A New Branch of Cellular Stress Response: The Split ISR

A study published in Nature reveals an alternative stress response mechanism in mammalian cells, termed the split integrated stress response (s-ISR). Unlike the canonical ISR (c-ISR), which is driven by phosphorylation of eIF2α and suppression of eIF2B activity, the s-ISR arises solely from reduced eIF2B activity—even without eIF2α phosphorylation. This alternative pathway relies on eIF4E-dependent translation and stabilization of ATF4 mRNA, activating a distinct transcriptional program including metabolic genes like PCK2. The s-ISR enables cells to rewire metabolism and maintain energy homeostasis under conditions of impaired eIF2B function, such as in certain leukodystrophies. These findings redefine the ISR as a plastic and modular response, expanding our understanding of how cells adapt to diverse stressors.