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Eukaryotic Translation Initiation Factor 4F Architectural Alterations Accompany Translation Initiation Factor Redistribution in Poxvirus-Infected Cells

Derek Walsh,^1,2, Carolina Arias,^1, Cesar Perez,¹ David Halladin,¹ Martin Escandon,¹ Takeshi Ueda,³ Rie Watanabe-Fukunaga,³ Rikiro Fukunaga,³ and Ian Mohr^1*

Department of Microbiology and New York University Cancer Center, New York University School of Medicine, New York, New York,¹ National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland,² Department of Genetics, Graduate School of Medicine and Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan³

Received 4 September 2007/ Returned for modification 28 September 2007/ Accepted 22 January 2008

Despite their self-sufficient ability to generate capped mRNAs from cytosolic DNA genomes, poxviruses must commandeer the critical eukaryotic translation initiation factor 4F (eIF4F) to recruit ribosomes. While eIF4F integrates signals to control translation, precisely how poxviruses manipulate the multisubunit eIF4F, composed of the cap-binding eIF4E and the RNA helicase eIF4A assembled onto an eIF4G platform, remains obscure. Here, we establish that the poxvirus infection of normal, primary human cells destroys the translational repressor eIF4E binding protein (4E-BP) and promotes eIF4E assembly into an active eIF4F complex bound to the cellular polyadenylate-binding protein (PABP). Stimulation of the eIF4G-associated kinase Mnk1 promotes eIF4E phosphorylation and enhances viral replication and protein synthesis. Remarkably, these eIF4F architectural alterations are accompanied by the concentration of eIF4E and eIF4G within cytosolic viral replication compartments surrounded by PABP. This demonstrates that poxvirus infection redistributes, assembles, and modifies core and associated components of eIF4F and concentrates them within discrete subcellular compartments. Furthermore, it suggests that the subcellular distribution of eIF4F components may potentiate the complex assembly.

Published ahead of print on 4 February 2008.

These authors contributed equally to this work.