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

Elizabeth Vink,Yueting Zheng,Laurie Krug,Thomas Stamminger,Patrick Hearing,Rukhsana Yeasmin

doi:10.3390/v7052428

Elizabeth Vink, Yueting Zheng + Show 4 more

Open Access

https://doi.org/10.3390/v7052428

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Journal: Viruses	Publication Date: May 13, 2015
Citations: 61	License type: CC BY 4.0

Affiliation: Stony Brook University, University of Erlangen-Nuremberg

Abstract

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.

Highlights

IntroductionThe outcome of adenovirus (Ad) infection is determined by the interplay between the ability of the host cell to mount an effective antiviral response and the ability of the virus to restrict host cell defenses
The outcome of adenovirus (Ad) infection is determined by the interplay between the ability of the host cell to mount an effective antiviral response and the ability of the virus to restrict host cell defenses.Successful Ad replication relies on functions provided by the early region four (E4)
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

Summary

Introduction

The outcome of adenovirus (Ad) infection is determined by the interplay between the ability of the host cell to mount an effective antiviral response and the ability of the virus to restrict host cell defenses. Successful Ad replication relies on functions provided by the early region four (E4). This region encodes seven known proteins required for counteracting the host cell antiviral response, effective shutoff of host-cell protein synthesis, late viral mRNA accumulation, and late viral protein synthesis [1,2,3]. Rather than targeting proteins for degradation, the 14 kDa E4-ORF3 protein promotes productive Ad infection by oligomerizing into filamentous nuclear inclusions termed tracks [12]

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