HGNC Approved Gene Symbol: EIF2A
Cytogenetic location: 3q25.1 Genomic coordinates (GRCh38): 3:150,546,787-150,586,016 (from NCBI)
By searching a human EST database for sequences similar to rabbit Eif2a, Zoll et al. (2002) identified EIF2A. The deduced 585-amino acid protein has a calculated molecular mass of 65.1 kD. Human EIF2A shares 28% amino acid identity with the S. cerevisiae protein. Northern blot analysis detected a 2.1-kb transcript in all human tissues examined, with highest expression in pancreas, followed by heart, brain, and placenta.
EIF2A should not be confused with EIF2-alpha (EIF2S1; 603907), a subunit of the critical trimolecular translation initiation complex EIF2.
Zoll et al. (2002) found that yeast Eif2a associated specifically with 40S subunits and 80S ribosomes. Deletion of yeast Eif2a did not affect growth rate or the distribution of ribosomal subunits or polysomes. However, knockout of both Eif2a and Eif5b (606086) yielded a yeast strain with a severe slow growth phenotype, suggesting that Eif2a and Eif5b genetically interact.
Komar et al. (2005) found that yeast Eif2A genetically interacted with Eif4e (133440). Eif2a/Eif4e double mutants showed a severe growth defect, disorganized actin cytoskeleton, and elevated actin levels, suggesting that these factors have a role in cell morphology. Expression of Eif2a downregulated Ure2 internal ribosome entry site (IRES) activity in yeast cells. Human EIF2A could partially suppress Ure2 IRES activity in yeast cells. Compared with the yeast protein, human EIF2A showed reduced association with 80S ribosomes and was instead predominantly associated with 40S ribosomes in yeast cells.
Effective immune surveillance by cytotoxic T cells requires newly synthesized polypeptides for presentation by major histocompatibility complex (MHC) class I (see 142800) molecules. These polypeptides are produced not only from conventional AUG-initiated, but also from cryptic non-AUG-initiated, reading frames by distinct translational mechanisms. In biochemical analysis of ribosomal initiation complexes at CUG versus AUG initiation codons, Starck et al. (2012) observed that cells used an elongator leucine-bound transfer RNA (Leu-tRNA; 189932) to initiate translation at cryptic CUG start codons. CUG/Leu-tRNA initiation was independent of the canonical initiator tRNA (AUG/Met-tRNAi(Met); see 180621) pathway but required expression of eIF2A. Thus, Starck et al. (2012) concluded that a tRNA-based translation initiation mechanism allows non-AUG-initiated protein synthesis and supplies peptides for presentation by MHC class I molecules.
The integrated stress response (ISR) modulates mRNA translation to regulate the mammalian unfolded protein response (UPR), immunity, and memory formation. A chemical ISR inhibitor, ISRIB, enhances cognitive function and modulates the UPR in vivo. To explore mechanisms involved in ISRIB action, Sekine et al. (2015) screened cultured mammalian cells for somatic mutations that reversed its effect on the ISR. Clustered missense mutations were found at the amino-terminal portion of the delta subunit of guanine nucleotide exchange factor (GEF) EIF2B (EIF2B4; 606687). When reintroduced by CRISPR-Cas9 gene editing of wildtype cells, these mutations reversed both ISRIB-mediated inhibition of the ISR and its stimulatory effect on EIF2B GEF activity toward its substrate, the translation initiation factor EIF2, in vitro. Sekine et al. (2015) concluded that ISRIB targets an interaction between EIF2 and EIF2B that lies at the core of the ISR.
Sharma et al. (2020) used molecular genetic studies in mice to dissect the neuronal circuits by which the integrated stress response gates cognitive processing. They found that learning reduced eIF2-alpha phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons expressing somatostatin, but not those expressing parvalbumin. Moreover, ablation of phosphorylated eIF2-alpha in either excitatory or somatostatin-expressing, but not parvalbumin-expressing, inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity, and enhanced long-term memory. Sharma et al. (2020) concluded that eIF2-alpha-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.
Zoll et al. (2002) determined that the EIF2A gene contains 15 or 16 exons and spans about 55 kb. The promoter region is TATA-less, but it contains the housekeeping element GGGCGC.
By genomic sequence analysis, Zoll et al. (2002) mapped the EIF2A gene to chromosome 3.
Komar, A. A., Gross, S. R., Barth-Baus, D., Strachan, R., Hensold, J. O., Kinzy, T. G., Merrick, W. C. Novel characteristics of the biological properties of the yeast Saccharomyces cerevisiae eukaryotic initiation factor 2A. J. Biol. Chem. 280: 15601-15611, 2005. [PubMed: 15718232] [Full Text: https://doi.org/10.1074/jbc.M413728200]
Sekine, Y., Zyryanova, A., Crespillo-Casado, A., Fischer, P. M., Harding, H. P., Ron, D. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science 348: 1027-1030, 2015. [PubMed: 25858979] [Full Text: https://doi.org/10.1126/science.aaa6986]
Sharma, V., Sood, R., Khlaifia, A., Javad Eslamizade, M., Hung, T.-Y., Lou, D., Asgarihafshejani, A., Lalzar, M., Kiniry, S. J., Stokes, M. P., Cohen, N., Nelson, A. J., and 18 others. eIF2-alpha controls memory consolidation via excitatory and somatostatin neurons. Nature 586: 412-416, 2020. [PubMed: 33029011] [Full Text: https://doi.org/10.1038/s41586-020-2805-8]
Starck, S. R., Jiang, V., Pavon-Eternod, M., Prasad, S., McCarthy, B., Pan, T., Shastri, N. Leucine-tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I. Science 336: 1719-1723, 2012. [PubMed: 22745432] [Full Text: https://doi.org/10.1126/science.1220270]
Zoll, W. L., Horton, L. E., Komar, A. A., Hensold, J. O., Merrick, W. C. Characterization of mammalian eIF2A and identification of the yeast homolog. J. Biol. Chem. 277: 37079-37087, 2002. [PubMed: 12133843] [Full Text: https://doi.org/10.1074/jbc.M207109200]