Integrated Stress Response (ISR) (ISR)

The Integrated Stress Response (ISR) is a highly conserved intracellular signaling network that enables eukaryotic cells to adapt to various environmental and physiological stressors, such as endoplasmic reticulum (ER) stress, nutrient deprivation, and viral infection [1, 8]. The pathway is characterized by the convergence of four specialized kinases—PERK, PKR, GCN2, and HRI—which phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) [3, 7]. This phosphorylation event leads to a global reduction in protein synthesis to conserve energy and prevent the accumulation of misfolded proteins, while selectively enhancing the translation of stress-adaptive mRNAs like Activating Transcription Factor 4 (ATF4) [4, 15]. In the context of ER stress, the ISR overlaps significantly with the Unfolded Protein Response (UPR), utilizing sensors like IRE1 and ATF6 to restore proteostasis [14, 16]. While initially cytoprotective, chronic or excessive activation of the ISR can trigger apoptosis through the induction of CHOP, contributing to the pathogenesis of neurodegenerative diseases, diabetes, and cancer [10, 17]. Therapeutic modulation of the ISR is a burgeoning field, with small molecules like ISRIB (an eIF2B activator) and Sephin1 (a GADD34 inhibitor) showing promise in restoring cellular function or selectively inducing death in malignant cells [2, 5, 6].

Other names

Unfolded Protein ResponseUPReIF2alpha signaling pathwayER stress responseEndoplasmic reticulum stress response

Modulation of the ISR occurs through several mechanisms: eIF2B activation (e.g., ISRIB) to bypass eIF2alpha phosphorylation; inhibition of eIF2alpha kinases like PERK or IRE1; inhibition of the GADD34/PP1 phosphatase complex (e.g., Sephin1) to prolong the adaptive phase; and direct activation of stress kinases (e.g., ONC201) to induce apoptosis in cancer cells.