title: Promyelocytic leukemia protein isoform II inhibits infection by human adenovirus type 5 through effects on HSP70 and the interferon response.
abstract: Promyelocytic leukemia (PML) proteins have been implicated in antiviral responses but PML and associated proteins are also suggested to support virus replication. One isoform, PML-II, is required for efficient transcription of interferon and interferon-responsive genes. We therefore investigated the PML-II contribution to human adenovirus 5 (Ad5) infection, using shRNA-mediated knockdown. HelaΔII cells showed a 2-3-fold elevation in Ad5 yield, reflecting an increase in late gene expression. This increase was found to be due in part to the reduced innate immune response consequent upon PML-II depletion. However, the effect was minor because the viral E4 Orf3 protein targets and inactivates this PML-II function. The major benefit to Ad5 in HelaΔII cells was exerted via an increase in HSP70; depletion of HSP70 completely reversed this replicative advantage. Increased Ad5 late gene expression was not due either to the previously described inhibition of inflammatory responses by HSP70 or to effects of HSP70 on major late promoter or L4 promoter activity, but might be linked to an observed increase in E1B 55K, as this protein is known to be required for efficient late gene expression. The induction of HSP70 by PML-II removal was specific for the HSPA1B gene among the HSP70 gene family and thus was not the consequence of a general stress response. Taken together, these data show that PML-II, through its various actions, has an overall negative effect on the Ad5 lifecycle.
authors.affiliation: University of Warwick, School of Life Sciences, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Zeenah
authors.initials: Z
authors.lastname: Atwan
authors.affiliation: University of Warwick, School of Life Sciences, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Jordan
authors.initials: J
authors.lastname: Wright
authors.affiliation: University of Warwick, School of Life Sciences, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Woodman
authors.affiliation: University of Warwick, School of Life Sciences, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Keith N
authors.initials: KN
authors.lastname: Leppard
mesh_terms: D000260:Adenoviruses, Human / Q000276:immunology*; D055785:Gene Knockdown Techniques; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C070576:PML protein, human; D007372:Interferons