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1
Vanneste, Joni, Thomas Vercruysse, Steven Boeynaems, Philip Van Van Damme, Dirk Daelemans, and Ludo Van Den Van Den Bosch. "Cellular Stress Induces Nucleocytoplasmic Transport Deficits Independent of Stress Granules." Biomedicines 10, no. 5 (May 3, 2022): 1057. http://dx.doi.org/10.3390/biomedicines10051057.
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Stress granules are non-membrane bound granules temporarily forming in the cytoplasm in response to stress. Proteins of the nucleocytoplasmic transport machinery were found in these stress granules and it was suggested that stress granules contribute to the nucleocytoplasmic transport defects in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). The aim of this study was to investigate whether there is a causal link between stress granule formation and nucleocytoplasmic transport deficits. Therefore, we uncoupled stress granule formation from cellular stress while studying nuclear import. This was carried out by preventing cells from assembling stress granules despite being subjected to cellular stress either by knocking down both G3BP1 and G3BP2 or by pharmacologically inhibiting stress granule formation. Conversely, we induced stress granules by overexpressing G3BP1 in the absence of cellular stress. In both conditions, nuclear import was not affected demonstrating that stress granule formation is not a direct cause of stress-induced nucleocytoplasmic transport deficits.
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An, Haiyan, Jing Tong Tan, and Tatyana A. Shelkovnikova. "Stress granules regulate stress-induced paraspeckle assembly." Journal of Cell Biology 218, no. 12 (October 21, 2019): 4127–40. http://dx.doi.org/10.1083/jcb.201904098.
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Eukaryotic cells contain a variety of RNA-protein macrocomplexes termed RNP granules. Different types of granules share multiple protein components; however, the crosstalk between spatially separated granules remains unaddressed. Paraspeckles and stress granules (SGs) are prototypical RNP granules localized exclusively in the nucleus and cytoplasm, respectively. Both granules are implicated in human diseases, such as amyotrophic lateral sclerosis. We characterized the composition of affinity-purified paraspeckle-like structures and found a significant overlap between the proteomes of paraspeckles and SGs. We further show that paraspeckle hyperassembly is typical for cells subjected to SG-inducing stresses. Using chemical and genetic disruption of SGs, we demonstrate that formation of microscopically visible SGs is required to trigger and maintain stress-induced paraspeckle assembly. Mechanistically, SGs may sequester negative regulators of paraspeckle formation, such as UBAP2L, alleviating their inhibitory effect on paraspeckles. Our study reveals a novel function for SGs as positive regulators of nuclear RNP granule assembly and suggests a role for disturbed SG-paraspeckle crosstalk in human disease.
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Piotrowska, Joanna, Spencer J. Hansen, Nogi Park, Katarzyna Jamka, Peter Sarnow, and Kurt E. Gustin. "Stable Formation of Compositionally Unique Stress Granules in Virus-Infected Cells." Journal of Virology 84, no. 7 (January 27, 2009): 3654–65. http://dx.doi.org/10.1128/jvi.01320-09.
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ABSTRACT Stress granules are sites of mRNA storage formed in response to a variety of stresses, including viral infections. Here, the mechanisms and consequences of stress granule formation during poliovirus infection were examined. The results indicate that stress granules containing T-cell-restricted intracellular antigen 1 (TIA-1) and mRNA are stably constituted in infected cells despite lacking intact RasGAP SH3-domain binding protein 1 (G3BP) and eukaryotic initiation factor 4G. Fluorescent in situ hybridization revealed that stress granules in infected cells do not contain significant amounts of viral positive-strand RNA. Infection does not prevent stress granule formation in response to heat shock, indicating that poliovirus does not block de novo stress granule formation. A mutant TIA-1 protein that prevents stress granule formation during oxidative stress also prevents formation in infected cells. However, stress granule formation during infection is more dependent upon ongoing transcription than is formation during oxidative stress or heat shock. Furthermore, Sam68 is recruited to stress granules in infected cells but not to stress granules formed in response to oxidative stress or heat shock. These results demonstrate that stress granule formation in poliovirus-infected cells utilizes a transcription-dependent pathway that results in the appearance of stable, compositionally unique stress granules.
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Sandqvist, Anton, and Lea Sistonen. "Nuclear stress granules." Journal of Cell Biology 164, no. 1 (January 5, 2004): 15–17. http://dx.doi.org/10.1083/jcb.200311102.
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Nuclear stress granules are subnuclear compartments that form in response to heat shock and other stress stimuli. Although many components of nuclear stress granules have been identified, including HSF1 and pre-mRNA processing factors, their function remains a mystery. A paper in this issue describes the stress-induced transcriptional activation of one of the nuclear stress granule target sites, a heterochromatic region that has been considered silent (Jolly et al., 2004). These intriguing findings will certainly give the research of these structures a new twist.
