Figure 6: Schematic diagram for eIF1A functions in Ago2-dependent miR-451 biogenesis, RNA interference and erythrocyte maturation in zebrafish.

The primary miRNA (priRNA) is cleaved by Drosha-DGCR8 pathways to generate pre-miRNA within the nucleus. Exportin-5 in complex with Ran-GTP exports the pre-miRNA to the cytoplasm, where the pre-miRNA is bound by DICER to form a RISC loading complex that includes Ago2. In the canonical miRNA biogenesis pathway, DICER removes the terminal loop region to yield the mature miRNA. The pre-miR-451 is loaded directly onto Ago2 and sliced on the 3′-hairpin arm. The miR-144 biogenesis is DICER dependent. The globular domain (GD) of eIF1A directly binds to the MID domain of Ago2 and forms an eIF1A–Ago2 complex promoting Ago2-mediated RNAi and miR-451 biogenesis. The MID domain of Ago2 binds to the GD of eIF1A and does not impair eIF1A functions in translation initiation. The 5′-term of guide strand of miRNA–miRNA* duplex is docked onto a pocket with residues mainly from the MID domain. The long and structured mRNAs are scanned by RISCs to recognize seed regions in miRNAs. After a perfect or imperfect complementary guide with miRNAs, mRNAs are nicked by the PIWI domain resulting in RNAi. eIF1A augments Ago2-mediated RNAi, miR-451 production and erythrocyte maturation. Black arrows are from previous reports of other groups^14,15,43; blue arrows are from this study.