Cells possess intricate defense systems to cope with challenging conditions and ensure survival. One such mechanism involves the formation of dynamic structures known as stress granules. These transient, membraneless cellular compartments form within the cytoplasm as a rapid response to various forms of cellular stress, helping cells manage and mitigate the impact of unfavorable environments.
Cellular Stress and Granule Formation
Stress granules are aggregates composed primarily of messenger RNAs (mRNAs) that have stalled during translation, along with RNA-binding proteins (RBPs) and translation initiation factors. They emerge when cells encounter environmental shifts that disrupt normal cellular operations. Triggers include heat shock, which elevates cellular temperature, and oxidative stress, caused by an imbalance of reactive oxygen species.
Other stressors include viral infections, which hijack cellular machinery, and nutrient deprivation. Exposure to toxins, like sodium arsenite, also induces their formation. These diverse stresses lead to a slowdown or shutdown of protein synthesis within the cell. This halt in translation causes untranslated mRNAs and RNA-binding proteins to accumulate, coalescing into stress granules. They are temporary and disassemble once stressful conditions subside.
The Assembly Process
Stress granule formation is governed by liquid-liquid phase separation (LLPS). This phenomenon involves molecules spontaneously separating from a homogenous solution to form dense, droplet-like phases, similar to how oil separates from water. Within the cellular environment, RNA-binding proteins and untranslated mRNAs undergo LLPS to create stress granule compartments.
Proteins such as Ras-GTPase-activating protein SH3-domain-binding protein 1 (G3BP1), T-cell-restricted intracellular antigen-1 (TIA-1), and Fused in Sarcoma (FUS) are important for the rapid and reversible assembly of stress granules. These proteins, often containing intrinsically disordered regions, facilitate the weak, multivalent interactions necessary for the condensation of RNA and protein into these dynamic structures. This assembly is a swift cellular response, allowing for adaptation to changing conditions.
The Role of Stress Granules in Cell Survival
Once formed, stress granules serve as centers for managing messenger RNA (mRNA) during adverse conditions. They act as triage centers, temporarily sequestering non-essential mRNAs that are not currently undergoing translation. This sequestration conserves cellular energy and resources that would otherwise be expended on synthesizing unnecessary proteins.
By holding these mRNAs in reserve, stress granules facilitate their sorting, allowing the cell to determine whether these transcripts should be stored for later use, degraded if damaged or no longer needed, or returned for translation once normal conditions resume. This selective management of mRNA allows the cell to prioritize the synthesis of proteins that are essential for survival and recovery from the stressful event. Stress granules contribute to the cell’s protective function, enabling it to endure challenging conditions and return to its typical state.
Stress Granules and Disease
When the normal formation and disassembly of stress granules are disrupted, it can contribute to various human diseases. In neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), mutations in genes encoding stress granule proteins, including TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma (FUS), can lead to their abnormal aggregation. This persistent accumulation contributes to the progression of these conditions.
Stress granules also play a role in certain cancers, where their formation can be exploited by cancer cells to promote survival and resistance to anti-cancer treatments. They can help tumor cells cope with stress, proliferate, and even metastasize. Viruses can manipulate stress granule dynamics, either by interfering with their formation to aid viral replication or by utilizing stress granule components to their advantage. Understanding the mechanisms of stress granule assembly and disassembly offers promising avenues for developing new therapeutic strategies for these diseases.