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Watanabe, Kazunori, and Takashi Ohtsuki. "Inhibition of HSF1 and SAFB Granule Formation Enhances Apoptosis Induced by Heat Stress." International Journal of Molecular Sciences 22, no. 9 (May 7, 2021): 4982. http://dx.doi.org/10.3390/ijms22094982.
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Stress resistance mechanisms include upregulation of heat shock proteins (HSPs) and formation of granules. Stress-induced granules are classified into stress granules and nuclear stress bodies (nSBs). The present study examined the involvement of nSB formation in thermal resistance. We used chemical compounds that inhibit heat shock transcription factor 1 (HSF1) and scaffold attachment factor B (SAFB) granule formation and determined their effect on granule formation and HSP expression in HeLa cells. We found that formation of HSF1 and SAFB granules was inhibited by 2,5-hexanediol. We also found that suppression of HSF1 and SAFB granule formation enhanced heat stress-induced apoptosis. In addition, the upregulation of HSP27 and HSP70 during heat stress recovery was suppressed by 2,5-hexanediol. Our results suggested that the formation of HSF1 and SAFB granules was likely to be involved in the upregulation of HSP27 and HSP70 during heat stress recovery. Thus, the formation of HSF1 and SAFB granules was involved in thermal resistance.
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Mollet, Stephanie, Nicolas Cougot, Ania Wilczynska, François Dautry, Michel Kress, Edouard Bertrand, and Dominique Weil. "Translationally Repressed mRNA Transiently Cycles through Stress Granules during Stress." Molecular Biology of the Cell 19, no. 10 (October 2008): 4469–79. http://dx.doi.org/10.1091/mbc.e08-05-0499.
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In mammals, repression of translation during stress is associated with the assembly of stress granules in the cytoplasm, which contain a fraction of arrested mRNA and have been proposed to play a role in their storage. Because physical contacts are seen with GW bodies, which contain the mRNA degradation machinery, stress granules could also target arrested mRNA to degradation. Here we show that contacts between stress granules and GW bodies appear during stress-granule assembly and not after a movement of the two preassembled structures. Despite this close proximity, the GW body proteins, which in some conditions relocalize in stress granules, come from cytosol rather than from adjacent GW bodies. It was previously reported that several proteins actively traffic in and out of stress granules. Here we investigated the behavior of mRNAs. Their residence time in stress granules is brief, on the order of a minute, although stress granules persist over a few hours after stress relief. This short transit reflects rapid return to cytosol, rather than transfer to GW bodies for degradation. Accordingly, most arrested mRNAs are located outside stress granules. Overall, these kinetic data do not support a direct role of stress granules neither as storage site nor as intermediate location before degradation.
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Buchan, J. Ross, Denise Muhlrad, and Roy Parker. "P bodies promote stress granule assembly in Saccharomyces cerevisiae." Journal of Cell Biology 183, no. 3 (November 3, 2008): 441–55. http://dx.doi.org/10.1083/jcb.200807043.
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Recent results indicate that nontranslating mRNAs in eukaryotic cells exist in distinct biochemical states that accumulate in P bodies and stress granules, although the nature of interactions between these particles is unknown. We demonstrate in Saccharomyces cerevisiae that RNA granules with similar protein composition and assembly mechanisms as mammalian stress granules form during glucose deprivation. Stress granule assembly is dependent on P-body formation, whereas P-body assembly is independent of stress granule formation. This suggests that stress granules primarily form from mRNPs in preexisting P bodies, which is also supported by the kinetics of P-body and stress granule formation both in yeast and mammalian cells. These observations argue that P bodies are important sites for decisions of mRNA fate and that stress granules, at least in yeast, primarily represent pools of mRNAs stalled in the process of reentry into translation from P bodies.
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Lindquist, Michael E., Aaron W. Lifland, Thomas J. Utley, Philip J. Santangelo, and James E. Crowe. "Respiratory Syncytial Virus Induces Host RNA Stress Granules To Facilitate Viral Replication." Journal of Virology 84, no. 23 (September 15, 2010): 12274–84. http://dx.doi.org/10.1128/jvi.00260-10.
