The Integrated Stress Response: A Cellular Lifeline

ISR is everywhere during stress

In the complex and dynamic environment of cellular biology, the Integrated Stress Response (ISR) plays a crucial role in maintaining homeostasis and ensuring cell survival under various stress conditions. This sophisticated cellular mechanism integrates multiple signaling pathways to respond to a wide range of stressors, thereby protecting cells from damage and facilitating adaptation. This article delves into the ISR, its components, functions, and its implications for health and disease.

From Wikipedia

Understanding the Integrated Stress Response

The ISR is a conserved cellular mechanism that helps cells cope with environmental and physiological stressors such as nutrient deprivation, hypoxia, viral infections, and oxidative stress. It achieves this by modulating protein synthesis and promoting the expression of stress-related genes.

At the heart of the ISR is the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2α). Under stress conditions, eIF2α is phosphorylated by one of four stress-sensing kinases:

1. PERK (Protein kinase RNA-like Endoplasmic Reticulum Kinase): Activated by endoplasmic reticulum (ER) stress due to the accumulation of misfolded proteins.
2. GCN2 (General Control Nonderepressible 2): Activated by amino acid deprivation.
3. PKR (Protein Kinase R): Activated by viral infections and double-stranded RNA.
4. HRI (Heme-Regulated Inhibitor): Activated by oxidative stress and heme deficiency.

Mechanism of Action

When eIF2α is phosphorylated, it inhibits general protein synthesis by preventing the formation of the eIF2-GTP-Met-tRNAi complex, which is essential for the initiation of translation. This reduction in global protein synthesis helps conserve cellular resources and reduces the load of misfolded proteins.

However, phosphorylated eIF2α selectively enhances the translation of specific mRNAs that contain upstream open reading frames (uORFs) in their 5' untranslated regions. One of the key proteins translated under these conditions is Activating Transcription Factor 4 (ATF4), which regulates genes involved in amino acid metabolism, redox homeostasis, and apoptosis.

Key Components and Pathways

1. eIF2α Phosphorylation: Central to the ISR, it adjusts protein synthesis rates and activates stress-related genes.
2. ATF4: A transcription factor upregulated by ISR that drives the expression of genes involved in stress adaptation.
3. CHOP (C/EBP Homologous Protein): Induced by ATF4, it promotes apoptosis under prolonged stress conditions.
4. GADD34: Part of a feedback loop that dephosphorylates eIF2α, restoring normal protein synthesis when stress is resolved.

The Role of ISR in Health and Disease

The ISR is essential for cellular adaptation and survival under stress. However, dysregulation of the ISR is implicated in various diseases:

1. Neurodegenerative Diseases: Chronic activation of the ISR, particularly through PERK, is associated with diseases like Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS). Persistent ISR activation can lead to neuronal death and disease progression​.
2. Cancer: Tumors often exploit the ISR to survive under harsh conditions such as hypoxia and nutrient deprivation. However, the ISR can also make cancer cells more susceptible to treatment. Certain chemotherapeutic agents induce ER stress and activate the ISR, leading to cell death.
3. Diabetes: The ISR is involved in the development of insulin resistance and β-cell dysfunction in diabetes. Chronic ER stress in pancreatic β-cells can lead to apoptosis and decreased insulin secretion.

Therapeutic Implications

Given its central role in various diseases, targeting the ISR presents potential therapeutic opportunities. Strategies include:

1. ISR Inhibitors: Small molecules that inhibit ISR kinases, such as PERK inhibitors, are being explored for treating neurodegenerative diseases. By reducing chronic ISR activation, these inhibitors aim to prevent neuronal death.
2. Enhancing ISR for Cancer Therapy: Inducing ER stress and the ISR selectively in cancer cells can enhance the efficacy of chemotherapy. Drugs that exacerbate stress conditions within tumors can push cancer cells towards apoptosis.
3. Modulating ISR in Diabetes: Reducing ER stress in pancreatic β-cells through chemical chaperones or small molecules can improve β-cell function and insulin secretion, offering a potential treatment for diabetes.

The Intersection with Immunogenic Cell Death (ICD)

The ISR also intersects with immunogenic cell death (ICD), a form of cell death that stimulates an immune response against dead-cell-associated antigens. During ICD, the activation of the ISR can enhance the immunogenicity of dying cells by promoting the release of DAMPs (damage-associated molecular patterns) such as calreticulin, ATP, and HMGB1. These DAMPs play a crucial role in recruiting and activating dendritic cells, which in turn present tumor antigens to T cells, initiating a robust anti-tumor immune response.

Conclusion

The Integrated Stress Response is a vital cellular mechanism that protects against various stressors by modulating protein synthesis and activating adaptive gene expression. Its role in health and disease highlights the importance of maintaining a balanced ISR for cellular homeostasis. As research progresses, targeting the ISR offers promising therapeutic avenues for treating neurodegenerative diseases, cancer, and diabetes, among other conditions. Understanding and manipulating the ISR not only provides insights into fundamental cellular processes but also opens new doors for innovative treatments and improved health outcomes.

Reference

Galluzzi, L., Kepp, O., Hett, E. et al. Immunogenic cell death in cancer: concept and therapeutic implications. J Transl Med 21, 162 (2023). https://doi.org/10.1186/s12967-023-04017-6