The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling

Zemke, Nathan R.; Berk, Arnold

doi:10.1016/j.chom.2017.11.008

Cited by 28 publications

(33 citation statements)

References 67 publications

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“…Adenoviruses, like other DNA viruses, exist as nuclear episomes and are very likely to exploit epigenetic mechanisms to regulate biological activities during their life cycle 21 , 49 , 50 . Although the Ad2 E1A protein has a global effect on cellular transcription by directly impact on histone modifications 22 and the activation of a subset of IFN-stimulated genes (ISGs) 51 , the assembly of a helper-dependent adenovirus DNA into chromatin for efficient gene expression is independent of viral DNA replication 25 , 52 . Similarly, we found that JQ1 also promoted gene delivery efficiency by an E1-deleted Ad, indicating transgene expression is independent of E1 gene function.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of adenovirus infection and adenoviral vector-mediated gene delivery by bromodomain inhibitor JQ1

et al. 2018

Sci Rep

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Adenovirus-based vectors are among the most commonly used platforms for gene delivery and gene therapy studies. One of the obstacles for potential application is dose-related toxicity. We show here that adenovirus infection and Ad-mediated gene delivery can be enhanced by inhibitors of bromodomain and extra-terminal (BET) family proteins. We showed that JQ1, but not its inactive enantiomer (−)-JQ1, dose-dependently promoted Ad infection and Ad-mediated gene delivery in both epithelial and lymphocyte cells. Given orally, JQ1 also enhanced transgene expression in a murine tumor model. Inhibitors of histone deacetylases (HDACi) are among the commonly reported small molecule compounds which enhance Ad-mediated gene delivery. We found that JQ1 treatment did not cause histone acetylation nor expression of Ad attachment receptor CAR. Instead, JQ1 treatment induced an increase in BRD4 association with CDK9, a subunit of P-TEFb of transcription elongation. Concurrently, we showed that CDK9 inhibition blocked Ad infection and JQ1 enhancement on the infection. The study exemplifies the potentials of BET inhibitors like JQ1 in oncolytic virotherapy.

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Section: Discussionmentioning

confidence: 99%

Enhancement of adenovirus infection and adenoviral vector-mediated gene delivery by bromodomain inhibitor JQ1

et al. 2018

Sci Rep

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“…It is likely to be at least partially attributed to similar and overlapping consensus DNA-binding motifs for the interferon regulatory factor (IRF) family, most notably IRF3 and IRF7, which are key regulators of type I IFN production, and for IFN-stimulated gene factor 3 (ISGF3), which promotes the expression of many ISGs in response to IFN signaling (57)(58)(59)(60). For example, an IRF3 chromatin immunoprecipitation sequencing (ChIP-seq) experiment with adenovirus-infected human primary bronchial/tracheal epithelial cells demonstrated IRF3 binding to the promoter region of induced ISGs, including MX1 and ISG15, which have the IFNstimulated response element (ISRE) bound by IRFs and ISGF3 in the promoter regions (61). Further investigation of ISG induction in the absence of IFN signaling during DI infection will determine whether an IFN-independent mechanism of DI immunostimulation does indeed exist.…”

Section: Downloaded Frommentioning

confidence: 99%

Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection

Wang

Forst

Chou

et al. 2020

mBio

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Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single-cell level and how it impacts virus-host interactions at a system level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A virus. We observed substantial variability in viral transcription between cells, including the accumulation of defective viral genomes (DVGs) that impact viral replication. We show (i) a correlation between DVGs and virus-induced variation of the host transcriptional program and (ii) an association between differential inductions of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single-cell level improve our understanding of the complex virus-host interplay during influenza virus infection. IMPORTANCE Defective influenza virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent viruses. These defective genomes are thought to modulate the disease severity and pathogenicity of an influenza virus infection. Different defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of defective virus genomes on host cell responses cannot be fully resolved at the population level, requiring single-cell transcriptional profiling. Here, we characterized virus and host transcriptomes in individual influenza virus-infected cells, including those of defective viruses that arise during influenza A virus infection. We established an association between defective virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant defective viral genome species in vitro. This study demonstrates the intricate effects of defective viral genomes on host transcriptional responses and highlights the importance of capturing host-virus interactions at the single-cell level.

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“…E1A also uses CtBP1/2 to bring itself to and activate promoters that are normally repressed (effectively converting cellular repressors into coactivators) ( 122 ). This region also binds the sequence-specific TFs FOXK1 and FOXK2 ( 65 , 70 ), and exciting new results from the Berk laboratory demonstrate that single molecules of E1A must simultaneously form complexes with FOXK1/2, DCAF7, and CtBP during infection in order to suppress IRF3-driven activation of interferon (IFN)-stimulated genes (ISGs) ( 123 ). These findings provided precise molecular details of how E1A acts as a molecular scaffold to carry out this newly discovered function of its C terminus.…”

Section: Data Modificationmentioning

confidence: 99%

“…It is still not entirely clear how some of these interactions benefit HAdV infection. However, different regions of E1A have been shown to cooperate to maximize control over specific interaction partners or to establish novel connections that regulate viral gene expression, as highlighted above ( 123 , 136 , 137 ). Effectively, E1A functions as a viral hub to coordinate a massive reshuffling of host transcriptional machinery.…”

Section: Data Modificationmentioning

confidence: 99%

Hacking the Cell: Network Intrusion and Exploitation by Adenovirus E1A

King

Zhang

Tessier

et al. 2018

mBio

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As obligate intracellular parasites, viruses are dependent on their infected hosts for survival. Consequently, viruses are under enormous selective pressure to utilize available cellular components and processes to their own advantage. As most, if not all, cellular activities are regulated at some level via protein interactions, host protein interaction networks are particularly vulnerable to viral exploitation. Indeed, viral proteins frequently target highly connected “hub” proteins to “hack” the cellular network, defining the molecular basis for viral control over the host. This widespread and successful strategy of network intrusion and exploitation has evolved convergently among numerous genetically distinct viruses as a result of the endless evolutionary arms race between pathogens and hosts. Here we examine the means by which a particularly well-connected viral hub protein, human adenovirus E1A, compromises and exploits the vulnerabilities of eukaryotic protein interaction networks. Importantly, these interactions identify critical regulatory hubs in the human proteome and help define the molecular basis of their function.

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The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling

Cited by 28 publications

References 67 publications

Enhancement of adenovirus infection and adenoviral vector-mediated gene delivery by bromodomain inhibitor JQ1

Enhancement of adenovirus infection and adenoviral vector-mediated gene delivery by bromodomain inhibitor JQ1

Cell-to-Cell Variation in Defective Virus Expression and Effects on Host Responses during Influenza Virus Infection

Hacking the Cell: Network Intrusion and Exploitation by Adenovirus E1A

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