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ABSTRACT Mammalian cell cytoplasmic RNA stress granules are induced during various conditions of stress and are strongly associated with regulation of host mRNA translation. Several viruses induce stress granules during the course of infection, but the exact function of these structures during virus replication is not well understood. In this study, we showed that respiratory syncytial virus (RSV) induced host stress granules in epithelial cells during the course of infection. We also showed that stress granules are distinct from cytoplasmic viral inclusion bodies and that the RNA binding protein HuR, normally found in stress granules, also localized to viral inclusion bodies during infection. Interestingly, we demonstrated that infected cells containing stress granules also contained more RSV protein than infected cells that did not form inclusion bodies. To address the role of stress granule formation in RSV infection, we generated a stable epithelial cell line with reduced expression of the Ras-GAP SH3 domain-binding protein (G3BP) that displayed an inhibited stress granule response. Surprisingly, RSV replication was impaired in these cells compared to its replication in cells with intact G3BP expression. In contrast, knockdown of HuR by RNA interference did not affect stress granule formation or RSV replication. Finally, using RNA probes specific for RSV genomic RNA, we found that viral RNA predominantly localized to viral inclusion bodies but a small percentage also interacted with stress granules during infection. These results suggest that RSV induces a host stress granule response and preferentially replicates in host cells that have committed to a stress response.
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Reineke, Lucas C., Jon D. Dougherty, Philippe Pierre, and Richard E. Lloyd. "Large G3BP-induced granules trigger eIF2α phosphorylation." Molecular Biology of the Cell 23, no. 18 (September 15, 2012): 3499–510. http://dx.doi.org/10.1091/mbc.e12-05-0385.
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Stress granules are large messenger ribonucleoprotein (mRNP) aggregates composed of translation initiation factors and mRNAs that appear when the cell encounters various stressors. Current dogma indicates that stress granules function as inert storage depots for translationally silenced mRNPs until the cell signals for renewed translation and stress granule disassembly. We used RasGAP SH3-binding protein (G3BP) overexpression to induce stress granules and study their assembly process and signaling to the translation apparatus. We found that assembly of large G3BP-induced stress granules, but not small granules, precedes phosphorylation of eIF2α. Using mouse embryonic fibroblasts depleted for individual eukaryotic initiation factor 2α (eIF2α) kinases, we identified protein kinase R as the principal kinase that mediates eIF2α phosphorylation by large G3BP-induced granules. These data indicate that increasing stress granule size is associated with a threshold or switch that must be triggered in order for eIF2α phosphorylation and subsequent translational repression to occur. Furthermore, these data suggest that stress granules are active in signaling to the translational machinery and may be important regulators of the innate immune response.
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Park, Ye-Jin, Dong Wook Choi, Sang Woo Cho, Jaeseok Han, Siyoung Yang, and Cheol Yong Choi. "Stress Granule Formation Attenuates RACK1-Mediated Apoptotic Cell Death Induced by Morusin." International Journal of Molecular Sciences 21, no. 15 (July 28, 2020): 5360. http://dx.doi.org/10.3390/ijms21155360.
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Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2α phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer.
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Xie, Wen, and Robert B. Denman. "Protein Methylation and Stress Granules: Posttranslational Remodeler or Innocent Bystander?" Molecular Biology International 2011 (February 24, 2011): 1–14. http://dx.doi.org/10.4061/2011/137459.
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Stress granules contain a large number of post-translationally modified proteins, and studies have shown that these modifications serve as recruitment tags for specific proteins and even control the assembly and disassembly of the granules themselves. Work originating from our laboratory has focused on the role protein methylation plays in stress granule composition and function. We have demonstrated that both asymmetrically and symmetrically dimethylated proteins are core constituents of stress granules, and we have endeavored to understand when and how this occurs. Here we seek to integrate this data into a framework consisting of the currently known post-translational modifications affecting stress granules to produce a model of stress granule dynamics that, in turn, may serve as a benchmark for understanding and predicting how post-translational modifications regulate other granule types.
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Van Treeck, Briana, David S. W. Protter, Tyler Matheny, Anthony Khong, Christopher D. Link, and Roy Parker. "RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome." Proceedings of the National Academy of Sciences 115, no. 11 (February 26, 2018): 2734–39. http://dx.doi.org/10.1073/pnas.1800038115.
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Stress granules are higher order assemblies of nontranslating mRNAs and proteins that form when translation initiation is inhibited. Stress granules are thought to form by protein–protein interactions of RNA-binding proteins. We demonstrate RNA homopolymers or purified cellular RNA forms assemblies in vitro analogous to stress granules. Remarkably, under conditions representative of an intracellular stress response, the mRNAs enriched in assemblies from total yeast RNA largely recapitulate the stress granule transcriptome. We suggest stress granules are formed by a summation of protein–protein and RNA–RNA interactions, with RNA self-assembly likely to contribute to other RNP assemblies wherever there is a high local concentration of RNA. RNA assembly in vitro is also increased by GR and PR dipeptide repeats, which are known to increase stress granule formation in cells. Since GR and PR dipeptides are involved in neurodegenerative diseases, this suggests that perturbations increasing RNA–RNA assembly in cells could lead to disease.
