The Integrated Stress Response (ISR) is a protective mechanism within eukaryotic cells, allowing cells to adapt and survive challenges. It restores cellular balance. This network adjusts protein production and gene expression to manage difficult conditions. The ISR is conserved across organisms, from yeast to humans, highlighting its role in cellular well-being.
Triggers of the Integrated Stress Response
Cells are exposed to stressors that activate the Integrated Stress Response. The ISR is initiated by several distinct cellular insults. Each type of stress engages specific sensing mechanisms that converge on the ISR pathway.
Amino acid starvation, a lack of protein building blocks, is one trigger. This deprivation signals a metabolic imbalance, prompting the ISR to conserve resources.
Viral infections also activate the ISR, particularly through double-stranded RNA (dsRNA) produced during replication. Endoplasmic Reticulum (ER) stress, also known as the Unfolded Protein Response (UPR), is another activator. This stress arises from misfolded protein accumulation within the ER, a compartment for protein folding. Finally, heme deficiency, a lack of iron-containing molecules, can also induce the ISR, reflecting metabolic disruption.
Key Players and Mechanisms
The ISR’s “integrated” aspect is evident in its core molecular machinery, where stress signals converge. Four main protein kinases initiate the ISR: Protein Kinase R (PKR), PKR-like ER Kinase (PERK), General Control Nonderepressible 2 (GCN2), and Heme-Regulated Inhibitor (HRI). Each kinase is activated by a specific stress:
PKR responds to viral double-stranded RNA.
PERK is activated by misfolded proteins in the endoplasmic reticulum.
GCN2 senses amino acid deprivation.
HRI detects heme deficiency.
Upon activation, these four kinases phosphorylate eukaryotic initiation factor 2 alpha (eIF2α) at serine 51. Phosphorylation of eIF2α is the central event that inhibits global protein synthesis, significantly decreasing new protein production. This general shutdown also selectively promotes the translation of specific stress-response proteins, such as activating transcription factor 4 (ATF4), which helps cells adapt. This dual action conserves energy by reducing overall protein production while synthesizing proteins needed to resolve stress.
Cellular Consequences
ISR activation leads to immediate effects within the cell. A primary consequence is global protein synthesis attenuation, due to eIF2α phosphorylation. This reduction conserves energy and reduces the burden on protein-folding machinery, especially during misfolded protein stress.
Despite this slowdown, the ISR also orchestrates selective translation of specific stress-response genes, such as ATF4. Certain messenger RNAs (mRNAs) are preferentially translated even when global protein synthesis is inhibited, producing proteins that help cells cope with stress. Another change is the formation of stress granules, transient cytoplasmic compartments where untranslated mRNAs and translation initiation factors are temporarily stored during stress. These granules contribute to cellular adaptation by sequestering non-essential mRNAs and conserving resources. The ISR can also trigger autophagy, a process involving the degradation and recycling of damaged cellular components, which helps maintain cellular health and remove harmful aggregates.
Role in Health and Disease
The Integrated Stress Response plays a role in health and disease, extending its impact beyond cellular adjustments. In normal states, the ISR contributes to protective roles, including antiviral defense, metabolic adaptation, and neuronal function. Its ability to fine-tune cellular responses helps maintain organismal balance.
However, chronic or dysregulated ISR activation can contribute to neurodegenerative diseases. Conditions like Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS) often feature persistent ISR activation, which can promote protein aggregation, impair neuronal function, and lead to neuronal cell death. In cancer, the ISR exhibits a dual role. Initially, it can act protectively by inducing cell cycle arrest or programmed cell death in stressed cancer cells, limiting tumor growth. If chronically activated, the ISR can promote tumor survival by helping cancer cells adapt to harsh microenvironments and develop resistance to therapies.
The ISR is also implicated in metabolic disorders such as diabetes and obesity, particularly through its involvement in endoplasmic reticulum stress within metabolic tissues. Understanding ISR pathways opens avenues for new therapeutic strategies. Modulating the ISR, by enhancing or suppressing its activity, holds promise for treating diseases, including those linked to aging, by restoring cellular homeostasis or inducing cell death in unhealthy cells.