The importance of translation inhibition for the combat against oxidative stress

Oxidative stress, identified by excessive reactive oxygen species (ROS), is one of many cellular conditions that elicit the Integrated Stress Response (ISR), designed for expression induction of rescue proteins. ISR begins with eIF2α phosphorylation-mediated eIF2B attenuation, leading to global inhibition of protein synthesis. Decreased eIF2B activity allows ATF4 synthesis, a stress-induced transcription factor, which in turn activates transcription of relevant target genes. The last phase is driven by GADD34 expression, a stress-induced eIF2α phosphatase, which facilitates resumption of global translation required for synthesis of the rescue proteins.

Vanishing White Matter Disease (VWMD) is a progressive fatal neurodegenerative disease caused by hypomorphic mutations in eIF2B genes, associated with defective ISR. Surprisingly and counter-intuitively, we discovered that genetic depletion of GADD34 prevents the VWMD-related clinical symptoms of eIF2B5^R132H/R132H mouse model for the disease. While eIF2B5^R132H/R132H MEFs exhibit higher ROS levels and are hyper-sensitive to arsenite-induced oxidative stress, GADD34 knock-out returns ROS to normal levels and increases viability under arsenite-induced oxidative stress. In contrast, GADD34 knock-out renders both WT and eIF2B5^R132H/R132H MEFS hyper-sensitive to thapsigargin-induced ER-stress. Interestingly, treatment with ISRIB, an ISR inhibitor, leads to hyper-sensitivity of WT MEFs to oxidative stress. Taken together, our results emphasize the crucial role of the translation inhibition phase of ISR for ROS removal. The key molecular events associated with the specific magnitude of the transient translation inhibition provoked by oxidative stress will be discussed.