Integrated stress response

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Integrated Stress Response (ISR) is a cellular mechanism that is activated in response to various types of environmental and physiological stress. The ISR aims to restore homeostasis by halting general protein synthesis while selectively increasing the production of proteins that aid in stress recovery. This response is crucial for cell survival under adverse conditions and plays a significant role in the development of diseases when dysregulated.

Mechanism

The ISR is initiated by four main kinases: Protein kinase R (PKR), General control nonderepressible 2 (GCN2), PKR-like endoplasmic reticulum kinase (PERK), and Heme-regulated inhibitor kinase (HRI). These kinases respond to different stress signals such as double-stranded RNA (indicative of viral infection), amino acid deprivation, endoplasmic reticulum stress, and heme deficiency, respectively. Activation of any of these kinases leads to the phosphorylation of the eukaryotic initiation factor 2 (eIF2α), which reduces general protein synthesis to conserve resources. However, this phosphorylation also allows for the selective translation of specific mRNAs, such as the transcription factor ATF4, which activates genes involved in stress recovery.

Functions

The ISR plays a critical role in maintaining cellular homeostasis and survival during stress conditions. By reducing general protein synthesis, the ISR helps to conserve energy and resources. The selective translation of mRNAs involved in stress response mechanisms allows cells to adapt to and survive adverse conditions. Additionally, the ISR is involved in the regulation of autophagy, oxidative stress response, and apoptosis.

Clinical Significance

Dysregulation of the ISR is associated with various diseases, including neurodegenerative diseases, cancer, and metabolic disorders. In neurodegenerative diseases, prolonged activation of the ISR can lead to neuronal death. In cancer, certain tumors exploit the ISR to support their growth and survival under stressful conditions, such as hypoxia and nutrient deprivation. In metabolic disorders, chronic activation of the ISR can contribute to insulin resistance and diabetes.

Research Directions

Research on the ISR is focused on understanding its role in health and disease and developing therapeutic strategies to modulate this pathway. Inhibitors and activators of the ISR kinases are being explored as potential treatments for diseases associated with ISR dysregulation. For example, ISR inhibitors may offer a new approach to treating neurodegenerative diseases by reducing neuronal death, while activators could be used to enhance the stress response in cancer cells, making them more susceptible to treatment.