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Dong, Xiuqin, Sheng Wang, and Zhongfeng Geng. "CFD Simulation on Hydrodynamic Behaviors of Anaerobic Granule Swarms." Processes 7, no. 12 (November 26, 2019): 880. http://dx.doi.org/10.3390/pr7120880.
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An internal circulation (IC) anaerobic reactor is widely used in the treatment of municipal and industrial wastewater with high volumetric loading rates. The performance of an IC reactor is closely related with hydrodynamic behaviors of anaerobic granules. Typically, anaerobic granules work in swarms and the settling behavior of a granule is disturbed by other granules. However, the research on anaerobic granule swarms is insufficient. In this work, Computational Fluid Dynamics (CFD) method was employed to study the hydrodynamic behaviors of anaerobic granule swarms with various voidages. The simulated results showed that the average velocity inside granules increased significantly as the voidage of granule swarm decreased and as the Reynolds number increased. The maximum shear stress on the granule’s surface increased with decreasing voidage and increasing Reynolds number. Based on the hydrodynamic behaviors of anaerobic granule swarms, an improved model of drag force coefficient for granule swarms was developed. The predicted expanded height, using the improved model, gives better consistency with experimental results. The improved model can embed in CFD code to improve the precision of the description of the IC reactor model and provide valuable information for designing and operating an IC reactor.
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Fomicheva, Anastasia, and Eric D. Ross. "From Prions to Stress Granules: Defining the Compositional Features of Prion-Like Domains That Promote Different Types of Assemblies." International Journal of Molecular Sciences 22, no. 3 (January 27, 2021): 1251. http://dx.doi.org/10.3390/ijms22031251.
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Stress granules are ribonucleoprotein assemblies that form in response to cellular stress. Many of the RNA-binding proteins found in stress granule proteomes contain prion-like domains (PrLDs), which are low-complexity sequences that compositionally resemble yeast prion domains. Mutations in some of these PrLDs have been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia, and are associated with persistent stress granule accumulation. While both stress granules and prions are macromolecular assemblies, they differ in both their physical properties and complexity. Prion aggregates are highly stable homopolymeric solids, while stress granules are complex dynamic biomolecular condensates driven by multivalent homotypic and heterotypic interactions. Here, we use stress granules and yeast prions as a paradigm to examine how distinct sequence and compositional features of PrLDs contribute to different types of PrLD-containing assemblies.
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Singatulina, Anastasia S., Maria V. Sukhanova, Bénédicte Desforges, Vandana Joshi, David Pastré, and Olga I. Lavrik. "PARP1 Activation Controls Stress Granule Assembly after Oxidative Stress and DNA Damage." Cells 11, no. 23 (December 5, 2022): 3932. http://dx.doi.org/10.3390/cells11233932.
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DNA damage causes PARP1 activation in the nucleus to set up the machinery responsible for the DNA damage response. Here, we report that, in contrast to cytoplasmic PARPs, the synthesis of poly(ADP-ribose) by PARP1 opposes the formation of cytoplasmic mRNA-rich granules after arsenite exposure by reducing polysome dissociation. However, when mRNA-rich granules are pre-formed, whether in the cytoplasm or nucleus, PARP1 activation positively regulates their assembly, though without additional recruitment of poly(ADP-ribose) in stress granules. In addition, PARP1 promotes the formation of TDP-43- and FUS-rich granules in the cytoplasm, two RNA-binding proteins which form neuronal cytoplasmic inclusions observed in certain neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Together, the results therefore reveal a dual role of PARP1 activation which, on the one hand, prevents the early stage of stress granule assembly and, on the other hand, enables the persistence of cytoplasmic mRNA-rich granules in cells which may be detrimental in aging neurons.
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Dougherty, M. K., C. Saul, L. Carman, M. D. Nelson, and J. C. Tudor. "0028 Sleep Duration Influences the Kinetics of Stress Granule Formation." Sleep 43, Supplement_1 (April 2020): A11—A12. http://dx.doi.org/10.1093/sleep/zsaa056.027.
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Abstract Introduction Stress granules are non-membrane bound aggregates of messenger ribonucleoproteins that are biomarkers of cellular stress. It has been shown in cells in vitro that suppression of the mammalian target of rapamycin (mTOR) pathway and its non-mammalian orthologue target of rapamycin (TOR) is associated with an increase in stress granule formation. It has also been shown that the mTOR pathway is suppressed in response to sleep deprivation in mice. Despite the possible connection via the TOR/mTOR pathway, there has not been any previous evidence linking sleep deprivation with stress granule formation. Methods Our present investigation uses the nematode Caenorhabditis elegans to model how stress granule formation and clearance are modified by sleep duration. We developed novel strains of C. elegans that model each type of sleep deprivation or enhancement and have RFP-labeled PAB-1 protein, a key component of stress granules. In addition to modifying sleep duration via genetic means, we also sleep deprived wildtype fluorescently labeled animals using mechanical disturbances. Results Animals with enhanced stress-induced sleep have stress granules that are smaller in size and cleared faster than wildtype, while sleep deprived animals have granules that are slower to clear (F11,473 = 7.752, ***p < 0.0001, one-way ANOVA). Animals that were manually deprived of stress-induced sleep were similarly slower to clear stress granules (F5,209 = 5.476 ***p < 0.0001, one-way ANOVA). Interestingly, animals genetically deprived of developmentally-timed sleep does not appear to have more stress granules in the middle of their sleep period than the sleeping wildtype stage (F2,42 = 2.659, p = 0.0729, one-way ANOVA). Conclusion This work demonstrates that the amount of sleep affects stress granule kinetics, which impacts the flow of genetic information inside cells. Support This work was supported by an R15GM122058 (NIH), John P. McNulty scholars program (SJU) and summer scholars program (SJU).
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Dang, Yongjun, Nancy Kedersha, Woon-Kai Low, Daniel Romo, Myriam Gorospe, Randal Kaufman, Paul Anderson, and Jun O. Liu. "Eukaryotic Initiation Factor 2α-independent Pathway of Stress Granule Induction by the Natural Product Pateamine A." Journal of Biological Chemistry 281, no. 43 (September 2, 2006): 32870–78. http://dx.doi.org/10.1074/jbc.m606149200.
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Stress granules are aggregates of small ribosomal subunits, mRNA, and numerous associated RNA-binding proteins that include several translation initiation factors. Stress granule assembly occurs in the cytoplasm of higher eukaryotic cells under a wide variety of stress conditions, including heat shock, UV irradiation, hypoxia, and exposure to arsenite. Thus far, a unifying principle of eukaryotic initiation factor 2α phosphorylation prior to stress granule formation has been observed from the majority of experimental evidence. Pateamine A, a natural product isolated from marine sponge, was recently reported to inhibit eukaryotic translation initiation and induce the formation of stress granules. In this report, the protein composition and fundamental progression of stress granule formation and disassembly induced by pateamine A was found to be similar to that for arsenite. However, pateamine A-induced stress granules were more stable and less prone to disassembly than those formed in the presence of arsenite. Most significantly, pateamine A induced stress granules independent of eukaryotic initiation factor 2α phosphorylation, suggesting an alternative mechanism of formation from that previously described for other cellular stresses. Taking into account the known inhibitory effect of pateamine A on eukaryotic translation initiation, a model is proposed to account for the induction of stress granules by pateamine A as well as other stress conditions through perturbation of any steps prior to the rejoining of the 60S ribosomal subunit during the entire translation initiation process.
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Boncella, Amy E., Jenifer E. Shattuck, Sean M. Cascarina, Kacy R. Paul, Matthew H. Baer, Anastasia Fomicheva, Andrew K. Lamb, and Eric D. Ross. "Composition-based prediction and rational manipulation of prion-like domain recruitment to stress granules." Proceedings of the National Academy of Sciences 117, no. 11 (March 3, 2020): 5826–35. http://dx.doi.org/10.1073/pnas.1912723117.
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Mutations in a number of stress granule-associated proteins have been linked to various neurodegenerative diseases. Several of these mutations are found in aggregation-prone prion-like domains (PrLDs) within these proteins. In this work, we examine the sequence features governing PrLD localization to stress granules upon stress. We demonstrate that many yeast PrLDs are sufficient for stress-induced assembly into microscopically visible foci that colocalize with stress granule markers. Additionally, compositional biases exist among PrLDs that assemble upon stress, and these biases are consistent across different stressors. Using these biases, we have developed a composition-based prediction method that accurately predicts PrLD assembly into foci upon heat shock. We show that compositional changes alter PrLD assembly behavior in a predictable manner, while scrambling primary sequence has little effect on PrLD assembly and recruitment to stress granules. Furthermore, we were able to design synthetic PrLDs that were efficiently recruited to stress granules, and found that aromatic amino acids, which have previously been linked to PrLD phase separation, were dispensable for this recruitment. These results highlight the flexible sequence requirements for stress granule recruitment and suggest that PrLD localization to stress granules is driven primarily by amino acid composition, rather than primary sequence.
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Davis, Michael, Andrea Montalbano, Megan P. Wood, and Jennifer A. Schisa. "Biphasic adaptation to osmotic stress in the C. elegans germ line." American Journal of Physiology-Cell Physiology 312, no. 6 (June 1, 2017): C741—C748. http://dx.doi.org/10.1152/ajpcell.00364.2016.
