UNDERSTANDING THE INTEGRATED STRESS RESPONSE (ISR)

The Integrated Stress Response (ISR) is a vital cellular mechanism that enables organisms to adapt to various stress conditions, including environmental and metabolic challenges. This pathway is primarily regulated by eIF2α kinases, which respond to different types of stress signals such as amino acid deprivation, oxidative stress, and mitochondrial dysfunction. The ISR plays a crucial role in maintaining cellular homeostasis by modulating protein synthesis and promoting protective cellular responses.

Why choose AnyGenes® for ISR research?

AnyGenes® provides advanced qPCR arrays designed to analyze the ISR and its molecular regulators. Our innovative solutions empower researchers to:

Investigate key regulators such as eIF2α, ATF4, and CHOP.
Analyze downstream targets, including GADD34, BiP, and XBP1.
Explore crosstalk between the ISR and other signaling pathways like UPR and mTOR.

Our qPCR arrays deliver precise and reproducible results, enabling researchers to decode the complex interactions within the ISR pathway.

Diagram of the Integrated Stress Response (ISR) pathway analyzed using AnyGenes® qPCR arrays.

Discover our advanced qPCR arrays for Integrated Stress Response research.

ISR signaling and mechanisms.

KEY COMPONENTS OF THE INTEGRATED STRESS RESPONSE

Stress Sensors:
Stressors such as nutrient deprivation or oxidative damage activate kinases like PERK, GCN2, PKR, and HRI.
Phosphorylation of eIF2α:
The central event of ISR is the phosphorylation of eIF2α, which reduces global protein synthesis to conserve resources while allowing translation of specific stress-related proteins.
ATF4 Activation:
Phosphorylated eIF2α enhances the translation of ATF4, a transcription factor that drives the expression of stress response genes.
CHOP and GADD34:
ATF4 regulates CHOP, which balances survival and apoptosis, and GADD34, which restores protein synthesis by dephosphorylating eIF2α.
Crosstalk with Other Pathways:
The ISR integrates signals from the Unfolded Protein Response (UPR), mTOR signaling, and autophagy pathways to optimize cellular adaptation.

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:

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.
eIF2α Phosphorylation: This step reduces general protein synthesis to conserve energy.
Selective Translation of ATF4: It drives the transcription of genes involved in stress mitigation, antioxidant defense, and amino acid metabolism.
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.
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.

CLINICAL SIGNIFICANCE OF ISR

Dysfunction in the ISR pathway contributes to various diseases:

Neurodegenerative Disorders: Aberrant ISR activity is associated with Alzheimer’s, Parkinson’s, and ALS.
Cancer: Tumors exploit ISR to survive under hypoxic and nutrient-deprived conditions.
Metabolic Disorders: ISR dysregulation is implicated in obesity and diabetes.
Infectious Diseases: Viruses manipulate ISR components to evade immune responses.

By studying ISR, researchers can uncover novel therapeutic targets for these conditions.

PHYSIOLOGICAL ROLES

The ISR has far-reaching implications for various physiological processes:

Cell Survival and Death: The ISR determines cell fate under chronic stress conditions. For instance, modulation of Protein Phosphatase 2A (PP2A) has been shown to influence drug responses and cell survival during proteolytic stress.
Metabolic Adaptation: The ISR integrates signals from metabolic pathways, adjusting cellular functions to optimize energy utilization under stress. It has been linked to changes in amino acid metabolism and lipid synthesis, crucial for maintaining energy balance.
Neuromodulation: Recent findings suggest that the ISR plays a role in synaptic plasticity, learning, and memory by influencing neuromodulatory neurons.

(1) Pakos-Zebrucka K & al. The integrated stress response.. EMBO Rep. (2016); 17(10):1374-1395.

(2) Santos-Ribeiro D & al. The integrated stress response system in cardiovascular disease. Drug Discov Today. (2018); 23(4):920-929.

(3) Wang C & al. Inhibiting the integrated stress response pathway prevents aberrant chondrocyte differentiation thereby alleviating chondrodysplasia. Elife. (2018) 19;7.

(4) Pavitt GD. Regulation of translation initiation factor eIF2B at the hub of the integrated stress response. Wiley Interdiscip Rev RNA. (2018);9(6).

(5) Wang SF & al. Activated Integrated Stress Response Induced by Salubrinal Promotes Cisplatin Resistance in Human Gastric Cancer Cells via Enhanced xCT Expression and Glutathione Biosynthesis. Int J Mol Sci. (2018) 29;19(11).

(6) Romero-Ramírez L& al. Integrated Stress Response as a Therapeutic Target for CNS Injuries. Biomed Res Int. (2017):6953156.

ISR SIGNALING PATHWAY BIOMARKER LIST

Customize your own signaling pathways (SignArrays®) with the factors of your choice!
Simply download and complete our Personalized SignArrays® information file and send it at contact@anygenes.com to get started on your project.

You can check the biomarker list included in this pathway, see below:

Species : Homo sapiens (human)

Signaling Pathways	Product ref	Informations
Integrated Stress Response	ISR1H1	List infos

Species : Mus musculus (mouse)

Signaling Pathways	Product ref	Informations
Integrated Stress Response	ISR1M1	List infos

Species : Rattus norvegicus (rat)

Signaling Pathways	Product ref	Informations
Integrated Stress Response	ISR1R1	List infos

Species : Sus Scrofa (Pig)

Signaling Pathways	Product ref	Informations
Integrated Stress Response	*******	List In progress...

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