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Open AccessArticle

Viral Ubiquitin Ligase Stimulates Selective Host MicroRNA Expression by Targeting ZEB Transcriptional Repressors

1
Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
3
Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
4
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
5
Department of Genetics, Computational Genomics and Bioinformatics Group, University of Granada, Granada 18071, Spain
6
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
*
Author to whom correspondence should be addressed.
Current address: Precision Immunology Institute, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA
Academic Editor: Thomas Stamminger
Viruses 2017, 9(8), 210; https://doi.org/10.3390/v9080210
Received: 10 July 2017 / Revised: 31 July 2017 / Accepted: 2 August 2017 / Published: 7 August 2017
(This article belongs to the Section Animal Viruses)
Infection with herpes simplex virus-1 (HSV-1) brings numerous changes in cellular gene expression. Levels of most host mRNAs are reduced, limiting synthesis of host proteins, especially those involved in antiviral defenses. The impact of HSV-1 on host microRNAs (miRNAs), an extensive network of short non-coding RNAs that regulate mRNA stability/translation, remains largely unexplored. Here we show that transcription of the miR-183 cluster (miR-183, miR-96, and miR-182) is selectively induced by HSV-1 during productive infection of primary fibroblasts and neurons. ICP0, a viral E3 ubiquitin ligase expressed as an immediate-early protein, is both necessary and sufficient for this induction. Nuclear exclusion of ICP0 or removal of the RING (really interesting new gene) finger domain that is required for E3 ligase activity prevents induction. ICP0 promotes the degradation of numerous host proteins and for the most part, the downstream consequences are unknown. Induction of the miR-183 cluster can be mimicked by depletion of host transcriptional repressors zinc finger E-box binding homeobox 1 (ZEB1)/-crystallin enhancer binding factor 1 (δEF1) and zinc finger E-box binding homeobox 2 (ZEB2)/Smad-interacting protein 1 (SIP1), which we establish as new substrates for ICP0-mediated degradation. Thus, HSV-1 selectively stimulates expression of the miR-183 cluster by ICP0-mediated degradation of ZEB transcriptional repressors. View Full-Text
Keywords: herpes simplex virus; HSV-1; microRNA; miR-183; miR-96; miR-182; ICP0; E3 ubiquitin ligase; ZEB; host shutoff herpes simplex virus; HSV-1; microRNA; miR-183; miR-96; miR-182; ICP0; E3 ubiquitin ligase; ZEB; host shutoff
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MDPI and ACS Style

Lutz, G.; Jurak, I.; Kim, E.T.; Kim, J.Y.; Hackenberg, M.; Leader, A.; Stoller, M.L.; Fekete, D.M.; Weitzman, M.D.; Coen, D.M.; Wilson, A.C. Viral Ubiquitin Ligase Stimulates Selective Host MicroRNA Expression by Targeting ZEB Transcriptional Repressors. Viruses 2017, 9, 210.

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