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Cells respond to environmental stress in multiple ways. In the germ line, heat shock and nutritive stress trigger the assembly of large ribonucleoprotein (RNP) granules via liquid-liquid phase separation (LLPS). The RNP granules are hypothesized to maintain the quality of oocytes during stress. The goal of this study was to investigate the cellular response to glucose in the germ line and determine if it is an osmotic stress response. We found that exposure to 500 mM glucose induces the assembly of RNP granules in the germ line within 1 h. Interestingly, the RNP granules are maintained for up to 3 h; however, they dissociate after longer periods of stress. The RNP granules include processing body and stress granule proteins, suggesting shared functions. Based on several lines of evidence, the germ line response to glucose largely appears to be an osmotic stress response, thus identifying osmotic stress as a trigger of LLPS. Although RNP granules are not maintained beyond 3 h of osmotic stress, the quality of oocytes does not appear to decrease after longer periods of stress, suggesting a secondary adaptation in the germ line. We used an indirect marker of glycerol and observed high levels after 5 and 20 h of glucose exposure. Moreover, in gpdh-1;gpdh-2 germ lines, glycerol levels are reduced concomitant with RNP granules being maintained for an extended period. We speculate that increased glycerol levels may function as a secondary osmoregulatory adaptive response in the germ line, following a primary response of RNP granule assembly.
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Takahara, Terunao, and Tatsuya Maeda. "Stress granules." Cell Cycle 11, no. 20 (September 14, 2012): 3707–8. http://dx.doi.org/10.4161/cc.22044.
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Anderson, Paul, and Nancy Kedersha. "Stress granules." Current Biology 19, no. 10 (May 2009): R397—R398. http://dx.doi.org/10.1016/j.cub.2009.03.013.
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Tomimoto, Naofumi, Teruaki Takasaki, and Reiko Sugiura. "Ar s enite treatment induces Hsp90 aggregates distinct from conventional stress granules in fission yeast." Microbial Cell 11 (July 19, 2024): 242–53. http://dx.doi.org/10.15698/mic2024.07.829.
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Abstract Various stress conditions, such as heat stress (HS) and oxidative stress, can cause biomolecular condensates represented by stress granules (SGs) via liquid-liquid phase separation. We have previously shown that Hsp90 forms aggregates in response to HS and that Hsp90 aggregates transiently co-localize with SGs as visualized by Pabp. Here, we showed that arsenite, one of the well-described SG-inducing stimuli, induces Hsp90 aggregates distinct from conventional SGs in fission yeast. Arsenite induced Hsp90 granules in a dose-dependent manner, and these granules were significantly diminished by the co-treatment with a ROS scavenger N-acetyl cysteine (NAC), indicating that ROS are required for the formation of Hsp90 granules upon arsenite stress. Notably, Hsp90 granules induced by arsenite do not overlap with conventional SGs as represented by eIF4G or Pabp, while HS-induced Hsp90 granules co-localize with SGs. Nrd1, an RNA-binding protein known as a HS-induced SG component, was recruited into Hsp90 aggregates but not to the conventional SGs upon arsenite stress. The non-phosphorylatable eIF2α mutants significantly delayed the Hsp90 granule formation upon arsenite treatment. Importantly, inhibition of Hsp90 by geldanamycin impaired the Hsp90 granule formation and reduced the arsenite tolerance. Collectively, arsenite stimulates two types of distinct aggregates, namely conventional SGs and a novel type of aggregates containing Hsp90 and Nrd1, wherein Hsp90 plays a role as a center for aggregation, and stress-specific compartmentalization of biomolecular condensates.
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Perelman, Rebecca T., Andreas Schmidt, Umar Khan, and Nils G. Walter. "Spontaneous Confinement of mRNA Molecules at Biomolecular Condensate Boundaries." Cells 12, no. 18 (September 11, 2023): 2250. http://dx.doi.org/10.3390/cells12182250.
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Cellular biomolecular condensates, termed ribonucleoprotein (RNP) granules, are often enriched in messenger RNA (mRNA) molecules relative to the surrounding cytoplasm. Yet, the spatial localization and diffusion of mRNAs in close proximity to phase separated RNP granules are not well understood. In this study, we performed single-molecule fluorescence imaging experiments of mRNAs in live cells in the presence of two types of RNP granules, stress granules (SGs) and processing bodies (PBs), which are distinct in their molecular composition and function. We developed a photobleaching- and noise-corrected colocalization imaging algorithm that was employed to determine the accurate positions of individual mRNAs relative to the granule’s boundaries. We found that mRNAs are often localized at granule boundaries, an observation consistent with recently published data. We suggest that mRNA molecules become spontaneously confined at the RNP granule boundary similar to the adsorption of polymer molecules at liquid–liquid interfaces, which is observed in various technological and biological processes. We also suggest that this confinement could be due to a combination of intermolecular interactions associated with, first, the screening of a portion of the RNP granule interface by the polymer and, second, electrostatic interactions due to a strong electric field induced by a Donnan potential generated across the thin interface.
