4EBP1 promotes survival under glucose starvation by curbing ROS

Most biological organisms encounter metabolic stress during their lifetime and rely on cellular pathways, which evolved to sense and respond stress, to survive and adapt to these conditions. We and others have shown that tumor cells are dependent on eEF2K, a negative regulator of mRNA translation, to survive under metabolic stress. We, therefore, hypothesize that negative regulators of mRNA translation promote cell survival under metabolic stress. eIF4E binding protein 1 (4EBP1) is an mRNA translation inhibitor activated under conditions of metabolic stress that restricts global protein synthesis and promotes selective mRNA translation, processes in which the translation efficiency of particular transcripts is increased or decreased. We found that 4EBP1-depleted cell lines exhibit reduced survival under glucose starvation, which can be rescued by mRNA translation inhibitors and anti-oxidants. Furthermore, 4EBP1 depleted cells exhibit reduced NADPH levels under glucose starvation. Using polysome profiling we identified mRNAs whose translation is regulated by 4EBP1 supporting a new role of 4EBP1 in ferroptosis regulation, a ROS dependent form of programed cell death. Together, our data support the model where 4EBP1 plays a key role in REDOX regulation to support cell adaptation to energetic stress.