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Journal of Virology, March 2008, p. 2642-2651, Vol. 82, No. 6
0022-538X/08/$08.00+0     doi:10.1128/JVI.02309-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Control of mRNA Export by Adenovirus E4orf6 and E1B55K Proteins during Productive Infection Requires E4orf6 Ubiquitin Ligase Activity

Departments of Biochemistry,¹ Oncology,³ the McGill Cancer Centre, McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6,⁴ Heinrich-Pette-Institute for Experimental Virology and Immunology, Martinistr. 52, 20251 Hamburg, Germany²

Received 24 October 2007/ Accepted 28 December 2007

During the adenovirus infectious cycle, the early proteins E4orf6 and E1B55K are known to perform several functions. These include nuclear export of late viral mRNAs, a block of nuclear export of the bulk of cellular mRNAs, and the ubiquitin-mediated degradation of selected proteins, including p53 and Mre11. Degradation of these proteins occurs via a cellular E3 ubiquitin ligase complex that is assembled through interactions between elongins B and C and BC boxes present in E4orf6 to form a cullin 5-based ligase complex. E1B55K, which has been known for some time to associate with the E4orf6 protein, is thought to bind to specific substrate proteins to bring them to the complex for ubiquitination. Earlier studies with E4orf6 mutants indicated that the interaction between the E4orf6 and E1B55K proteins is optimal only when E4orf6 is able to form the ligase complex. These and other observations suggested that most if not all of the functions ascribed to E4orf6 and E1B55K during infection, including the control of mRNA export, are achieved through the degradation of specific substrates by the E4orf6 ubiquitin ligase activity. We have tested this hypothesis through the generation of a virus mutant in which the E4orf6 product is unable to form a ligase complex and indeed have found that this mutant behaves identically to an E4orf6^– virus in production of late viral proteins, growth, and export of the late viral L5 mRNA.

Published ahead of print on 9 January 2008.

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