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Moon, Sungjin, and Sim Namkoong. "Ribonucleoprotein Granules: Between Stress and Transposable Elements." Biomolecules 13, no. 7 (June 23, 2023): 1027. http://dx.doi.org/10.3390/biom13071027.
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Transposable elements (TEs) are DNA sequences that can transpose and replicate within the genome, leading to genetic changes that affect various aspects of host biology. Evolutionarily, hosts have also developed molecular mechanisms to suppress TEs at the transcriptional and post-transcriptional levels. Recent studies suggest that stress-induced formation of ribonucleoprotein (RNP) granules, including stress granule (SG) and processing body (P-body), can play a role in the sequestration of TEs to prevent transposition, suggesting an additional layer of the regulatory mechanism for TEs. RNP granules have been shown to contain factors involved in RNA regulation, including mRNA decay enzymes, RNA-binding proteins, and noncoding RNAs, which could potentially contribute to the regulation of TEs. Therefore, understanding the interplay between TEs and RNP granules is crucial for elucidating the mechanisms for maintaining genomic stability and controlling gene expression. In this review, we provide a brief overview of the current knowledge regarding the interplay between TEs and RNP granules, proposing RNP granules as a novel layer of the regulatory mechanism for TEs during stress.
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Gwon, Youngdae, Brian A. Maxwell, Regina-Maria Kolaitis, Peipei Zhang, Hong Joo Kim, and J. Paul Taylor. "Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner." Science 372, no. 6549 (June 24, 2021): eabf6548. http://dx.doi.org/10.1126/science.abf6548.
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Stress granules are dynamic, reversible condensates composed of RNA and protein that assemble in eukaryotic cells in response to a variety of stressors and are normally disassembled after stress is removed. The composition and assembly of stress granules is well understood, but little is known about the mechanisms that govern disassembly. Impaired disassembly has been implicated in some diseases including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Using cultured human cells, we found that stress granule disassembly was context-dependent: Specifically in the setting of heat shock, disassembly required ubiquitination of G3BP1, the central protein within the stress granule RNA-protein network. We found that ubiquitinated G3BP1 interacted with the endoplasmic reticulum–associated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP (valosin-containing protein). Thus, targeting of G3BP1 weakened the stress granule–specific interaction network, resulting in granule disassembly.
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Moradifar, R., A. Rahi, M. H. Kadivar, F. Eslami, and S. Salimi. "The Mechanical Strength of Granular Sulphur and its Relation to Size Distribution and Storage Silo Clogging." Applied Mechanics and Materials 110-116 (October 2011): 83–90. http://dx.doi.org/10.4028/www.scientific.net/amm.110-116.83.
Full textAbstract:
The purpose of this study was to investigate the effect of particle size distribution on the mechanical properties of granular sulphur and its relation to silo blockage at South Pars Gas Complex Phases 2 & 3. Solid elemental sulphur is a relatively hard, friable crystalline material that tends to break up into smaller particles when subjected to force or stress of any magnitude. Conglomeration of the dust so produced clogs storage silos, making truck loading difficult. Grain size selection is based on the “friability value” and “maximum entropy” for granules in a static state. The model of the behavior of confined granular sulphur is based on the principle of continuum mechanics. Granules were formed by feeding liquid sulphur and water to a rotating granulation drum. Sample granules were classified into different size fractions (300 μm – 4.75 mm) by sieve analysis, and friability tests were done by the Fines 28-inch tumbler S5-77 test. Friability and granule size data collected over four years were studied. The implication of field analysis and laboratory tests is that the granule size should be controlled during sulphur solidification while ensuring that only granular material with the correct mechanical characteristics is stored in the silo and shipped.
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Zhang, Xue, Fengchao Wang, Yi Hu, Runze Chen, Dawei Meng, Liang Guo, Hailong Lv, Jisong Guan, and Yichang Jia. "In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model." Brain 143, no. 5 (May 1, 2020): 1350–67. http://dx.doi.org/10.1093/brain/awaa076.
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Abstract Many RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.
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Heberle, Alexander Martin, Patricia Razquin Navas, Miriam Langelaar-Makkinje, Katharina Kasack, Ahmed Sadik, Erik Faessler, Udo Hahn, et al. "The PI3K and MAPK/p38 pathways control stress granule assembly in a hierarchical manner." Life Science Alliance 2, no. 2 (March 28, 2019): e201800257. http://dx.doi.org/10.26508/lsa.201800257.
