Skip to main content
Log in

In Silico Intensive Analysis for the E4 Gene Evolution of Human Adenovirus Species D

  • Virology
  • Published:
Journal of Microbiology Aims and scope Submit manuscript

Abstract

Adenovirus (Ad) is a ubiquitous pathogen capable of infecting a wide range of animals and humans. Human Adenovirus (HAdV) can cause severe infection, particularly in individuals with compromised immune systems. To date, over 110 types of HAdV have been classified into seven species from A to G, with the majority belonging to the human adenovirus species D (HAdV-D). In the HAdV-D, the most significant factor for the creation of new adenovirus types is homologous recombination between viral genes involved in determining the virus tropism or evading immune system of host cells. The E4 gene, consisting of seven Open Reading Frames (ORFs), plays a role in both the regulation of host cell metabolism and the replication of viral genes. Despite long-term studies, the function of each ORF remains unclear. Based on our updated information, ORF2, ORF3, and ORF4 have been identified as regions with relatively high mutations compared to other ORFs in the E4 gene, through the use of in silico comparative analysis. Additionally, we managed to visualize high mutation sections, previously undetectable at the DNA level, through a powerful amino acid sequence analysis tool known as proteotyping. Our research has revealed the involvement of the E4 gene in the evolution of human adenovirus, and has established accurate sequence information of the E4 gene, laying the groundwork for further research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

The supporting data for this study can be received from the corresponding author upon a rational demand.

References

  • Bridge, E., & Ketner, G. (1989). Redundant control of adenovirus late gene expression by early region 4. Journal of Virology, 63, 631–638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang, S. Y., Lee, C. N., Lin, P. H., Huang, H. H., Chang, L. Y., Ko, W., Chang, S. F., Lee, P. I., Huang, L. M., & Kao, C. L. (2008). A community-derived outbreak of adenovirus type 3 in children in Taiwan between 2004 and 2005. Journal of Medical Virology, 80, 102–112.

    Article  CAS  PubMed  Google Scholar 

  • Charman, M., Herrmann, C., & Weitzman, M. D. (2019). Viral and cellular interactions during adenovirus DNA replication. FEBS Letters, 593, 3531–3550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dix, I., & Leppard, K. N. (1995). Expression of adenovirus type 5 E4 Orf2 protein during lytic infection. The Journal of General Virology, 76, 1051–1055.

    Article  CAS  PubMed  Google Scholar 

  • Evans, J. D., & Hearing, P. (2003). Distinct roles of the adenovirus E4 ORF3 protein in viral DNA replication and inhibition of genome concatenation. Journal of Virology, 77, 5295–5304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frese, K. K., Lee, S. S., Thomas, D. L., Latorre, I. J., Weiss, R. S., Glaunsinger, B. A., & Javier, R. T. (2003). Selective PDZ protein-dependent stimulation of phosphatidylinositol 3-kinase by the adenovirus E4-ORF1 oncoprotein. Oncogene, 22, 710–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodrum, F. D., & Ornelles, D. A. (1999). Roles for the E4 orf6, orf3, and E1b 55-kilodalton proteins in cell cycle-independent adenovirus replication. Journal of Virology, 73, 7474–7488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harman, J. L., Loes, A. N., Warren, G. D., Heaphy, M. C., Lampi, K. J., & Harms, M. J. (2020). Evolution of multifunctionality through a pleiotropic substitution in the innate immune protein S100A9. eLife, 9, e54100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hernández-Magaña, L. E., Mosqueda-Gracida, A., Cruz-Holguín, V. J., Martínez-Castillo, M., Fuentes-Pananá, E. M., Rozmyslowicz, T., León-Juárez, M., & Arévalo-Romero, H. (2023). E4orf1 as a key modulator in oncogenesis and of metabolism in Adenovirus infection. Frontiers in Virology, 3, 1195717.

    Article  Google Scholar 

  • Horwitz, M. S. (2004). Function of adenovirus E3 proteins and their interactions with immunoregulatory cell proteins. The Journal of Gene Medicine, 6, S172–S183.

    Article  CAS  PubMed  Google Scholar 

  • Huang, M. M., & Hearing, P. (1989). The adenovirus early region 4 open reading frame 6/7 protein regulates the DNA binding activity of the cellular transcription factor, E2F, through a direct complex. Genes & Development, 3, 1699–1710.

    Article  CAS  Google Scholar 

  • Humbert, P. O., Grzeschik, N. A., Brumby, A. M., Galea, R., Elsum, I., & Richardson, H. E. (2008). Control of tumourigenesis by the Scribble/Dlg/Lgl polarity module. Oncogene, 27, 6888–6907.

    Article  CAS  PubMed  Google Scholar 

  • Ishidate, T., Matsumine, A., Toyoshima, K., & Akiyama, T. (2000). The APC-hDLg complex negatively regulates cell cycle progression from the G0/G1 to S phase. Oncogene, 19, 365–372.

    Article  CAS  PubMed  Google Scholar 

  • Ismail, A. M., Lee, J. S., Lee, J. Y., Singh, G., Dyer, D. W., Seto, D., Chodosh, J., & Rajaiya, J. (2018). Adenoviromics: Mining the human adenovirus species d genome. Frontiers in Microbiology, 9, 2178.

    Article  PubMed  PubMed Central  Google Scholar 

  • Källsten, M., Gromova, A., Zhao, H., Valdés, A., Konzer, A., Pettersson, U., & Lind, S. B. (2017). Temporal characterization of the non-structural Adenovirus type 2 proteome and phosphoproteome using high-resolving mass spectrometry. Virology, 511, 240–248.

    Article  PubMed  Google Scholar 

  • Kumar, M., Kong, K., & Javier, R. T. (2014). Hijacking Dlg1 for oncogenic phosphatidylinositol 3-kinase activation in human epithelial cells is a conserved mechanism of human adenovirus E4-ORF1 proteins. Journal of Virology, 88, 14268–14277.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee, J. Y., Lee, J. S., Materne, E. C., Rajala, R., Ismail, A. M., Seto, D., Dyer, D. W., Rajaiya, J., & Chodosh, J. (2018). Bacterial RecA protein promotes adenoviral recombination during in vitro infection. mSphere, 3, e00105-18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leppard, K. N. (1997). E4 gene function in adenovirus, adenovirus vector and adeno-associated virus infections. The Journal of General Virology, 78, 2131–2138.

    Article  CAS  PubMed  Google Scholar 

  • Lynch, J. P., 3rd., Fishbein, M., & Echavarria, M. (2011). Adenovirus. Seminars in Respiratory and Critical Care Medicine, 32, 494–511.

    Article  PubMed  Google Scholar 

  • Müller, U., Kleinberger, T., & Shenk, T. (1992). Adenovirus E4orf4 protein reduces phosphorylation of c-Fos and E1A proteins while simultaneously reducing the level of AP-1. Journal of Virology, 66, 5867–5878.

    Article  PubMed  PubMed Central  Google Scholar 

  • Obenauer, J. C., Denson, J., Mehta, P. K., Su, X., Mukatira, S., Finkelstein, D. B., Xu, X., Wang, J., Ma, J., Fan, Y., et al. (2006). Large-scale sequence analysis of avian influenza isolates. Science, 311, 1576–1580.

    Article  CAS  PubMed  Google Scholar 

  • Park, A., Lee, C., Lee, J. Y. (2024). Genomic evolution and recombination dynamics of human adenovirus d species: Insights from comprehensive bioinformatic analysis. Journal of Microbiology, 62. https://doi.org/10.1007/s12275-024-00112-5.

