title: Rapamycin and wortmannin enhance replication of a defective encephalomyocarditis virus.
abstract: Inhibitors of the phosphatidylinositol 3-kinase (PI3 kinase)-FKBP-rapamycin-associated protein (FRAP) pathway, such as rapamycin and wortmannin, induce dephosphorylation and activation of the suppressor of cap-dependent translation, 4E-BP1. Encephalomyocarditis virus (EMCV) infection leads to activation of 4E-BP1 at the time of host translation shutoff. Consistent with these data, rapamycin mildly enhances the synthesis of viral proteins and the shutoff of host cell protein synthesis after EMCV infection. In this study, two defective EMCV strains were generated by deleting portions of the 2A coding region of an infectious cDNA clone. These deletions dramatically decreased the efficiency of viral protein synthesis and abolished the virus-induced shutoff of host translation after infection of BHK-21 cells. Both translation and processing of the P1-2A capsid precursor polypeptide are impaired by the deletions in 2A. The translation and yield of mutant viruses were increased significantly by the presence of rapamycin and wortmannin during infection. Thus, inhibition of the PI3 kinase-FRAP signaling pathway partly complements mutations in 2A protein and reverses a slow-virus phenotype.
authors.affiliation: Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada H3G 1Y6.
authors.forename: Y V
authors.initials: YV
authors.lastname: Svitkin
authors.forename: H
authors.initials: H
authors.lastname: Hahn
authors.forename: A C
authors.initials: AC
authors.lastname: Gingras
authors.forename: A C
authors.initials: AC
authors.lastname: Palmenberg
authors.forename: N
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D003673:Defective Viruses / Q000187:drug effects*; D004686:Encephalomyocarditis virus / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011090:Polyenes / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011817:Rabbits; D020123:Sirolimus; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011090:Polyenes; D014764:Viral Proteins; D020123:Sirolimus; D000077191:Wortmannin