eIF4F Architectural Alterations Accompany Translation Initiation Factor Redistribution in Poxvirus-infected Cells

Department of Microbiology & NYU Cancer Center, New York University School of Medicine, New York, NY USA; National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland; Department of Genetics, Graduate School of Medicine & Graduate School of Frontier Biosciences,, Osaka University,, Osaka, Japan

^* To whom correspondence should be addressed. Email: ian.mohr{at}med.nyu.edu.

	Abstract

Despite their self-sufficient ability to generate capped mRNAs from cytosolic DNA genomes, poxviruses must commandeer the critical translation initiation factor eIF4F to recruit ribosomes. While eIF4F integrates signals to control translation, precisely how poxviruses manipulate the multi-subunit eIF4F, comprised of the cap-binding eIF4E and RNA helicase eIF4A assembled onto an eIF4G platform, remains obscure. Here, we establish that poxvirus infection of normal, primary human cells destroys the translational repressor 4E-BP1 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 concentration of eIF4E and eIF4G within cytosolic viral replication compartments surrounded by PABP. This demonstrates that poxvirus infection redistributes, assembles and modifies eIF4F-core and associated components, concentrating them within discrete subcellular compartments. Furthermore, it suggests that the subcellular distribution of eIF4F components may potentiate complex assembly.