  • Radke, J. R., & Cook, J. L. (2018). Human adenovirus infections: Update and consideration of mechanisms of viral persistence. Current Opinion in Infectious Diseases, 31, 251–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajaiya, J., Saha, A., Zhou, X., & Chodosh, J. (2021). Human adenovirus species D interactions with corneal stromal cells. Viruses, 13, 2505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson, C. M., Singh, G., Lee, J. Y., Dehghan, S., Rajaiya, J., Liu, E. B., Yousuf, M. A., Betensky, R. A., Jones, M. S., Dyer, D. W., et al. (2013). Molecular evolution of human adenoviruses. Scientific Reports, 3, 1812.

    Article  PubMed  PubMed Central  Google Scholar 

  • Saha, B., & Parks, R. J. (2017). Human adenovirus type 5 vectors deleted of early region 1 (E1) undergo limited expression of early replicative E2 proteins and DNA replication in non-permissive cells. PLoS ONE, 12, e0181012.

    Article  PubMed  PubMed Central  Google Scholar 

  • Singh, G., Ismail, A. M., Lee, J. Y., Ramke, M., Lee, J. S., Dyer, D. W., Seto, D., Rajaiya, J., & Chodosh, J. (2019). Divergent evolution of E1A CR3 in human adenovirus species D. Viruses, 11, 143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stasiak, A. C., & Stehle, T. (2020). Human adenovirus binding to host cell receptors: A structural view. Medical Microbiology and Immunology, 209, 325–333.

    Article  PubMed  Google Scholar 

  • Tabbara, K. F., Omar, N., Hammouda, E., Akanuma, M., Ohguchi, T., Ariga, T., Tagawa, Y., Kitaichi, N., Ishida, S., Aoki, K., et al. (2010). Molecular epidemiology of adenoviral keratoconjunctivitis in Saudi Arabia. Molecular Vision, 16, 2132–2136.

    PubMed  PubMed Central  Google Scholar 

  • Thai, M., Graham, N. A., Braas, D., Nehil, M., Komisopoulou, E., Kurdistani, S. K., McCormick, F., Graeber, T. G., & Christofk, H. R. (2014). Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication. Cell Metabolism, 19, 694–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vangipuram, S. D., Yu, M., Tian, J., Stanhope, K. L., Pasarica, M., Havel, P. J., Heydari, A. R., & Dhurandhar, N. V. (2007). Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells. International Journal of Obesity, 31, 87–96.

    Article  CAS  PubMed  Google Scholar 

  • Virtanen, A., Gilardi, P., Näslund, A., LeMoullec, J. M., Pettersson, U., & Perricaudet, M. (1984). mRNAs from human adenovirus 2 early region 4. Journal of Virology, 51, 822–831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss, R. S., Gold, M. O., Vogel, H., & Javier, R. T. (1997a). Mutant adenovirus type 9 E4 ORF1 genes define three protein regions required for transformation of CREF cells. Journal of Virology, 71, 4385–4394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss, R. S., Lee, S. S., Prasad, B. V., & Javier, R. T. (1997b). Human adenovirus early region 4 open reading frame 1 genes encode growth-transforming proteins that may be distantly related to dUTP pyrophosphatase enzymes. Journal of Virology, 71, 1857–1870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2021R1F1A1063240) and research funds for newly appointed professors of Jeonbuk National University in 2020.

Author information

Authors and Affiliations

Authors

Contributions

C.L. arranged the sequences of E4 gene of adenovirus from NCBI, analyzed all data using bioinformatics tools and wrote the manuscript; A.P. contributed to the collection of adenovirus sequences and performed proteotyping analysis; J. L. supervised the data analysis and the manuscript writing.

Corresponding author

Correspondence to Jeong Yoon Lee.

Ethics declarations

Conflict of Interest

The authors have no financial conflicts of interest to declare.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 666 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, C., Park, A. & Lee, J.Y. In Silico Intensive Analysis for the E4 Gene Evolution of Human Adenovirus Species D. J Microbiol. (2024). https://doi.org/10.1007/s12275-024-00132-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12275-024-00132-1

Keywords

Navigation