Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus.
Infection of cells with picornaviruses, such as poliovirus and encephalomyocarditis virus (EMCV), causes a shutoff of host protein synthesis. The molecular mechanism of the shutoff has been partly elucidated for poliovirus but not for EMCV. Translation initiation in eukaryotes is facilitated by the mRNA 5' cap structure to which the multisubunit translation initiation factor eIF4F binds to promote ribosome binding. Picornaviruses use a mechanism for the translation of their RNA that is independent of the cap structure. Poliovirus infection engenders the cleavage of the eIF4G (formerly p220) component of eIF4F and renders this complex inactive for cap-dependent translation. In contrast, EMCV infection does not result in eIF4G cleavage. Here, we report that both EMCV and poliovirus activate a translational repressor, 4E-BP1, that inhibits cap-dependent translation by binding to the cap-binding subunit eIF4E. Binding of eIF4E occurs only to the underphosphorylated form of 4E-BP1, and this interaction is highly regulated in cells. We show that 4E-BP1 becomes dephosphorylated upon infection with both EMCV and poliovirus. Dephosphorylation of 4E-BP1 temporally coincides with the shutoff of protein synthesis by EMCV but lags behind the shutoff and eIF4G cleavage in poliovirus-infected cells. Dephosphorylation of 4E-BP1 by specifically inhibiting cap-dependent translation may be the major cause of the shutoff phenomenon in EMCV-infected cells.
Gingras
A C
AC
Department of Biochemistry and McGill Cancer Centre, McGill University, Montreal, Canada.
Svitkin
Y
Y
Belsham
G J
GJ
Pause
A
A
Sonenberg
N
N
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D002287:Carcinoma, Krebs 2 / Q000378:metabolism*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004686:Encephalomyocarditis virus / Q000502:physiology*; D039562:Eukaryotic Initiation Factor-4F; D039642:Eukaryotic Initiation Factors; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D010766:Phosphorylation; D017955:Poliovirus / Q000502:physiology*; D014176:Protein Biosynthesis; D012315:RNA Caps / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; D039562:Eukaryotic Initiation Factor-4F; D039642:Eukaryotic Initiation Factors; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D012315:RNA Caps; D012097:Repressor Proteins