Truncated initiation factor eIF4G lacking an eIF4E binding site can support capped mRNA translation

Picornavirus proteases cleave translation initiation factor eIF4G into a C- terminal two-thirds fragment (hereafter named p100) and an N-terminal one-t hird fragment, which interacts with the cap-binding factor eIF4E. As the ti ming of this cleavage correlates broadly with the shut-off of host cell pro tein synthesis in infected cells, a very widespread presumption has been th at p100 cannot support capped mRNA translation. Through the use of an eIF4G -depleted reticulocyte lysate system, we show that this presumption is inco rrect. Moreover, recombinant p100 can also reverse the inhibition of capped mRNA translation caused either by m(7)GpppG cap analogue, by 4E-BP1, which sequesters eIF4E and thus blocks its association with eIF4G, or by cleavag e of endogenous eIF4G by picornavirus proteases. The concentration of p100 required for maximum translation of capped mRNAs is similar to4-fold higher than the endogenous eIF4G concentration in reticulocyte lysates. Our resul ts imply that picornavirus-induced shut-off is not due to an intrinsic inab ility of p100 to support capped mRNA translation, but to the viral RNA outc ompeting host cell mRNA for the limiting concentration of p100.