UNDERSTANDING THE INTEGRATED STRESS RESPONSE (ISR)

MECHANISMS OF ACTION OF INTEGRATED STRESS RESPONSE

The ISR is activated through the phosphorylation of eIF2α, leading to a decrease in general protein synthesis while enhancing the translation of specific stress-responsive genes. The ISR coordinates a response that ensures cell survival or, in severe cases, triggers apoptosis. Key mechanisms include:

1. Stress Signal Sensing: Stress is detected by specific kinases, including PERK (Protein Kinase RNA-like ER Kinase), GCN2 (General Control Nonderepressible 2), PKR (Protein Kinase R), and HRI (Heme-Regulated Inhibitor). These kinases are activated by different stress stimuli, such as ER stress, amino acid deprivation, viral infections, or heme deficiency.
2. eIF2α Phosphorylation: This step reduces general protein synthesis to conserve energy.
3. Selective Translation of ATF4: It drives the transcription of genes involved in stress mitigation, antioxidant defense, and amino acid metabolism.
4. Downstream Effects:
   • Stress Resolution: If the stress is resolved, ISR promotes cell recovery through antioxidant responses, protein homeostasis, and metabolic adaptation.
   • Apoptosis Activation: If the stress persists, ISR can activate pro-apoptotic factors like CHOP (C/EBP Homologous Protein), leading to programmed cell death.
5. Crosstalk with Other Pathways: ISR interacts with other cellular pathways, such as the unfolded protein response (UPR), mTOR signaling, and autophagy mechanisms, creating a comprehensive network to address cellular stress.