Eukaryotic translation initiation machinery can operate in a bacterial-like mode without eIF2

Viruses have found mechanisms to translate their RNAs in the face of antiviral responses. Data now indicate that the hepatitis C virus internal ribosome entry site can use eIF5B to initiate translation in a bacterial-like mode when eIF2 is inactivated under stress. Unlike bacteria, a specialized eukaryotic initiation factor (eIF)-2, in the form of the ternary complex eIF2–GTP–Met-tRNA i Met , is used to deliver the initiator tRNA to the ribosome in all eukaryotic cells. Here we show that the hepatitis C virus (HCV) internal ribosome entry site (IRES) can direct translation without eIF2 and its GTPase-activating protein eIF5. In addition to the general eIF2- and eIF5-dependent pathway of 80S complex assembly, the HCV IRES makes use of a bacterial-like pathway requiring as initiation factors only eIF5B (an analog of bacterial IF2) and eIF3. The switch from the conventional eukaryotic mode of translation initiation to the eIF2-independent mechanism occurs when eIF2 is inactivated by phosphorylation under stress conditions.