Adenovirus Evasion of Interferon-Mediated Innate Immunity by Direct Antagonism of a Cellular Histone Posttranslational Modification

Abstract

Overcoming the cellular type I interferon (IFN) host defense response is critical for a virus to ensure successful infection. Investigating the effects of human adenovirus (HAdV) infection on global cellular histone posttranslational modification (hPTM), we discovered that virus infection-induced activation of IFN signaling triggers a global increase in the monoubiquitination of histone 2B (H2B) at lysine 120, which is a mark for transcriptionally active chromatin. This hPTM, catalyzed by the hBre1/RNF20 complex, is necessary for activation of the cellular IFN-stimulated gene (ISG) expression program in response to viruses. To establish effective infection, the HAdV E1A protein binds to and dissociates the hBre1 complex to block IFN-induced H2B monoubiquitination and associated ISG expression. Together, these data uncover a key role for H2B monoubiquitination in the type I IFN response and a viral mechanism of antagonizing this hPTM to evade the IFN response.

Unabated Adenovirus Replication following Activation of the cGAS/STING-Dependent Antiviral Response in Human Cells

“…E1A suppresses signaling downstream of IFNR activation at STAT1 (51,81), compromises IFN-directed ISG activation by disrupting IFN-induced histone 2B monoubiquitination required for ISG induction (82), and blocks RNA activation of a TRIF/BS69 signalosome, which leads to NF-B and IRF3 activation (83). E1B functions to effectively repress IFN-induced antiviral strategies that impact replication (53,54).…”

Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate

“…Aberrant H2Bub1 levels can affect development (Wright et al 2011), apoptosis (Walter et al 2010), stem cell differentiation (Buszczak et al 2009;Fuchs et al 2012;Karpiuk et al 2012), viral infection outcome (Sarkari et al 2009;Fonseca et al 2012), and cell cycle progression (Hwang and Madhani 2009) and can promote cancer Blank et al 2012;Johnsen 2012;. Several mechanisms have been proposed to underlie the ability of H2Bub1 to exert those diverse effects, including impact on higher-order chromatin organization (Fierz et al 2011), altered nucleosome stability (Chandrasekharan et al 2009), regulation of H2A-H2B dimer displacement (Pavri et al 2006), and modulation of the recruitment of specific factors to chromatin (Shema-Yaacoby et al 2013).…”

Fighting Cancer with Mathematics and Viruses

“…Further complexities may be added to a mathematical model to explicitly account for the interplay between multiplicities of viral infection and the antiviral states mediated by interferon [119,122,123] as a cellular response to viral infection. Of course, the model would require additional distinction of antiviral and non-antiviral states [122] for uninfected cells (See [73] for example).…”