Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Jun:17:200277.
doi: 10.1016/j.tvr.2024.200277. Epub 2024 Feb 28.

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

Lilian Göttig  1 , Sabrina Schreiner  2
Affiliations
Review

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

Lilian Göttig et al. Tumour Virus Res. 2024 Jun.

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.

Keywords: AdV vectors; Adipogenesis; E4orf1; HAdV-C5; HAdV-D36; HAdV-D9; Oncogenesis; Oncolytic AdV; PI3K-Akt.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
HAdV genome organization. The viral DNA genome is shown as a blue box of around 36 kb with the ITRs at either end, packaging sequence Ψ, and MLP (Major Late Promoter). The arrows indicate the orientation of the initial transcription units, E1-4, pIX, IVa2, and Major Late Transcripts. The E4 region is expanded to show the splice products: E4orf1, E4orf2, E4orf3, E4orf4, E4orf3/4, E4orf6, E4orf6/7. The proteins marked in red represent HAdV oncogenes.
Fig. 2
Fig. 2
E4orf1 sequence analysis. (A) Multiple gene sequence alignment of E4orf1-C5, -D9, and -D36 with Clustal Omega (EMBL-EBI; [346]). (B) Multiple protein sequence alignment of E4orf1-C5, -D9, and -D36 with Clustal Omega (EMBL-EBI; [346]). “*” indicates conservative residues in all three sequences, “:” represents residues with strongly similar properties, and “.” represents residues with weakly similar properties. (C) In silico prediction of E4orf1-C5, -D9, and -D36 protein tertiary structures based on SWISS-MODEL Workspace computation [88,89] with sequence coloring highlighting the strand folds within the tertiary structure [88]. (D) E4orf1 carboxy-terminal domain of E4orf1-D9, -D36, and -C5 with the known PBM domain of all three types (red), as well as the known PI3K-interacting domain (green), Dlg1-binding domain (blue), and trimerization domain (black) for E4orf1-D9. Putative but unresolved PI3K-interacting, Dlg1-binding, and trimerization domains for E4orf1-D36 and -C5 are indicated in grey.
Fig. 3
Fig. 3
Overview of the E4orf1 molecular mode of action. Schematic overview of various interactions between E4orf1 (blue) and cellular proteins, including the consequences of such interactions. See the main text for detailed descriptions that refer to this figure. HAdV infection and HAdV-induced mechanisms are described in blue, including arrows, while cellular mechanisms are described in black, including arrows. The Raf-Mek-Erk signaling pathway, which induces MYC expression, is faded out, since although HAdV infection activates this pathway, the E4orf1 mode of action is suggested to strongly favor PI3K-Akt-mTOR pathway activation. Red crosses are abrogating modes of action, and yellow stars represent activating signaling.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Hierholzer J.C. Adenoviruses in the immunocomprimised host. Clin. Microbiol. Rev. 1992;5:262–274. - PMC - PubMed
    1. Sivan A.V., Lee T., Binn L.N., Gaydos J.C. Adenovirus-associated acute respiratory disease in healthy adolescents and adults: a literature review. Mil. Med. 2007;172:1198–1203. - PubMed
    1. Lynch J.P., 3rd, Fishbein M., Echavarria M. Adenovirus. Semin. Respir. Crit. Care Med. 2011;32:494–511. - PubMed
    1. Lenaerts L., DeClercq E., Naesens L. Clinical features and treatment of adenovirus infections. Rev. Med. Virol. 2008;18:357–374. - PubMed
    1. Lion T. Adenovirus infections in immunocompetent and immunocompromised patients. Clin. Microbiol. Rev. 2014;27:441–462. - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources