1695-Plasticity of the Mammalian Integrated Stress Response

This research investigates the split integrated stress response (s-ISR), a newly identified cellular mechanism that occurs when eIF2B activity is reduced without the typical induction of eIF2α phosphorylation seen in the canonical integrated stress response. Unlike the conventional pathway, this alternative mechanism relies on the eIF4E–DDX3X axis and uORF1 translation to stabilize ATF4 mRNA and activate specific metabolic genes like PCK2, helping cells maintain energy homeostasis under mild stressors such as moderate hypoglycemia. Furthermore, the findings demonstrate that disease-causing mutations associated with vanishing white matter disease trigger this specific s-ISR pathway, leading to metabolic adaptations that become vulnerable to subsequent endoplasmic reticulum stress. Ultimately, these discoveries reveal a previously unrecognized plasticity in mammalian stress responses, illustrating how cells tailor their transcriptional, translational, and metabolic programs based on the specific nature and intensity of cellular stress.

References:

• Chen C W, Papadopoli D, Szkop K J, et al. Plasticity of the mammalian integrated stress response[J]. Nature, 2025, 641(8065): 1319-1328.