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  1. Article ; Online: E4orf1: The triple agent of adenovirus - Unraveling its roles in oncogenesis, infectious obesity and immune responses in virus replication and vector therapy.

    Göttig, Lilian / Schreiner, Sabrina

    Tumour virus research

    2024  Volume 17, Page(s) 200277

    Abstract: Human Adenoviruses (HAdV) are nearly ubiquitous pathogens comprising numerous sub-types that infect various tissues and organs. Among many encoded proteins that facilitate viral replication and subversion of host cellular processes, the viral E4orf1 ... ...

    Abstract Human Adenoviruses (HAdV) are nearly ubiquitous pathogens comprising numerous sub-types that infect various tissues and organs. Among many encoded proteins that facilitate viral replication and subversion of host cellular processes, the viral E4orf1 protein has emerged as an intriguing yet under-investigated player in the complex interplay between the virus and its host. E4orf1 has gained attention as a metabolism activator and oncogenic agent, while recent research is showing that E4orf1 may play a more important role in modulating cellular pathways such as PI3K-Akt-mTOR, Ras, the immune response and further HAdV replication stages than previously anticipated. In this review, we aim to explore the structure, molecular mechanisms, and biological functions of E4orf1, shedding light on its potentially multifaceted roles during HAdV infection, including metabolic diseases and oncogenesis. Furthermore, we discuss the role of functional E4orf1 in biotechnological applications such as Adenovirus (AdV) vaccine vectors and oncolytic AdV. By dissecting the intricate relationships between HAdV types and E4orf1 proteins, this review provides valuable insights into viral pathogenesis and points to promising areas of future research.
    Language English
    Publishing date 2024-02-28
    Publishing country Netherlands
    Document type Journal Article ; Review
    ISSN 2666-6790
    ISSN (online) 2666-6790
    DOI 10.1016/j.tvr.2024.200277
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The human adenovirus PI3K-Akt activator E4orf1 is targeted by the tumor suppressor p53.

    Göttig, Lilian / Jummer, Simone / Staehler, Luisa / Groitl, Peter / Karimi, Maryam / Blanchette, Paola / Kosulin, Karin / Branton, Philip E / Schreiner, Sabrina

    Journal of virology

    2024  Volume 98, Issue 4, Page(s) e0170123

    Abstract: Human adenoviruses (HAdV) are classified as DNA tumor viruses due to their potential to mediate oncogenic transformation in non-permissive mammalian cells and certain human stem cells. To achieve transformation, the viral early proteins of the E1 and E4 ... ...

