5 Translation Initiation by Viral Internal Ribosome Entry Sites

Abstract

The initiation of protein synthesis is a complex and highly regulated process in all organisms. In eukaryotic cells, the 40S ribosomal subunit must be recruited to an mRNA and correctly positioned at the initiation codon prior to joining with the 60S subunit to form a translationally active complex. In most mRNAs, this step is initiated by an interaction of the cap-binding protein complex eukaryotic initiation factor 4F (eIF4F), composed of factors eIF4E, eIF4A, and eIF4G, with the m⁷GpppN cap structure, which is located at the 5′ end of all polymerase-II-transcribed mRNAs. Subsequently, the 40S subunit that carries the initiator methionyl-tRNA–eIF2–GTP complex is thought to attach at or near the 5′ end of the mRNA, aided by an interaction of 40S-associated factor eIF3 with eIF4G. The 40S subunit then scans the mRNA in a 5′ to 3′ direction until an appropriate AUG start codon is encountered where the 60S subunit joins to form a translation-competent 80S ribosome with the AUG positioned in the ribosomal P site (for review, see Kozak 1989; Dever 2002; Chapter 4). The mRNA is thought to have a passive role in this process, and typically lacks significant secondary structure upstream of the AUG start codon that might interfere with scanning.

In intriguing contrast, certain viral mRNAs and cellular mRNAs that encode products involved in growth control, differentiation, apoptosis, and oncogenesis contain untranslated regions that are often highly conserved, may extend for several hundred nucleotides, and appear to contain extensive secondary and tertiary structures. As predicted...