Stress granules are dynamic components found within our cells. They represent a cellular response mechanism that activates when cells encounter adverse conditions. These temporary structures form rapidly to help cells cope with challenges and maintain balance. Their transient nature allows cells to quickly adapt and recover from various forms of stress.
Cellular Emergency Shelters
Stress granules are dynamic, transient aggregates of proteins and RNA molecules that form rapidly within the cytoplasm when a cell experiences stress. They function as “emergency shelters” for messenger RNA (mRNA), temporarily halting protein production. This temporary pause allows the cell to conserve energy and protect its machinery from damage during unfavorable conditions. By sequestering non-translating mRNAs, cells can quickly regulate gene expression and prioritize the synthesis of proteins needed for survival and recovery.
These membraneless organelles are formed through liquid-liquid phase separation, where components condense into distinct droplets within the cytoplasm. Their main components include stalled translation pre-initiation complexes, 40S ribosomal subunits, translation initiation factors like eIF4E and eIF4G, and various RNA-binding proteins (RBPs) such as TIA-1 and G3BP1. Nuclear stress granules have also been observed.
Triggers for Their Formation
Stress granule formation is induced by a variety of environmental or internal cellular stresses. Common triggers include heat shock, which involves exposure to elevated temperatures, and oxidative stress, caused by an imbalance between reactive oxygen species and the cell’s ability to detoxify them. Other stressors include viral infections and nutrient deprivation. Certain chemical exposures, like sodium arsenite, also induce stress granule formation.
These diverse stresses lead to a global shutdown of protein synthesis, which is a key event preceding stress granule assembly. Many stresses activate pathways that result in the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). This phosphorylation prevents the initiation of new protein synthesis, causing messenger RNAs (mRNAs) to stall and detach from ribosomes. These mRNAs then become available for sequestration into stress granules. The aggregation of RNA-binding proteins also contributes to the nucleation and growth of these structures.
Their Impact on Health and Disease
Stress granules play a dual role in cellular well-being, beneficial during acute stress but potentially detrimental if their dynamics become imbalanced. Their formation helps cells survive by protecting mRNAs and reallocating resources. This protective mechanism allows the cell to recover once the stress subsides, with stress granules typically disassembling within a few hours to a day after the return to normal conditions.
If stress granules persist abnormally or their components become dysfunctional, they can contribute to various pathologies. Dysregulation of stress granule dynamics has been linked to several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), and Alzheimer’s disease. In these conditions, mutations or chronic stress can lead to the irreversible accumulation of stress granule-related proteins, forming pathological aggregates that impair neuronal function.
Stress granules also have implications in certain cancers, where their formation can promote cell survival and drug resistance, making them a target for therapeutic interventions. In viral infections, some viruses manipulate stress granule formation to their advantage, either by inhibiting assembly to facilitate viral replication or by incorporating viral components into these granules. Understanding stress granule formation, disassembly, and interaction with disease pathways offers avenues for developing new therapeutic strategies aimed at modulating their behavior in human diseases.