Caracterización funcional de las eIF2alfa quinasas de Schizosaccharomyces pombe en distintas situaciones de estrés

Resumen

Reversible phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha) by eIF2alpha kinases under stress conditions plays a fundamental role in regulating protein synthesis in eukaryotic cells. In Schizosaccharomyces pombe, three kinases phosphorylate eIF2alpha at the serine fifty two under environmental stress situations: Gcn2, Hri1 and Hri2. Our results reveal that each eIF2alpha kinase is involved in the response to different stress conditions. Thus, Gcn2 participates in the response to oxidative stress, nitrogen starvation or exposure to genotoxic stress produced by MMS. However, Hri2 is involved in the response to heat shock and low glucose conditions, while Hri1 is activated under nitrogen and glucose starvation. Moreover, the expression of the three eIF2alpha kinases is modified as a consequence of the application of several stress conditions such as oxidative stress and heat shock. Because the most important response under environmental stress situations is regulated by the MAPK Sty1, we studied the relationship between this pathway and the eIF2alpha kinases pathway. We discovered that Sty1 negatively regulates eIF2alpha kinases activity under oxidative stress and nitrogen starvation, but not under other stress conditions such as heat shock or genotoxic stress. Under nitrogen starvation, fission yeast cells promote the exit from the vegetative cell cycle in G1 phase to initiate sexual differentiation and to produce spores, in order to survive to this stress condition. According to the results presented here, the activity of Gcn2 and the phosphorylation of eIF2alpha seem to be required to arrest the cell cycle on time upon nitrogen starvation. Our results also show that eIF2alpha phosphorylation must be important in processes leading to sexual differentiation and sporulation. Under nitrogen starvation, we have studied a possible relationship between Tor1 pathway, MAPK Sty1 and eIF2alpha kinases pathway, and we found that Gcn2 seems to be essential for Sty1 activation. Finally, in this work we have also demonstrated that Gcn2 and eIF2alfa fosforilation have an important role in cell survival under different stress conditions, such as oxidative stress, heat shock or low glucose. Thus, the stress response pathway involving the eIF2alpha kinases participates in important processes that allow cells to increase the possibilities of survival.