Disruption of NBS1/MRN Complex Formation by E4orf3 Supports NF-κB That Licenses E1B55K-Deleted Adenovirus-Infected Cells to Accumulate DNA&gt;4n

Almuzaini, Nujud; Moore, Madison; Robert-Guroff, Marjorie; Thomas, M. Albert

doi:10.1128/spectrum.01881-21

Cited by 6 publications

(8 citation statements)

References 86 publications

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“…In other cell systems, Akt allows the activation of mTOR1 that mediates the phosphorylation activation of NF-kB [51]. In a recent publication we provide further evidence supporting a link between E4orf1 and activation of NF-kB [17] which is known for its involvement in the induction of innate cytokine genes important for stimulating both innate and adaptive arms of the immune system [16]. Moreover, we showed that E4orf1-deleted ∆E4 1 Ad-immunized rhesus macaques produced higher levels of IFNγ-producing memory T-cells (Figure 4), higher levels of transgene-specific IgG1 (Figure 6), and antibodies able to mediate greater ADCC activity (Figure 8) than the E4orf1containting ∆E1B parental Ad.…”

Section: Discussionsupporting

confidence: 58%

“…In Figure 2B, HeLa cells were infected with the ∆E1B Ad and treated 4 h later with or without AktIV, known to prevent the phosphorylation of Akt. The same antibodies used in Figure 2A did not recognize phosphorylated Akt in AktIV-treated ∆E1B Ad infected cells, confirming the antibody specificity and supporting the notion that cells infected with ∆E3 or ∆E1B Ad contain phosphorylated Akt (Ser473 and Thr308), in stark contrast to cells infected with ∆E4 1 Ad (Figure 2A, [13,17]). A PCR for the Ad fiber gene (Figure 2B) was used to confirm infection of the cells.…”

Section: E4orf1 Limits Intrinsic Innate Cytokine Gene Expression In ∆...supporting

confidence: 67%

“…Of the E4 products in the ∆E4 1 Ad, E4orf3 is reported to inactivate type 1 and type 2 interferon responses [10]. We showed recently that E4orf1 cooperates with E4orf3 to allow Ad-infected cells to survive with DNA > 4n which required NF-kB [17]. Thus, in ∆E1B Ad-infected cells, E4orf3 may cooperate with E4orf1 in suppressing immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to cell survival, the PI3-kinase/Akt pathway also mediates immune responses [14] and is implicated in the phosphorylation of NF-κB [15] which is best known for its involvement in the induction of innate cytokine genes important for stimulating both innate and adaptive arms of the immune system [16]. In another article [17], we showed that E4orf1 signals induce NF-κB. To evaluate the possibility that E4orf1 could mediate immune responses, we created a ∆E1B Ad in which we deleted E4orf1 and replaced the E3 with rhFLSC [11], similarly to what we have done before [12,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses

et al. 2022

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As demonstrated by the recent COVID pandemic, vaccines can reduce the burden arising from infectious agents. Adenoviruses (Ads) with deletion of the early region 1B55K (ΔE1B Ad) are currently being explored for use in vaccine delivery. ΔE1B Ads are different from Ads with deletions in early region 1 and early region 3 (ΔE1/E3) used in most Ad vaccine vectors in that they contain the Ad early region 1A (E1A), and therefore the ability to replicate. Common to almost all Ads that are being explored for clinical use is the Ad early region 4 (E4). Among the E4 genes is open reading frame 1 (E4orf1), which mediates signals through the PI3-kinase/Akt pathway that is known to modulate immune responses. This suggests that E4orf1 might also modulate immune responses, although it has remained unexplored in ΔE1B Ad. Here, we show that cells infected with an E1B55K and E4orf1-deleted (ΔE41) Ad exhibited reduced levels of phosphorylated Akt (Ser473 and Thr308)) and expressed different intrinsic innate immune cytokines from those induced in cells infected with an E4orf1-containing, ΔE1B parental Ad that exhibited elevated levels of phosphorylated Akt. Rhesus macaques immunized with a ΔE41 Ad that expressed rhFLSC (HIV-1BaL gp120 linked to rhesus CD4 D1 and D2), exhibited higher levels of rhFLSC-specific interferon γ-producing memory T-cells, higher titers of rhFLSC-specific IgG1 binding antibody in serum, and antibodies able to mediate antibody-dependent cellular cytotoxicity (ADCC) with greater killing capacity than the ΔE1B Ad. Therefore, E4orf1, perhaps by acting through the PI3-kinase/Akt pathway, limits intrinsic innate and system-wide adaptive immune responses that are important for improved ΔE1B Ad-based vaccines.

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Section: Discussionsupporting

confidence: 58%

Section: E4orf1 Limits Intrinsic Innate Cytokine Gene Expression In ∆...supporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses

et al. 2022

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“…Recently, Sangare and co-authors identified E4orf1 as a co-factor with E1B–55K that limited the immune response, since rhesus macaques immunized by an E1B–55K- and E4orf1-deleted HAdV-C5 vector produced higher levels of HIV-envelope-specific interferon γ-producing memory T-cells, higher titers of specific IgG1 binding antibody, and antibodies that were able to mediate antibody-dependent cellular cytotoxicity with greater killing capacity than the original deleted E1B–55K vector [ 25 ]. Since the PI3K-Akt-mTOR pathway also mediates immune responses through activating the NF-κB-mediated transcription of cytokine genes that are important for stimulating innate and adaptive parts of the immune system, E4orf1 activation of PI3K may also induce NF-κB and seems to be involved in HAdV-C5 vector system immune response signaling [ 25 , [343] , [344] , [345] ]. Although it remains to be investigated to what degree E4orf1 is “active” within AdV vectors, these studies indicate that the inclusion of the E4orf1 coding region clearly affects immunogenicity and oncolysis of these vectors [ 25 , 327 ].…”

Section: Biotechnological Adv Vector Applications and The Role Of E4orf1mentioning

confidence: 99%

E4orf1: The triple agent of adenovirus – Unraveling its roles in oncogenesis, infectious obesity and immune responses in virus replication and vector therapy

Göttig,

Schreiner

2024

Tumour Virus Research

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The human adenovirus PI3K-Akt activator E4orf1 is targeted by the tumor suppressor p53

Göttig,

Jummer,

Staehler

et al. 2024

J Virol

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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. IMPORTANCE Human 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.

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Disruption of NBS1/MRN Complex Formation by E4orf3 Supports NF-κB That Licenses E1B55K-Deleted Adenovirus-Infected Cells to Accumulate DNA>4n

Cited by 6 publications

References 86 publications

E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses

E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses

E4orf1: The triple agent of adenovirus – Unraveling its roles in oncogenesis, infectious obesity and immune responses in virus replication and vector therapy

The human adenovirus PI3K-Akt activator E4orf1 is targeted by the tumor suppressor p53

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