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Viruses 2018, 10(7), 359; https://doi.org/10.3390/v10070359

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

1,†
,
1,2,†
,
1
and
1,3,4,*
1
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
2
College of Pharmacy, Xinxiang Medical University, Xinxiang 453000, China
3
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
4
Vanderbilt Institute for Infection, Immunology and Inflammation, Nashville, TN 37232, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 29 May 2018 / Revised: 25 June 2018 / Accepted: 3 July 2018 / Published: 6 July 2018
(This article belongs to the Section Animal Viruses)
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Abstract

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. View Full-Text
Keywords: KSHV; RTA; viral lytic reactivation; FUS; RNA Polymerase II; Restriction Factor KSHV; RTA; viral lytic reactivation; FUS; RNA Polymerase II; Restriction Factor
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Dunker, W.; Song, Y.; Zhao, Y.; Karijolich, J. FUS Negatively Regulates Kaposi’s Sarcoma-Associated Herpesvirus Gene Expression. Viruses 2018, 10, 359.

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