title: Viral stress-inducible protein p56 inhibits translation by blocking the interaction of eIF3 with the ternary complex eIF2.GTP.Met-tRNAi.
abstract: Viral stress-inducible protein p56 is produced in response to viral stress-inducing agents such as double-stranded RNA and interferon, as well as other poorly understood mechanisms of viral infection. It has been shown previously that p56 is able to bind the eukaryotic initiation factor 3e(eIF3e) (p48/Int-6) subunit of the eukaryotic translation initiation factor eIF3 and function as an inhibitor of translation in vitro and in vivo. The exact mechanism by which p56 is able to interfere with protein synthesis is not understood. Based on the known roles of eIF3 in the initiation pathway, we employed assays designed to individually look at specific functions of eIF3 and the effect of p56 on these eIF3-mediated functions. These assays examined the effect of p56 on ribosome dissociation, the eIF3.eIF4F interaction, and enhancement of the ternary complex eIF2.GTP.Met-tRNAi formation. Here we report that p56 is able to inhibit translation initiation specifically at the level of eIF3.ternary complex formation. The effect of p56-mediated inhibition was also examined in two different contexts, cap-mediated and encephalomyocarditis virus internal ribosomal entry site-mediated translation. Whereas cap-dependent initiation was severely inhibited by p56, internal ribosomal entry site-mediated translation appeared to be insensitive to p56.
authors.affiliation: Department of Molecular Biology, The Lerner Research Institute, Cleveland Clinic Foundation, and Graduate Program in Molecular Virology, Case Western Reserve University School of Medicine, Ohio, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hui
authors.forename: C Ramana
authors.initials: CR
authors.lastname: Bhasker
authors.forename: William C
authors.initials: WC
authors.lastname: Merrick
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism*; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism*; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008954:Models, Biological; D014176:Protein Biosynthesis; D012358:RNA, Transfer, Met / Q000378:metabolism*; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015852:Eukaryotic Initiation Factor-2; D039621:Eukaryotic Initiation Factor-3; D039562:Eukaryotic Initiation Factor-4F; C484290:IFIT1 protein, human; D046911:Macromolecular Substances; C112736:Met-tRNA(i)(Met); D012358:RNA, Transfer, Met; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D006160:Guanosine Triphosphate