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Stress Granules Cytoplasmic Aggregation of These Eif2α Phosphorylation CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Magazine R397 40S ribosomal subunits and eIF3). assembled, even in the absence of Stress granules Cytoplasmic aggregation of these eIF2α phosphorylation. abortively initiated mRNPs results While drugs that stall initiation can Paul Anderson and Nancy Kedersha in the formation of stress granules. cause stress granule assembly, drugs Independent of eIF2α phosphorylation, that inhibit translational elongation, What are stress granules? Stress agents such as hippuristanol and such as cycloheximide, prevent granules are non-membranous pateamine A target the eIF4A helicase, stress granule assembly and force cytoplasmic foci ranging in size which enables the complete 48S the disassembly of pre- formed from 0.1 to 2.0 μm, composed initiation complex (containing eIF2) stress granules, revealing that stress of non-translating messenger to scan the mRNA in search of the granule mRNPs are in dynamic ribonucleoproteins (mRNPs) that start codon. When eIF4A function equilibrium with polysomes. More rapidly aggregate in cells exposed to is blocked, translational initiation directly, measurements made adverse environmental conditions. is stalled and stress granules are using fluorescence recovery after 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 Figure 1. Stress granules and P-bodies in arsenite-treated human U2OS cells. of eIF2α reduces the availability of Met (A) Stress granules (SG, purple arrows) are visualized by staining for TIA-1 (blue), a translational the eIF2α–GTP–tRNAi ternary silencer. As stress granules also contain the RNA helicase RCK1 (stained in red), the merged complex that is required for translation colors appear purple. Similarly, P-bodies (PB, yellow arrows) are visualized by hedls/GE-1 initiation, thereby resulting in stalled staining (green) but appear yellow due to RCK1 colocalization. A single cell can contain iso- translation. Elongating ribosomes are lated P-bodies and stress granules, as well as interacting pairs of stress granules and P-bod- not affected, and proceed to run off ies. (B) Large ribosomal subunits (RP0, green) are excluded from stress granules or localized the stalled polysomes, resulting in to the edges, defined by small ribosomal subunits (RPSB, red) and eIF3b (blue). (C) P-bodies (DCP1a, green) and stress granules (eIF3b, blue) both contain eIF4E (red). (D) A region of (A), polyadenylated, circularized mRNA showing separated colors in the inset. (E) Stress granules exclusively contain eIF3b (blue) and transcripts that are still bound to the eIF4G (green), whereas eIF4E (red) is found both in stress granules and in a bound P-body. preinitiation machinery (comprising Insets show the separate colors within the boxed regions. Current Biology Vol 19 No 10 R398 photobleaching reveal that the half-life express a non-phosphorylatable form of stress-granule-associated RNA- of eIF2α (S51A) cannot assemble Primer binding proteins is very brief, on the stress granules in response to arsenite- order of seconds to minutes, despite induced oxidative stress and are the fact that time-lapse microscopy hypersensitive to the toxic effects of Inhibition in cortical reveals that individual stress granules low doses of arsenite. Whether this persist for hours. This rapid shuttling of is due to defective stress-induced circuits protein and RNA within stress granules translational silencing or defective suggests that their mRNP contents stress granule assembly is not yet Rodney J. Douglas are continually sorted via fleeting clear. In other cases, the sequestration and Kevan A.C. Martin associations with the translational of signaling molecules not directly machinery. Unlike other types of RNA linked to RNA metabolism (such as Inhibition was introduced as a concept granule, such as germ cell granules or TRAF2, RACK1 and FAST) in stress to physiology and psychology at the neuronal granules, stress granules are granules has been shown to regulate beginning of the 19th century, and not sites of long-term mRNP storage. the survival of stressed cells. by the early 20th century Sherrington had established that inhibition is an What are the core components Any known associates…? P-bodies active process in spinal reflexes. of stress granules? Stress granules are related dynamic mRNP granules Inhibition is mediated principally by are primarily composed of the stalled that often associate with stress the neurotransmitters γ-amino butyric 48S complexes containing bound granules. Although stress granules acid (GABA) in the brain and glycine mRNAs derived from disassembling and P-bodies have some protein and in the spinal cord. Knowledge of the polysomes. These contain poly(A)+ mRNA components in common, they structure and physiology of the GABA RNA bound to early initiation factors are structurally, compositionally, and and glyine receptors has greatly aided (such as eIF4E, eIF3, eIF4A, eIFG) functionally distinct (Figure 1). The core our understanding of analgesics, and small, but not large, ribosomal component of P-bodies is the mRNA anti-epileptics and especially of subunits. In addition to these core decay machinery, which includes mood-altering drugs, such as components, stress granules contain enzymes that remove the 7meG cap benzodiazepine, which acts directly an eclectic assembly of proteins that and poly(A) tail and degrade the mRNA on the GABA receptor. Our knowledge vary with cell type and with the nature in a 5’–3’ direction; these degradative of the neuronal types and their and duration of the stress involved. enzymes are excluded from stress synaptic physiology is most advanced RNA-binding proteins, transcription granules. Conversely, many signature for the mammalian cerebral cortex, factors, RNA helicases, nucleases, components of stress granules (such but even here the roles of inhibition in kinases and signaling molecules have as eIF3 and ribosomal 40S subunits) the neuronal responses evident at the been reported to accumulate in stress are excluded from P-bodies. The same circuit level are still dimly understood. granules. In some cases, recruitment of species of reporter mRNA can be Here we shall consider the varieties of signaling proteins into stress granules present in stress granules and P-bodies inhibitor neurons and their actions in influences cell survival. More recently, within the same cell, suggesting that the mammalian brain. stress granules have been shown these structures house mRNPs at to contain the Argonaute proteins, different stages of the mRNA life cycle, My name is legion… microRNAs, a number of mRNA-editing rather than different types of transcript. Over the past 100 years, many enzymes, and proteins required for Interactions between stress granules and descriptions have accumulated of transposon activity. P-bodies mirror the regulation of mRNA the morphological types of inhibitory translation and decay in stressed cells. neuron that inhabit the cerebral What are their speculated cortex, so many different descriptions functions? The dynamic nature of Where can I find out more? in fact, that an international stress granules suggests that they Anderson, P., and Kedersha, N. (2006). RNA granules. consortium recently convened J. Cell Biol. 172, 803–808. are sites of mRNA triage, wherein Anderson, P., and Kedersha, N. (2008). Stress at Ramon y Cajal’s birthplace in individual mRNAs are dynamically granules: the Tao of RNA triage. Trends Biochem. Petilla, Spain, to find new ways of Sci. 33, 141–150. sorted for storage, degradation, or Arimoto, K., Fukuda, H., Imajoh-Ohmi, S., Saito, H., classifying and naming them. The translation during stress and recovery. and Takekawa, M. (2008). Formation of stress Petilla consortium [1] concluded, Short-lived mRNAs bearing adenine– granules inhibits apoptosis by suppressing ruefully, that a major overhaul of stress-responsive MAPK pathways. Nat. Cell uridine-rich destabilizing elements in Biol. 10, 1324–1332. the terminology and criteria for their 3’ untranslated regions bind to Kim, W.J., Back, S.H., Kim, V., Ryu, I., and Jang, classification was ‘premature’. S.K. (2005). Sequestration of TRAF2 into stress TTP and BRF1/2, proteins that promote granules interrupts
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