title: A ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation.
abstract: Adenoviral replication depends on viral as well as cellular proteins. However, little is known about cellular proteins promoting adenoviral replication. In our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral replication. Our binding assays mapped a specific interaction between the N-terminal domains of both viral E1B-55K and USP7, a deubiquitinating enzyme. RNA interference-mediated downregulation of USP7 severely reduced E1B-55K protein levels, but more importantly negatively affected adenoviral replication. We also succeeded in resynthesizing an inhibitor of USP7, which like the knockdown background reduced adenoviral replication. Further assays revealed that not only adenoviral growth, but also adenoviral oncogene-driven cellular transformation relies on the functions of USP7. Our data provide insights into an intricate mechanistic pathway usurped by an adenovirus to promote its replication and oncogenic functions, and at the same time open up possibilities for new antiviral strategies.
authors.affiliation: Department of Molecular Virology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Ching
authors.forename: Emre
authors.initials: E
authors.lastname: Koyuncu
authors.forename: Sonia
authors.initials: S
authors.lastname: Singh
authors.forename: Christina
authors.initials: C
authors.lastname: Arbelo-Roman
authors.forename: Barbara
authors.initials: B
authors.lastname: Hartl
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Thomas
authors.initials: T
authors.lastname: Speiseder
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
authors.forename: Thomas
authors.initials: T
authors.lastname: Dobner
mesh_terms: D000260:Adenoviruses, Human / Q000472:pathogenicity / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D015536:Down-Regulation; D010450:Endopeptidases / Q000378:metabolism*; D020868:Gene Silencing; D054884:Host-Pathogen Interactions; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; D014779:Virus Replication / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D010450:Endopeptidases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; D018631:ras Proteins
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