RADIATION INDUCES EIF2AK3/PERK AND ERN1/IRE1 MEDIATED PRO-SURVIVAL AUTOPHAGY

Cellular effects of ionizing radiation include oxidative damage to macromolecules, unfolded protein response (UPR) and metabolic imbalances. Oxidative stress and UPR have been shown to induce macroautophagy/autophagy in a context-dependent manner and are crucial factors in determining the fate of irradiated cells. However, an in-depth analysis of the relationship between radiation-induced damage and autophagy has not been explored. In the present study, we investigated the relationship between radiation-induced oxidative stress, UPR and autophagy in murine macrophage cells. A close association was observed between radiation-induced oxidative burst, UPR and induction of autophagy, with the possible involvement of EIF2AK3/PERK (eukaryotic translation initiation factor 2 alpha kinase 3) and ERN1/IRE1 (endoplasmic reticulum [ER] to nucleus signaling 1). Inhibitors of either UPR or autophagy reduced the cell survival indicating the importance of these processes after radiation exposure. Moreover, modulation of autophagy affected lethality in the whole body of irradiated <i>C57BL/6</i> mouse. These findings indicate that radiation-induced autophagy is a pro-survival response initiated by oxidative stress and mediated by EIF2AK3 and ERN1.

电离辐射的细胞生物学效应包括大分子氧化损伤、未折叠蛋白反应（unfolded protein response，UPR）以及代谢失衡。氧化应激与未折叠蛋白反应已被证实可通过情境依赖性方式诱导巨自噬/自噬（macroautophagy/autophagy），是决定辐射暴露细胞命运的关键调控因素。然而，目前尚未有针对辐射诱导损伤与自噬之间关联的深入分析研究。本研究以小鼠巨噬细胞为模型，探究了辐射诱导的氧化应激、未折叠蛋白反应与自噬三者间的关联。研究观察到辐射诱导的氧化爆发、未折叠蛋白反应与自噬诱导之间存在紧密关联，该过程可能涉及真核翻译起始因子2α激酶3（EIF2AK3/PERK，eukaryotic translation initiation factor 2 alpha kinase 3）与内质网至细胞核信号转导因子1（ERN1/IRE1，endoplasmic reticulum [ER] to nucleus signaling 1）的介导作用。未折叠蛋白反应或自噬抑制剂均可降低细胞存活率，提示上述过程在辐射暴露后具有重要生物学意义。此外，调控自噬可影响辐射暴露后C57BL/6小鼠的整体致死率。上述研究结果表明，辐射诱导的自噬是一种由氧化应激启动、经EIF2AK3与ERN1介导的促存活反应。