Figure 6. Revised mechanism for HCV IRES-driven initiation.
This model is described in the main text. Briefly, we propose that the HCV IRES (and probably other type 3 IRESs) recruits a pre-assembled ‘TC-deficient’ PIC containing eIF1, 1A, and 3 (grey oval), which is an intermediate in the normal 40S recycling process. IRES binding to this PIC partially remodels it to include displacing eIF3 (yellow, ‘3*’) and either passively or actively releasing eIF1. This remodeled PIC is used under both eIF2 active and inactive conditions (grey shaded box). When active eIF2 is abundant, delivery of tRNA through the TC presumably requires movement of IRES domain II to an alternate position (Yamamoto et al., 2014) to resolve a steric clash (Figure 1—figure supplement 1B and C). If eIF2 is inhibited, this would have the effect of increasing the amount of available ‘TC-deficient’ PICs and perhaps free tRNAi. While we cannot prove that an ‘alternate’ factor is not used to deliver tRNAi under these conditions, we assert that available evidence supports a mode of tRNAi recruitment using eIF1A and eIF5B..