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FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi’s sarcoma. KSHV is also causally associated with the development of lymphoproliferative diseases, including primary effusion lymphoma (PEL). KSHV reactivation from latency plays an integral...

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Autores principales: Dunker, William, Song, Yu, Zhao, Yang, Karijolich, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070805/
https://www.ncbi.nlm.nih.gov/pubmed/29986386
http://dx.doi.org/10.3390/v10070359
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author Dunker, William
Song, Yu
Zhao, Yang
Karijolich, John
author_facet Dunker, William
Song, Yu
Zhao, Yang
Karijolich, John
author_sort Dunker, William
collection PubMed
description Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi’s sarcoma. KSHV is also causally associated with the development of lymphoproliferative diseases, including primary effusion lymphoma (PEL). KSHV reactivation from latency plays an integral role in the progression to KSHV-associated disease as several lytic proteins have angiogenic and anti-apoptotic functions essential to the tumor microenvironment. Thus, restriction of KSHV reactivation represents an attractive therapeutic target. Here, we demonstrate that the cellular protein Fused-in-sarcoma (FUS) restricts KSHV lytic reactivation in PEL and in an epithelial cell-based model. Depletion of FUS significantly enhances viral mRNA and protein expression, resulting in increased viral replication and production of infectious virions. Chromatin immunoprecipitation analyses demonstrate that FUS is present at several KSHV lytic cycle genes during the latent stage of infection. We further demonstrate that FUS interacts with RNA polymerase II and negatively affects Serine-2 phosphorylation of its C-terminal domain at the KSHV RTA gene, decreasing nascent RNA synthesis. Knockdown of FUS increases transcription of RTA, thus driving enhanced expression of KSHV lytic genes. Collectively, these data reveal a novel role for FUS in regulating viral gene expression and are the first to demonstrate its role as a viral restriction factor.
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spelling pubmed-60708052018-08-09 FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression Dunker, William Song, Yu Zhao, Yang Karijolich, John Viruses Article Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi’s sarcoma. KSHV is also causally associated with the development of lymphoproliferative diseases, including primary effusion lymphoma (PEL). KSHV reactivation from latency plays an integral role in the progression to KSHV-associated disease as several lytic proteins have angiogenic and anti-apoptotic functions essential to the tumor microenvironment. Thus, restriction of KSHV reactivation represents an attractive therapeutic target. Here, we demonstrate that the cellular protein Fused-in-sarcoma (FUS) restricts KSHV lytic reactivation in PEL and in an epithelial cell-based model. Depletion of FUS significantly enhances viral mRNA and protein expression, resulting in increased viral replication and production of infectious virions. Chromatin immunoprecipitation analyses demonstrate that FUS is present at several KSHV lytic cycle genes during the latent stage of infection. We further demonstrate that FUS interacts with RNA polymerase II and negatively affects Serine-2 phosphorylation of its C-terminal domain at the KSHV RTA gene, decreasing nascent RNA synthesis. Knockdown of FUS increases transcription of RTA, thus driving enhanced expression of KSHV lytic genes. Collectively, these data reveal a novel role for FUS in regulating viral gene expression and are the first to demonstrate its role as a viral restriction factor. MDPI 2018-07-06 /pmc/articles/PMC6070805/ /pubmed/29986386 http://dx.doi.org/10.3390/v10070359 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dunker, William
Song, Yu
Zhao, Yang
Karijolich, John
FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression
title FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression
title_full FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression
title_fullStr FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression
title_full_unstemmed FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression
title_short FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression
title_sort fus negatively regulates kaposi’s sarcoma-associated herpesvirus gene expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070805/
https://www.ncbi.nlm.nih.gov/pubmed/29986386
http://dx.doi.org/10.3390/v10070359
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