The Human Adenovirus E4-ORF1 Protein Subverts Discs Large 1 to Mediate Membrane Recruitment and Dysregulation of Phosphatidylinositol 3-Kinase

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Adenoviruses cause acute illnesses in people, and are additionally utilized both as vehicles to cure genetic diseases, fight cancer, and deliver vaccines, and as tools to discover how cancers develop due to a capacity to generate tumors in experimental animals. The adenovirus E4-ORF1 protein reprograms cell metabolism to enhance virus production in infected cells and promotes cell survival and tumors by activating the important cellular protein phosphatidylinositol 3-kinase (PI3K). How E4-ORF1 activates PI3K is not known, though this function depends on E4-ORF1 binding to the membrane-associated cellular protein Discs Large 1 (Dlg1), which many different viruses evolved to target. In this study, we identify PI3K as a new direct target of E4-ORF1. Results further show that E4-ORF1 binds to PI3K in the cytoplasm and delivers it to Dlg1 at the membrane where the three proteins form a complex that activates PI3K and induces oncogenic growth in cells. This novel molecular mechanism in which adenovirus subverts Dlg1 to dysregulate PI3K may serve as a paradigm to understand PI3K activation mediated by other important pathogenic viruses, such as human papillomavirus, human T-cell leukemia virus type 1, and influenza A virus, which also target Dlg1 in infected cells.

Vyšlo v časopise: The Human Adenovirus E4-ORF1 Protein Subverts Discs Large 1 to Mediate Membrane Recruitment and Dysregulation of Phosphatidylinositol 3-Kinase. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004102
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004102

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