title: Suppression of Type I Interferon Signaling by E1A via RuvBL1/Pontin.
abstract: Suppression of interferon signaling is of paramount importance to a virus. Interferon signaling significantly reduces or halts the ability of a virus to replicate; therefore, viruses have evolved sophisticated mechanisms that suppress activation of the interferon pathway or responsiveness of the infected cell to interferon. Adenovirus has multiple modes of inhibiting the cellular response to interferon. Here, we report that E1A, previously shown to regulate interferon signaling in multiple ways, inhibits interferon-stimulated gene expression by modulating RuvBL1 function. RuvBL1 was previously shown to affect type I interferon signaling. E1A binds to RuvBL1 and is recruited to RuvBL1-regulated promoters in an interferon-dependent manner, preventing their activation. Depletion of RuvBL1 impairs adenovirus growth but does not appear to significantly affect viral protein expression. Although RuvBL1 has been shown to play a role in cell growth, its depletion had no effect on the ability of the virus to replicate its genome or to drive cells into S phase. E1A was found to bind to RuvBL1 via the C terminus of E1A, and this interaction was important for suppression of interferon-stimulated gene transcriptional activation and recruitment of E1A to interferon-regulated promoters. Here, we report the identification of RuvBL1 as a new target for adenovirus in its quest to suppress the interferon response.IMPORTANCEFor most viruses, suppression of the interferon signaling pathway is crucial to ensure a successful replicative cycle. Human adenovirus has evolved several different mechanisms that prevent activation of interferon or the ability of the cell to respond to interferon. The viral immediate-early geneE1Awas previously shown to affect interferon signaling in several different ways. Here, we report a novel mechanism reliant on RuvBL1 that E1A uses to prevent activation of interferon-stimulated gene expression following infection or interferon treatment. This adds to the growing knowledge of how viruses are able to inhibit interferon and identifies a novel target used by adenovirus for modulation of the cellular interferon pathway.
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Oladunni
authors.initials: O
authors.lastname: Olanubi
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Jasmine Rae
authors.initials: JR
authors.lastname: Frost
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Sandi
authors.initials: S
authors.lastname: Radko
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada peter.pelka@umanitoba.ca.|Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Pelka
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000256:Adenoviridae / Q000276:immunology*; D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004265:DNA Helicases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D007108:Immune Tolerance; D007113:Immunity, Innate; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D025941:Protein Interaction Mapping; D015398:Signal Transduction
chemical_list: D017500:Adenovirus E1A Proteins; D002352:Carrier Proteins; D007370:Interferon Type I; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C486549:RUVBL1 protein, human
keywords: E1A; Pontin; RuvBL1; adenovirus; interferon