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• W4243584933 abstract "What are stress granules? Stress granules are non-membranous cytoplasmic foci ranging in size from 0.1 to 2.0 μm, composed of non-translating messenger ribonucleoproteins (mRNPs) that rapidly aggregate in cells exposed to adverse environmental conditions. Their assembly is triggered by a variety of environmental stresses including heat shock, oxidative stress, hyperosmolarity, viral infection, and UV irradiation, but not X-irradiation or DNA-damaging agents. Their mRNA composition is selective — they contain transcripts encoding housekeeping genes but exclude those encoding stress-induced genes such as HSP70. Stress granules are found in both cultured cell lines and intact tissues. Which organisms have stress granules? Bona fide stress granules have been observed in yeast (such as Saccharomyces pombe), protozoa (Trypanosoma brucei) and metazoa (such as Homo sapiens and Caenorhabditis elegans). They have also been observed in plants and in chloroplasts, suggesting that they may be assembled in prokaryotes as well. What regulates the assembly and disassembly of stress granules? In most cases, the stress-induced phosphorylation of the translation initiation factor eIF2α induces stress granule assembly by preventing or delaying translational initiation. A family of structurally related eIF2α kinases, each activated by a different type of stress, phosphorylates the regulatory serine of eIF2α. Of these kinases, PKR is activated by double-stranded RNAs, PERK is activated by endoplasmic reticulum stress, HRI is activated by oxidative stress, and GCN2 is activated by nutrient stress. Phosphorylation of eIF2α reduces the availability of the eIF2α–GTP–tRNAiMet ternary complex that is required for translation initiation, thereby resulting in stalled translation. Elongating ribosomes are not affected, and proceed to run off the stalled polysomes, resulting in polyadenylated, circularized mRNA transcripts that are still bound to the preinitiation machinery (comprising 40S ribosomal subunits and eIF3). Cytoplasmic aggregation of these abortively initiated mRNPs results in the formation of stress granules. Independent of eIF2α phosphorylation, agents such as hippuristanol and pateamine A target the eIF4A helicase, which enables the complete 48S initiation complex (containing eIF2) to scan the mRNA in search of the start codon. When eIF4A function is blocked, translational initiation is stalled and stress granules are assembled, even in the absence of eIF2α phosphorylation. While drugs that stall initiation can cause stress granule assembly, drugs that inhibit translational elongation, such as cycloheximide, prevent stress granule assembly and force the disassembly of pre-formed stress granules, revealing that stress granule mRNPs are in dynamic equilibrium with polysomes. More directly, measurements made using fluorescence recovery after photobleaching reveal that the half-life of stress-granule-associated RNA-binding proteins is very brief, on the order of seconds to minutes, despite the fact that time-lapse microscopy reveals that individual stress granules persist for hours. This rapid shuttling of protein and RNA within stress granules suggests that their mRNP contents are continually sorted via fleeting associations with the translational machinery. Unlike other types of RNA granule, such as germ cell granules or neuronal granules, stress granules are not sites of long-term mRNP storage. What are the core components of stress granules? Stress granules are primarily composed of the stalled 48S complexes containing bound mRNAs derived from disassembling polysomes. These contain poly(A)+ RNA bound to early initiation factors (such as eIF4E, eIF3, eIF4A, eIFG) and small, but not large, ribosomal subunits. In addition to these core components, stress granules contain an eclectic assembly of proteins that vary with cell type and with the nature and duration of the stress involved. RNA-binding proteins, transcription factors, RNA helicases, nucleases, kinases and signaling molecules have been reported to accumulate in stress granules. In some cases, recruitment of signaling proteins into stress granules influences cell survival. More recently, stress granules have been shown to contain the Argonaute proteins, microRNAs, a number of mRNA-editing enzymes, and proteins required for transposon activity. What are their speculated functions? The dynamic nature of stress granules suggests that they are sites of mRNA triage, wherein individual mRNAs are dynamically sorted for storage, degradation, or translation during stress and recovery. Short-lived mRNAs bearing adenine–uridine-rich destabilizing elements in their 3′ untranslated regions bind to TTP and BRF1/2, proteins that promote interactions between stress granules and processing bodies (P-bodies) and induce mRNA decay. It is therefore likely that stress granules can regulate the stability of selected mRNAs. Beyond mRNP sorting, the recruitment of other signaling molecules into stress granules suggests that they link mRNP sorting with other signaling events. Cells that express a non-phosphorylatable form of eIF2α (S51A) cannot assemble stress granules in response to arsenite-induced oxidative stress and are hypersensitive to the toxic effects of low doses of arsenite. Whether this is due to defective stress-induced translational silencing or defective stress granule assembly is not yet clear. In other cases, the sequestration of signaling molecules not directly linked to RNA metabolism (such as TRAF2, RACK1 and FAST) in stress granules has been shown to regulate the survival of stressed cells. Any known associates…? P-bodies are related dynamic mRNP granules that often associate with stress granules. Although stress granules and P-bodies have some protein and mRNA components in common, they are structurally, compositionally, and functionally distinct (Figure 1). The core component of P-bodies is the mRNA decay machinery, which includes enzymes that remove the 7meG cap and poly(A) tail and degrade the mRNA in a 5′–3′ direction; these degradative enzymes are excluded from stress granules. Conversely, many signature components of stress granules (such as eIF3 and ribosomal 40S subunits) are excluded from P-bodies. The same species of reporter mRNA can be present in stress granules and P-bodies within the same cell, suggesting that these structures house mRNPs at different stages of the mRNA life cycle, rather than different types of transcript. Interactions between stress granules and P-bodies mirror the regulation of mRNA translation and decay in stressed cells." @default.
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• W4243584933 date "2009-05-01" @default.
• W4243584933 modified "2023-10-13" @default.
• W4243584933 title "Stress granules" @default.
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• W4243584933 doi "https://doi.org/10.1016/j.cub.2009.03.013" @default.
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