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Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein
Interferon-γ (IFN-γ) represents one of the most important innate immunity responses in a host to combat infections of many human viruses including human herpesviruses. Human N-myc interactor (Nmi) protein, which has been shown to interact with signal transducer and activator of transcription (STAT)...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805366/ https://www.ncbi.nlm.nih.gov/pubmed/29377960 http://dx.doi.org/10.1371/journal.ppat.1006867 |
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author | Feng, Linyuan Sheng, Jingxue Vu, Gia-Phong Liu, Yujun Foo, Chingman Wu, Songbin Trang, Phong Paliza-Carre, Marco Ran, Yanhong Yang, Xiaoping Sun, Xu Deng, Zemin Zhou, Tianhong Lu, Sangwei Li, Hongjian Liu, Fenyong |
author_facet | Feng, Linyuan Sheng, Jingxue Vu, Gia-Phong Liu, Yujun Foo, Chingman Wu, Songbin Trang, Phong Paliza-Carre, Marco Ran, Yanhong Yang, Xiaoping Sun, Xu Deng, Zemin Zhou, Tianhong Lu, Sangwei Li, Hongjian Liu, Fenyong |
author_sort | Feng, Linyuan |
collection | PubMed |
description | Interferon-γ (IFN-γ) represents one of the most important innate immunity responses in a host to combat infections of many human viruses including human herpesviruses. Human N-myc interactor (Nmi) protein, which has been shown to interact with signal transducer and activator of transcription (STAT) proteins including STAT1, is important for the activation of IFN-γ induced STAT1-dependent transcription of many genes responsible for IFN-γ immune responses. However, no proteins encoded by herpesviruses have been reported to interact with Nmi and inhibit Nmi-mediated activation of IFN-γ immune responses to achieve immune evasion from IFN-γ responses. In this study, we show strong evidence that the UL23 protein of human cytomegalovirus (HCMV), a human herpesvirus, specifically interacts with Nmi. This interaction was identified through a yeast two-hybrid screen and co-immunoprecipitation in human cells. We observed that Nmi, when bound to UL23, was not associated with STAT1, suggesting that UL23 binding of Nmi disrupts the interaction of Nmi with STAT1. In cells overexpressing UL23, we observed (a) significantly reduced levels of Nmi and STAT1 in the nuclei, the sites where these proteins act to induce transcription of IFN-γ stimulated genes, and (b) decreased levels of the induction of the transcription of IFN-γ stimulated genes. UL23-deficient HCMV mutants induced higher transcription of IFN-γ stimulated genes and exhibited lower titers than parental and control revertant viruses expressing functional UL23 in IFN-γ treated cells. Thus, UL23 appears to interact directly with Nmi and inhibit nuclear translocation of Nmi and its associated protein STAT1, leading to a decrease of IFN-γ induced responses and an increase of viral resistance to IFN-γ. Our results further highlight the roles of UL23-Nmi interactions in facilitating viral immune escape from IFN-γ responses and enhancing viral resistance to IFN antiviral effects. |
format | Online Article Text |
id | pubmed-5805366 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-58053662018-02-23 Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein Feng, Linyuan Sheng, Jingxue Vu, Gia-Phong Liu, Yujun Foo, Chingman Wu, Songbin Trang, Phong Paliza-Carre, Marco Ran, Yanhong Yang, Xiaoping Sun, Xu Deng, Zemin Zhou, Tianhong Lu, Sangwei Li, Hongjian Liu, Fenyong PLoS Pathog Research Article Interferon-γ (IFN-γ) represents one of the most important innate immunity responses in a host to combat infections of many human viruses including human herpesviruses. Human N-myc interactor (Nmi) protein, which has been shown to interact with signal transducer and activator of transcription (STAT) proteins including STAT1, is important for the activation of IFN-γ induced STAT1-dependent transcription of many genes responsible for IFN-γ immune responses. However, no proteins encoded by herpesviruses have been reported to interact with Nmi and inhibit Nmi-mediated activation of IFN-γ immune responses to achieve immune evasion from IFN-γ responses. In this study, we show strong evidence that the UL23 protein of human cytomegalovirus (HCMV), a human herpesvirus, specifically interacts with Nmi. This interaction was identified through a yeast two-hybrid screen and co-immunoprecipitation in human cells. We observed that Nmi, when bound to UL23, was not associated with STAT1, suggesting that UL23 binding of Nmi disrupts the interaction of Nmi with STAT1. In cells overexpressing UL23, we observed (a) significantly reduced levels of Nmi and STAT1 in the nuclei, the sites where these proteins act to induce transcription of IFN-γ stimulated genes, and (b) decreased levels of the induction of the transcription of IFN-γ stimulated genes. UL23-deficient HCMV mutants induced higher transcription of IFN-γ stimulated genes and exhibited lower titers than parental and control revertant viruses expressing functional UL23 in IFN-γ treated cells. Thus, UL23 appears to interact directly with Nmi and inhibit nuclear translocation of Nmi and its associated protein STAT1, leading to a decrease of IFN-γ induced responses and an increase of viral resistance to IFN-γ. Our results further highlight the roles of UL23-Nmi interactions in facilitating viral immune escape from IFN-γ responses and enhancing viral resistance to IFN antiviral effects. Public Library of Science 2018-01-29 /pmc/articles/PMC5805366/ /pubmed/29377960 http://dx.doi.org/10.1371/journal.ppat.1006867 Text en © 2018 Feng 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 Feng, Linyuan Sheng, Jingxue Vu, Gia-Phong Liu, Yujun Foo, Chingman Wu, Songbin Trang, Phong Paliza-Carre, Marco Ran, Yanhong Yang, Xiaoping Sun, Xu Deng, Zemin Zhou, Tianhong Lu, Sangwei Li, Hongjian Liu, Fenyong Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein |
title | Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein |
title_full | Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein |
title_fullStr | Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein |
title_full_unstemmed | Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein |
title_short | Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein |
title_sort | human cytomegalovirus ul23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human n-myc interactor protein |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805366/ https://www.ncbi.nlm.nih.gov/pubmed/29377960 http://dx.doi.org/10.1371/journal.ppat.1006867 |
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