title: Functional cooperation between human adenovirus type 5 early region 4, open reading frame 6 protein, and cellular homeobox protein HoxB7.
abstract: Human adenovirus type 5 (HAdV5) E4orf6 (early region 4 open reading frame 6 protein) is a multifunctional early viral protein promoting efficient replication and progeny production. E4orf6 complexes with E1B-55K to assemble cellular proteins into a functional E3 ubiquitin ligase complex that not only mediates proteasomal degradation of host cell substrates but also facilitates export of viral late mRNA to promote efficient viral protein expression and host cell shutoff. Recent findings defined the role of E4orf6 in RNA splicing independent of E1B-55K binding. To reveal further functions of the early viral protein in infected cells, we used a yeast two-hybrid system and identified the homeobox transcription factor HoxB7 as a novel E4orf6-associated protein. Using a HoxB7 knockdown cell line, we observed a positive role of HoxB7 in adenoviral replication. Our experiments demonstrate that the absence of HoxB7 leads to inefficient viral progeny production, as HAdV5 gene expression is highly regulated by HoxB7-mediated activation of various adenoviral promoters. We have thus identified a novel role of E4orf6 in HAdV5 gene transcription via regulation of homeobox protein-dependent modulation of viral promoter activity.
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Müller
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schreiner
authors.forename: Melanie
authors.initials: M
authors.lastname: Schmid
authors.forename: Peter
authors.initials: P
authors.lastname: Groitl
authors.forename: Michael
authors.initials: M
authors.lastname: Winkler
authors.forename: Thomas
authors.initials: T
authors.lastname: Dobner
mesh_terms: D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism; D017504:Adenovirus E4 Proteins / Q000235:genetics / Q000378:metabolism*; D000260:Adenoviruses, Human / Q000502:physiology*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000502:physiology*
chemical_list: D017501:Adenovirus E1B Proteins; D017504:Adenovirus E4 Proteins; C553318:E4orf6 protein, adenovirus; C490538:HOXB7 protein, human; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D012367:RNA, Viral; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex