Biology of the adenovirus E4orf4 protein: from virus infection to cancer cell death

Kleinberger, Tamar

doi:10.1002/1873-3468.13704

Cited by 12 publications

(4 citation statements)

References 170 publications

(174 reference statements)

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“…The most well-characterized functions of individual E4 proteins include mislocalization of antiviral restriction factors by E4orf3 ( 40 , 41 ), and degradation of antiviral proteins by the retargeting of a host ubiquitin ligase through the combined actions of E4orf6 and E1B55K ( 57–59 ). The E4orf4 product can also modulate diverse cellular processes, including RNA transcription and splicing, through effects on cellular signaling pathways ( 60 ). Two independently derived deletions of the E4 region (dl1004 and dl366) produced dsRNA after infection of A549 cells ( Supplementary Figure S2A ).…”

Section: Resultsmentioning

confidence: 99%

Adenovirus prevents dsRNA formation by promoting efficient splicing of viral RNA

Price

Steinbock

et al. 2021

Nucleic Acids Research

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Eukaryotic cells recognize intracellular pathogens through pattern recognition receptors, including sensors of aberrant nucleic acid structures. Sensors of double-stranded RNA (dsRNA) are known to detect replication intermediates of RNA viruses. It has long been suggested that annealing of mRNA from symmetrical transcription of both top and bottom strands of DNA virus genomes can produce dsRNA during infection. Supporting this hypothesis, nearly all DNA viruses encode inhibitors of dsRNA-recognition pathways. However, direct evidence that DNA viruses produce dsRNA is lacking. Contrary to dogma, we show that the nuclear-replicating DNA virus adenovirus (AdV) does not produce detectable levels of dsRNA during infection. In contrast, abundant dsRNA is detected within the nucleus of cells infected with AdV mutants defective for viral RNA processing. In the presence of nuclear dsRNA, the cytoplasmic dsRNA sensor PKR is relocalized and activated within the nucleus. Accumulation of viral dsRNA occurs in the late phase of infection, when unspliced viral transcripts form intron/exon base pairs between top and bottom strand transcripts. We propose that DNA viruses actively limit dsRNA formation by promoting efficient splicing and mRNA processing, thus avoiding detection and restriction by host innate immune sensors of pathogenic nucleic acids.

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Section: Resultsmentioning

confidence: 99%

Adenovirus prevents dsRNA formation by promoting efficient splicing of viral RNA

Price

Steinbock

et al. 2021

Nucleic Acids Research

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“…Besides E4orf3, E4orf4 regulates E1A activity, the E4 promoter, and activation of the Ad E2 promoter which controls viral DNA synthesis and induces apoptosis. Both E4orf1 and E4orf4 affect cap-dependent translation, S-phase entry and viral progeny production in normal and growth-limiting conditions [74]. In primary quiescent epithelial cells (SAEC), however, E4orf4 was shown to be more adept at activating mTOR than E4orf1 [75].…”

Section: Discussionmentioning

confidence: 99%

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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“…Alternative T-Antigens, a tumor-associated antigen encoded by ORF5 in human polyomavirus, is thought to disrupt the signaling pathway of tumor cell proliferation [ 35 ]. When expressed alone, adenovirus ORF4 protein induces an evolutionarily conserved, Caspase-independent, cancer-selective cell death [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Open Reading Frame-3a gene of the 2019 novel coronavirus inhibits the occurrence and development of colorectal cancer

Han

Mao

et al. 2022

Discov Onc

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Intestinal microecology is composed of bacteria, fungi and viruses. As a part of intestinal microecology, viruses participate in the occurrence and development of colorectal cancer. The 2019-nCoV was detected in stool samples from patients during COVID-19, suggesting that the 2019-nCoV may be associated with intestinal microecology. However, the relationship of the 2019-nCoV and CRC is unclear. The aim of this study is to explore the role of Open Reading Frame-3a (ORF3a) of the 2019-nCoV in CRC. After the pCDH-CMV-MCS-EF1-Puro vector that provides high expression of ORF3a was transfected into the SW480 CRC cell line, immunofluorescence was used to determine the localization of ORF3a in SW480 cells. The proliferation, migration, invasion, apoptosis, and cell cycle progression of SW480 cells were measured using the Cell Counting Kit-8 (CCK-8), wound healing, Transwell assay, flow cytometry, the TUNEL assay, and propidium iodide single staining. The results showed that ORF3a inhibited the proliferation, invasion, and migration of SW480 cells and induced their apoptosis after 24, 48, 72 h. Meanwhile, ORF3a inhibited the cell cycle and blocked SW480 CRC cells in the G1 phase. In in vivo experiments, high ORF3a expression was associated with decreased tumor volume, tumor weight, relative tumor volume, and tumor activity. ORF3a inhibited the growth and induced apoptosis and necrosis of tumor tissues. Based on this, we demonstrated that ORF3a might play a role in CRC, providing a new direction for the prevention and treatment of CRC.

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Biology of the adenovirus E4orf4 protein: from virus infection to cancer cell death

Cited by 12 publications

References 170 publications

Adenovirus prevents dsRNA formation by promoting efficient splicing of viral RNA

Adenovirus prevents dsRNA formation by promoting efficient splicing of viral RNA

E4orf1 Suppresses E1B-Deleted Adenovirus Vaccine-Induced Immune Responses

Open Reading Frame-3a gene of the 2019 novel coronavirus inhibits the occurrence and development of colorectal cancer

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