    Abstract Human adenoviruses (HAdV) are classified as DNA tumor viruses due to their potential to mediate oncogenic transformation in non-permissive mammalian cells and certain human stem cells. To achieve transformation, the viral early proteins of the E1 and E4 regions must block apoptosis and activate proliferation: the former predominantly through modulating the cellular tumor suppressor p53 and the latter by activating cellular pro-survival and pro-metabolism protein cascades, such as the phosphoinositide 3-kinase (PI3K-Akt) pathway, which is activated by HAdV E4orf1. Focusing on HAdV-C5, we show that E4orf1 is necessary and sufficient to stimulate Akt activation through phosphorylation in H1299 cells, which is not only hindered but repressed during HAdV-C5 infection with a loss of E4orf1 function in p53-positive A549 cells. Contrary to other research, E4orf1 localized not only in the common, cytoplasmic PI3K-Akt-containing compartment, but also in distinct nuclear aggregates. We identified a novel inhibitory mechanism, where p53 selectively targeted E4orf1 to destabilize it, also stalling E4orf1-dependent Akt phosphorylation. Co-IP and immunofluorescence studies showed that p53 and E4orf1 interact, and since p53 is bound by the HAdV-C5 E3 ubiquitin ligase complex, we also identified E4orf1 as a novel factor interacting with E1B-55K and E4orf6 during infection; overexpression of E4orf1 led to less-efficient E3 ubiquitin ligase-mediated proteasomal degradation of p53. We hypothesize that p53 specifically subverts the pro-survival function of E4orf1-mediated PI3K-Akt activation to protect the cell from metabolic hyper-activation or even transformation.IMPORTANCEHuman adenoviruses (HAdV) are nearly ubiquitous pathogens comprising numerous subtypes that infect various tissues and organs. Among many encoded proteins that facilitate viral replication and subversion of host cellular processes, the viral E4orf1 protein has emerged as an intriguing yet under-investigated player in the complex interplay between the virus and its host. Nonetheless, E4orf1 has gained attention as a metabolism activator and oncogenic agent, while recent research is showing that E4orf1 may play a more important role in modulating the cellular pathways such as phosphoinositide 3-kinase-Akt-mTOR. Our study reveals a novel and general impact of E4orf1 on host mechanisms, providing a novel basis for innovative antiviral strategies in future therapeutic settings. Ongoing investigations of the cellular pathways modulated by HAdV are of great interest, particularly since adenovirus-based vectors actually serve as vaccine or gene vectors. HAdV constitute an ideal model system to analyze the underlying molecular principles of virus-induced tumorigenesis.
    MeSH term(s) Humans ; Adenovirus E4 Proteins/genetics ; Adenovirus E4 Proteins/metabolism ; Adenovirus Infections, Human/virology ; Adenoviruses, Human/growth & development ; Adenoviruses, Human/metabolism ; Cell Line, Tumor ; HEK293 Cells ; Open Reading Frames/genetics ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/agonists ; Proto-Oncogene Proteins c-akt/metabolism ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Virus Replication
    Chemical Substances Adenovirus E4 Proteins ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2024-03-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.01701-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Apobec3A Deamination Functions Are Involved in Antagonizing Efficient Human Adenovirus Replication and Gene Expression.

    Göttig, Lilian / Weiß, Christina / Stubbe, Miona / Hanrieder, Lisa / Hofmann, Samuel / Grodziecki, Alessandro / Stadler, Daniela / Carpentier, Arnaud / Protzer, Ulrike / Schreiner, Sabrina

    mBio

    2023  Volume 14, Issue 3, Page(s) e0347822

    Abstract: Apobec3A is involved in the antiviral host defense, targeting nuclear DNA, introducing point mutations, and thereby activating DNA damage response (DDR). Here, we found a significant upregulation of Apobec3A during HAdV infection, including Apobec3A ... ...

    Abstract Apobec3A is involved in the antiviral host defense, targeting nuclear DNA, introducing point mutations, and thereby activating DNA damage response (DDR). Here, we found a significant upregulation of Apobec3A during HAdV infection, including Apobec3A protein stabilization mediated by the viral proteins E1B-55K and E4orf6, which subsequently limited HAdV replication and most likely involved a deaminase-dependent mechanism. The transient silencing of Apobec3A enhanced adenoviral replication. HAdV triggered Apobec3A dimer formation and enhanced activity to repress the virus. Apobec3A decreased E2A SUMOylation and interfered with viral replication centers. A comparative sequence analysis revealed that HAdV types A, C, and F may have evolved a strategy to escape Apobec3A-mediated deamination via reduced frequencies of TC dinucleotides within the viral genome. Although viral components induce major changes within infected cells to support lytic life cycles, our findings demonstrate that host Apobec3A-mediated restriction limits virus replication, albeit that HAdV may have evolved to escape this restriction. This allows for novel insights into the HAdV/host-cell interplay, which broaden the current view of how a host cell can limit HAdV infection.
    MeSH term(s) Humans ; Adenoviruses, Human/physiology ; Adenoviridae/genetics ; Virus Replication ; COVID-19 Vaccines ; Deamination ; COVID-19 ; Adenovirus Infections, Human ; Antiviral Agents/metabolism ; Gene Expression
    Chemical Substances APOBEC3A protein, human (EC 3.5.4.5) ; COVID-19 Vaccines ; Antiviral Agents
    Language English
    Publishing date 2023-05-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.03478-22
    Database MEDical Literature Analysis and Retrieval System OnLINE

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