Adenovirus-specific translation by displacement of kinase Mnk1 from cap-initiation complex eIF4F.
Translation of cellular mRNAs involves formation of a cap-binding translation initiation complex known as eIF4F, containing phosphorylated cap-binding protein eIF4E, eIF4E kinase Mnk1, eIF4A, poly(A)-binding protein and eIF4G. Adenovirus is shown to prevent cellular translation by displacing Mnk1 from eIF4F, thereby blocking phosphorylation of eIF4E. Over expression of an eIF4E mutant that cannot be phosphorylated by Mnk1 impairs translation of cellular but not viral late mRNAs. Adenovirus 100k protein is shown to bind the C-terminus of eIF4G in vivo and in vitro, the same region bound by Mnk1. In vivo, 100k protein displaces Mnk1 from eIF4G during adenovirus infection, or in transfected cells. Purified 100k protein also evicts Mnk1 from isolated eIF4F complexes in vitro. A mutant adenovirus with a temperature-sensitive 100k protein that cannot inhibit cellular protein synthesis at restrictive temperature no longer blocks Mnk1 binding to eIF4G, or phosphorylation of eIF4E. We describe a mechanism whereby adenovirus selectively inhibits the translation of cellular but not viral mRNAs by displacement of Mnk1 from eIF4G and inhibition of eIF4E phosphorylation.
Cuesta
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Department of Microbiology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
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Schneider
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D000256:Adenoviridae / Q000502:physiology*; D000257:Adenoviridae Infections / Q000201:enzymology; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D039562:Eukaryotic Initiation Factor-4F; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D017931:DNA Primers; D039562:Eukaryotic Initiation Factor-4F; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; D011993:Recombinant Fusion Proteins; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases