| First Author | Legrand N | Year | 2015 |
| Journal | Nucleic Acids Res | Volume | 43 |
| Issue | 17 | Pages | 8392-404 |
| PubMed ID | 26264663 | Mgi Jnum | J:233395 |
| Mgi Id | MGI:5784587 | Doi | 10.1093/nar/gkv827 |
| Citation | Legrand N, et al. (2015) The impact of the phosphomimetic eIF2alphaS/D on global translation, reinitiation and the integrated stress response is attenuated in N2a cells. Nucleic Acids Res 43(17):8392-404 |
| abstractText | A plethora of stresses trigger a rapid downregulation of protein synthesis. However, a fraction of mRNAs continue to be recruited onto polysomes and their protein products play a key role in deciding cell fate. These transcripts are characterized by the presence of uORFs within their 5' TL coupling protein expression to reinitiation. The translational brake arises due to the activation of a family of kinases targeting the alpha subunit of the trimolecular eIF2(alphabetagamma) initiation factor. Phosphorylation of eIF2alphaSer51 inhibits ternary complex regeneration reducing the pool of 43S ribosomes. It is popular to mimic this event, and hence the integrated stress response (ISR), by the expression of the phosphomimetic eIF2alphaS51D. However, we report that whereas the ISR is reproduced by eIF2alphaS51D expression in human HEK293T cells this is not the case in N2a mouse neuroblastoma cells. With regards to translational downregulation, this arises due to the failure of the phosphomimetic protein to assemble an eIF2 complex with endogenous eIF2beta/gamma. This can be compensated for by the transient co-expression of all three subunits. Curiously, these conditions do not modulate reinitiation and consequently fail to trigger the ISR. This is the first demonstration that the inhibitory and reinitiation functions of eIF2alphaS/D can be separated. |
