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Open AccessArticle

Impact of Adenovirus E4-ORF3 Oligomerization and Protein Localization on Cellular Gene Expression

Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5222, USA
Department of Computer Science, Stony Brook University, Stony Brook, NY 11794, USA
Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Schlossgarten 4, Erlangen 91054, Germany
Author to whom correspondence should be addressed.
Current address: Department of Microbiology, New York University Langone Medical Center, New York, NY 10016, USA;
Academic Editor: Joanna Parish
Viruses 2015, 7(5), 2428-2449;
Received: 31 March 2015 / Revised: 23 April 2015 / Accepted: 11 May 2015 / Published: 13 May 2015
(This article belongs to the Special Issue Tumour Viruses)
The Adenovirus E4-ORF3 protein facilitates virus replication through the relocalization of cellular proteins into nuclear inclusions termed tracks. This sequestration event disrupts antiviral properties associated with target proteins. Relocalization of Mre11-Rad50-Nbs1 proteins prevents the DNA damage response from inhibiting Ad replication. Relocalization of PML and Daxx impedes the interferon-mediated antiviral response. Several E4-ORF3 targets regulate gene expression, linking E4-ORF3 to transcriptional control. Furthermore, E4-ORF3 was shown to promote the formation of heterochromatin, down-regulating p53-dependent gene expression. Here, we characterize how E4-ORF3 alters cellular gene expression. Using an inducible, E4-ORF3-expressing cell line, we performed microarray experiments to highlight cellular gene expression changes influenced by E4-ORF3 expression, identifying over four hundred target genes. Enrichment analysis of these genes suggests that E4-ORF3 influences factors involved in signal transduction and cellular defense, among others. The expression of mutant E4-ORF3 proteins revealed that nuclear track formation is necessary to induce these expression changes. Through the generation of knockdown cells, we demonstrate that the observed expression changes may be independent of Daxx and TRIM33 suggesting that an additional factor(s) may be responsible. The ability of E4-ORF3 to manipulate cellular gene expression through the sequestration of cellular proteins implicates a novel role for E4-ORF3 in transcriptional regulation. View Full-Text
Keywords: adenovirus; E4-ORF3; transcription; cellular gene expression adenovirus; E4-ORF3; transcription; cellular gene expression
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Vink, E.I.; Zheng, Y.; Yeasmin, R.; Stamminger, T.; Krug, L.T.; Hearing, P. Impact of Adenovirus E4-ORF3 Oligomerization and Protein Localization on Cellular Gene Expression. Viruses 2015, 7, 2428-2449.

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