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Journal of Virology, September 2000, p. 7869-7877, Vol. 74, No. 17
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Induction of p53-Independent Apoptosis by the Adenovirus E4orf4 Protein Requires Binding to the Balpha Subunit of Protein Phosphatase 2A

Richard C. Marcellus,1 Helen Chan,1 Denis Paquette,1 Sarah Thirlwell,2 Dominique Boivin,1 and Philip E. Branton2,3,*

Departments of Biochemistry2 and Oncology,3 McGill University, Montreal, Quebec, Canada H3G 1Y6, and GeminX Biotechnologies Inc., Montreal, Quebec, Canada H2W 2M91

Received 8 February 2000/Accepted 31 May 2000

Previous studies have indicated that the E4orf4 protein of human adenovirus type 2 (Ad2) induces p53-independent apoptosis. We believe that this process may play a role in cell death and viral spread at the final stages of productive infection. E4orf4 may also be of therapeutic value in treating some diseases, including cancer, through its ability to induce apoptosis when expressed individually. The only previously identified biochemical function of E4orf4 is its ability to associate with the Balpha subunit of protein phosphatase 2A (PP2A). We have used a genetic approach to determine the role of such interactions in E4orf4-induced cell death. E4orf4 deletion mutants were of only limited value, as all were highly defective. We found that E4orf4 proteins from most if not all adenovirus serotypes induced cell death, and thus point mutations were introduced that converted the majority of highly conserved residues to alanines. Such mutants were used to correlate Balpha -subunit binding, association with PP2A activity, and cell killing following the transfection of appropriate cDNAs into p53-null H1299 or C33A cells. The results indicated that binding of the Balpha subunit is essential for induction of cell death, as every mutant that failed to bind efficiently was totally defective for cell killing. This class of mutations (class I) largely involved residues between amino acids 51 and 89. Almost all E4orf4 mutant proteins that associated with PP2A killed cancer cells at high levels; however, several mutants that associated with significant levels of PP2A were defective for killing (class II). Thus, binding of E4orf4 to PP2A is essential for induction of p53-independent apoptosis, but E4orf4 may possess one or more additional functions required for cell killing.

* Corresponding author. Mailing address: Department of Biochemistry and Oncology, McGill University, McIntyre Medical Building, 3655 Drummond St., Montreal, Quebec H3G 1Y6, Canada. Phone: (514) 398-7263. Fax: (514) 398-7384. E-mail: branton{at}med.mcgill.ca.

Journal of Virology, September 2000, p. 7869-7877, Vol. 74, No. 17
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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