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Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes

Dengue virus (DENV) disruption of the innate immune response is critical to establish infection. DENV non-structural protein 5 (NS5) plays a central role in this disruption, such as antagonism of STAT2. We recently found that DENV serotype 2 (DENV2) NS5 interacts with Polymerase associated factor 1...

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Autores principales: Petit, Marine J., Kenaston, Matthew W., Pham, Oanh H., Nagainis, Ariana A., Fishburn, Adam T., Shah, Priya S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641875/
https://www.ncbi.nlm.nih.gov/pubmed/34797876
http://dx.doi.org/10.1371/journal.ppat.1010100
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author Petit, Marine J.
Kenaston, Matthew W.
Pham, Oanh H.
Nagainis, Ariana A.
Fishburn, Adam T.
Shah, Priya S.
author_facet Petit, Marine J.
Kenaston, Matthew W.
Pham, Oanh H.
Nagainis, Ariana A.
Fishburn, Adam T.
Shah, Priya S.
author_sort Petit, Marine J.
collection PubMed
description Dengue virus (DENV) disruption of the innate immune response is critical to establish infection. DENV non-structural protein 5 (NS5) plays a central role in this disruption, such as antagonism of STAT2. We recently found that DENV serotype 2 (DENV2) NS5 interacts with Polymerase associated factor 1 complex (PAF1C). The primary members of PAF1C are PAF1, LEO1, CTR9, and CDC73. This nuclear complex is an emerging player in the immune response. It promotes the expression of many genes, including genes related to the antiviral, antimicrobial and inflammatory responses, through close association with the chromatin of these genes. Our previous work demonstrated that NS5 antagonizes PAF1C recruitment to immune response genes. However, it remains unknown if NS5 antagonism of PAF1C is complementary to its antagonism of STAT2. Here, we show that knockout of PAF1 enhances DENV2 infectious virion production. By comparing gene expression profiles in PAF1 and STAT2 knockout cells, we find that PAF1 is necessary to express immune response genes that are STAT2-independent. Finally, we mapped the viral determinants for the NS5-PAF1C protein interaction. We found that NS5 nuclear localization and the C-terminal region of the methyltransferase domain are required for its interaction with PAF1C. Mutation of these regions rescued the expression of PAF1-dependent immune response genes that are antagonized by NS5. In sum, our results support a role for PAF1C in restricting DENV2 replication that NS5 antagonizes through its protein interaction with PAF1C.
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spelling pubmed-86418752021-12-04 Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes Petit, Marine J. Kenaston, Matthew W. Pham, Oanh H. Nagainis, Ariana A. Fishburn, Adam T. Shah, Priya S. PLoS Pathog Research Article Dengue virus (DENV) disruption of the innate immune response is critical to establish infection. DENV non-structural protein 5 (NS5) plays a central role in this disruption, such as antagonism of STAT2. We recently found that DENV serotype 2 (DENV2) NS5 interacts with Polymerase associated factor 1 complex (PAF1C). The primary members of PAF1C are PAF1, LEO1, CTR9, and CDC73. This nuclear complex is an emerging player in the immune response. It promotes the expression of many genes, including genes related to the antiviral, antimicrobial and inflammatory responses, through close association with the chromatin of these genes. Our previous work demonstrated that NS5 antagonizes PAF1C recruitment to immune response genes. However, it remains unknown if NS5 antagonism of PAF1C is complementary to its antagonism of STAT2. Here, we show that knockout of PAF1 enhances DENV2 infectious virion production. By comparing gene expression profiles in PAF1 and STAT2 knockout cells, we find that PAF1 is necessary to express immune response genes that are STAT2-independent. Finally, we mapped the viral determinants for the NS5-PAF1C protein interaction. We found that NS5 nuclear localization and the C-terminal region of the methyltransferase domain are required for its interaction with PAF1C. Mutation of these regions rescued the expression of PAF1-dependent immune response genes that are antagonized by NS5. In sum, our results support a role for PAF1C in restricting DENV2 replication that NS5 antagonizes through its protein interaction with PAF1C. Public Library of Science 2021-11-19 /pmc/articles/PMC8641875/ /pubmed/34797876 http://dx.doi.org/10.1371/journal.ppat.1010100 Text en © 2021 Petit et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://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
Petit, Marine J.
Kenaston, Matthew W.
Pham, Oanh H.
Nagainis, Ariana A.
Fishburn, Adam T.
Shah, Priya S.
Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes
title Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes
title_full Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes
title_fullStr Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes
title_full_unstemmed Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes
title_short Nuclear dengue virus NS5 antagonizes expression of PAF1-dependent immune response genes
title_sort nuclear dengue virus ns5 antagonizes expression of paf1-dependent immune response genes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641875/
https://www.ncbi.nlm.nih.gov/pubmed/34797876
http://dx.doi.org/10.1371/journal.ppat.1010100
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