Eukaryotic initiation factor 2A (eIF2A), a 65 kDa single-chain protein, was initially mis-taken as the eukaryotic equivalent of prokaryotic IF2. It's now known that eIF2A promotes Met-tRNAi recruitment to 40S/mRNA complexes under eIF2-inhibited conditions. It is involved in non-canonical translation initiation events like re-initiation, internal initiation, or non-AUG initiation, which are crucial for the translational control of specific mRNAs [1].

eIF2A-knockout (KO) mouse models have provided valuable insights. eIF2A-KO mice exhibit a reduced lifespan and display features of metabolic syndrome, including disrupted lipid homeostasis, glucose tolerance, and insulin resistance. Also, eIF2A affects the abundance of B lymphocytes and dendritic cells in the thymic medulla, and shows sex-specific differences in its effects [2]. In yeast, eIF2A null mutants have minimal impact on translation initiation and uORF-mediated translational control, suggesting that only a few mRNAs use eIF2A for Met-tRNAi recruitment, even under stress [3].

In summary, eIF2A plays important roles in non-canonical translation initiation. The eIF2A KO mouse model has revealed its significance in metabolic syndrome and central tolerance, enhancing our understanding of the gene's function in mammalian systems in vivo and providing potential targets for further research on these disease areas.

References:

1. Komar, Anton A, Merrick, William C. 2020. A Retrospective on eIF2A-and Not the Alpha Subunit of eIF2. In International journal of molecular sciences, 21, . doi:10.3390/ijms21062054. https://pubmed.ncbi.nlm.nih.gov/32192132/

2. Anderson, Richard, Agarwal, Anchal, Ghosh, Arnab, Kondratov, Roman V, Komar, Anton A. . eIF2A-knockout mice reveal decreased life span and metabolic syndrome. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35, e21990. doi:10.1096/fj.202101105R. https://pubmed.ncbi.nlm.nih.gov/34665898/

3. Gaikwad, Swati, Ghobakhlou, Fardin, Zhang, Hongen, Hinnebusch, Alan G. 2024. Yeast eIF2A has a minimal role in translation initiation and uORF-mediated translational control in vivo. In eLife, 12, . doi:10.7554/eLife.92916. https://pubmed.ncbi.nlm.nih.gov/38266075/