correlated with its antiviral activity and induced by virus replication
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548403/
https://www.ncbi.nlm.nih.gov/pubmed/31116799
http://dx.doi.org/10.1371/journal.ppat.1007798
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