A LATE ADENOVIRUS FACTOR INDUCES EIF-4E DEPHOSPHORYLATION AND INHIBITION OF CELL PROTEIN-SYNTHESIS

Adenovirus prevents host cell protein synthesis during its phase of re plication in large part by causing the underphosphorylation of transla tion initiation factor eIF-4E, a component of initiation factor eIF-4F (cap-binding protein complex). Late adenovirus mRNAs are preferential ly translated because they possess a reduced requirement for eIF-4F. T his study continues the characterization of the mechanism by which ade novirus inhibits cellular protein synthesis. First it is shown that ad enovirus blocks the addition of phosphate to eIF-4E rather than enhanc ing its removal, establishing that the virus impairs a signalling path way or protein kinase activity involved in eIF-4E phosphorylation. It is then shown that shutoff of cell protein synthesis and translation o f late viral mRNAs are already undergoing translation. Finally, by usi ng a variety of genetic mutants stalled at different stages in the vir al life cycle, it was found that dephosphorylation eIF-4E and inhibiti on of cell translation are not caused by early adenovirus gene product s acting at late times or by events related to viral DNA replication. Instead, it is shown that inhibition of eIF-4E phosphorylation and cel l translation are mediated upon activation of the viral major late tra nscription unit. These and other results presented indicate that the a denovirus signal which induces eIF-4E dephosphorylation and shutoff of cell protein synthesis is linked either to an activity of one or more late viral polypeptides, to double-stranded RNA produced by oppositio n of the early and late viral transcription units, or to both.