title: Impact of Adenovirus E4-ORF3 Oligomerization and Protein Localization on Cellular Gene Expression.
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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5222, USA. Elizabeth.Vink@nyumc.org.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Vink
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5222, USA. yueting.zheng@stonybrook.edu.
authors.forename: Yueting
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Computer Science, Stony Brook University, Stony Brook, NY 11794, USA. rukhsana.yeasmin@stonybrook.edu.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Yeasmin
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Schlossgarten 4, Erlangen 91054, Germany. Thomas.Stamminger@viro.med.uni-erlangen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stamminger
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5222, USA. laurie.krug@stonybrook.edu.
authors.forename: Laurie T
authors.initials: LT
authors.lastname: Krug
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5222, USA. patrick.hearing@stonybrook.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hearing
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D017504:Adenovirus E4 Proteins / Q000378:metabolism*; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D046228:Microarray Analysis; D055503:Protein Multimerization
chemical_list: D017504:Adenovirus E4 Proteins; C553317:E4orf3 protein, adenovirus
keywords: E4-ORF3; adenovirus; cellular gene expression; transcription