A New Crucial Protein Interaction Element That Targets the Adenovirus E4-ORF1 Oncoprotein to Membrane Vesicles


Human adenovirus type 9 exclusively elicits mammary tumors in experimental animals, and the primary oncogenic determinant of this virus is the E4-ORF1 oncogene, as opposed to the well-known E1A and E1Boncogenes. The tumorigenic potential of E4-ORF1, as well as its ability to oncogenically stimulate phosphatidylinositol 3-kinase (PI3K), depends on a carboxyl-terminal PDZ domain-binding motif (PBM) that mediates interactions with several different membrane-associated cellular PDZ proteins, including MUPP1, PATJ, MAGI-1, ZO-2, and Dlg1. Nevertheless, because certain E4-ORF1 mutations that alter neither the sequence nor the function of the PBM abolish E4-ORF1-induced PI3K activation and cellular transformation, we reasoned that E4-ORF1 must possess an additional crucial protein element. In the present study, we identified seven E4-ORF1 amino acid residues that define this new element, designated domain 2, and showed that it mediates binding to a 70-kDa cellular phosphoprotein. We also discovered that domain 2 or the PBM independently promotes E4-ORF1 localization to cytoplasmic membrane vesicles and that this activity of domain 2 depends on E4-ORF1 trimerization. Consistent with the latter observation, molecular-modeling analyses predicted that E4-ORF1 trimerization brings together six out of seven domain 2 residues at each of the three subunit interfaces. These findings importantly demonstrate that PI3K activation and cellular transformation induced by E4-ORF1 require two separate protein interaction elements, domain 2 and the PBM, each of which targets E4-ORF1 to vesicle membranes in cells.



adenovirus, mammary tumors, E4-ORF1, phosphatidylinositol 3-kinase, PDZ domain-binding motif, PI 3-kinase


Copyright 2007 Journal of Virology. Recommended citation: Chung, Sang-Hyuk, Kristopher K. Frese, Robert S. Weiss, BV Venkataram Prasad, and Ronald T. Javier. "A new crucial protein interaction element that targets the adenovirus E4-ORF1 oncoprotein to membrane vesicles." Journal of virology 81, no. 9 (2007): 4787-4797. DOI: 10.1128/JVI.02855-06. URL: https://jvi.asm.org/content/81/9/4787/article-info. Reproduced in accordance with the original publisher's licensing terms and with permission from the author(s).