Integrated Stress Response (ISR)

The integrated stress response (ISR) is a highly conserved cellular signaling network present in eukaryotic cells. Its primary function is to help cells adapt to a wide range of internal and external stressors by reprogramming gene expression, thereby restoring or maintaining cellular homeostasis. The ISR achieves this by modulating protein synthesis rates and activating specific genes that promote cell survival or, if the damage is irreparable, trigger programmed cell death. The central event in ISR activation is the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). This phosphorylation event is catalyzed by one of four specialized kinases: PERK, GCN2, PKR, and HRI. Phosphorylated eIF2α inhibits its guanine nucleotide exchange factor (eIF2B), leading to a global reduction in protein synthesis while selectively enhancing translation of specific mRNAs such as ATF4—a transcription factor that orchestrates downstream adaptive responses. The ISR plays critical roles in development, immunity (antiviral defense), neuroprotection/neurodegeneration, cancer progression/resistance mechanisms, and metabolic diseases. Dysregulation can contribute directly to disease pathogenesis or therapy resistance.

Modulation of eIF2α phosphorylation; affects downstream signaling cascades influencing translation, transcription, and apoptosis.