Full textAbstract:
All cells and organisms exhibit stress-coping mechanisms to ensure survival. Cytoplasmic protein-RNA assemblies termed stress granules are increasingly recognized to promote cellular survival under stress. Thus, they might represent tumor vulnerabilities that are currently poorly explored. The translation-inhibitory eIF2α kinases are established as main drivers of stress granule assembly. Using a systems approach, we identify the translation enhancers PI3K and MAPK/p38 as pro-stress-granule-kinases. They act through the metabolic master regulator mammalian target of rapamycin complex 1 (mTORC1) to promote stress granule assembly. When highly active, PI3K is the main driver of stress granules; however, the impact of p38 becomes apparent as PI3K activity declines. PI3K and p38 thus act in a hierarchical manner to drive mTORC1 activity and stress granule assembly. Of note, this signaling hierarchy is also present in human breast cancer tissue. Importantly, only the recognition of the PI3K-p38 hierarchy under stress enabled the discovery of p38’s role in stress granule formation. In summary, we assign a new pro-survival function to the key oncogenic kinases PI3K and p38, as they hierarchically promote stress granule formation.
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Ripin, Nina, and Roy Parker. "Are stress granules the RNA analogs of misfolded protein aggregates?" RNA 28, no. 1 (October 20, 2021): 67–75. http://dx.doi.org/10.1261/rna.079000.121.
Full textAbstract:
Ribonucleoprotein granules are ubiquitous features of eukaryotic cells. Several observations argue that the formation of at least some RNP granules can be considered analogous to the formation of unfolded protein aggregates. First, unfolded protein aggregates form from the exposure of promiscuous protein interaction surfaces, while some mRNP granules form, at least in part, by promiscuous intermolecular RNA–RNA interactions due to exposed RNA surfaces when mRNAs are not engaged with ribosomes. Second, analogous to the role of protein chaperones in preventing misfolded protein aggregation, cells contain abundant “RNA chaperones” to limit inappropriate RNA–RNA interactions and prevent mRNP granule formation. Third, analogous to the role of protein aggregates in diseases, situations where RNA aggregation exceeds the capacity of RNA chaperones to disaggregate RNAs may contribute to human disease. Understanding that RNP granules can be considered as promiscuous, reversible RNA aggregation events allow insight into their composition and how cells have evolved functions for RNP granules.
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Kimball, Scot R., Rick L. Horetsky, David Ron, Leonard S. Jefferson, and Heather P. Harding. "Mammalian stress granules represent sites of accumulation of stalled translation initiation complexes." American Journal of Physiology-Cell Physiology 284, no. 2 (February 1, 2003): C273—C284. http://dx.doi.org/10.1152/ajpcell.00314.2002.
Full textAbstract:
In eukaryotic cells subjected to environmental stress, untranslated mRNA accumulates in discrete cytoplasmic foci that have been termed stress granules. Recent studies have shown that in addition to mRNA, stress granules also contain 40S ribosomal subunits and various translation initiation factors, including the mRNA binding proteins eIF4E and eIF4G. However, eIF2, the protein that transfers initiator methionyl-tRNAi(Met-tRNAi) to the 40S ribosomal subunit, has not been detected in stress granules. This result is surprising because the eIF2 · GTP · Met-tRNAi complex is thought to bind to the 40S ribosomal subunit before the eIF4G · eIF4E · mRNA complex. In the present study, we show in both NIH-3T3 cells and mouse embryo fibroblasts that stress granules contain not only eIF2 but also the guanine nucleotide exchange factor for eIF2, eIF2B. Moreover, we show that phosphorylation of the α-subunit of eIF2 is necessary and sufficient for stress granule formation during the unfolded protein response. Finally, we also show that stress granules contain many, if not all, of the components of the 48S preinitiation complex, but not 60S ribosomal subunits, suggesting that they represent stalled translation initiation complexes.
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Liu, Jia, and Grant McFadden. "SAMD9 Is an Innate Antiviral Host Factor with Stress Response Properties That Can Be Antagonized by Poxviruses." Journal of Virology 89, no. 3 (November 26, 2014): 1925–31. http://dx.doi.org/10.1128/jvi.02262-14.
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We show that SAMD9 is an innate host antiviral stress response element that participates in the formation of antiviral granules. Poxviruses, myxoma virus and vaccinia virus specifically, utilize a virus-encoded host range factor(s), such as a member of the C7L superfamily, to antagonize SAMD9 to prevent granule formation in a eukaryotic initiation factor 2α (eIF2α)-independent manner. When SAMD9 is stimulated due to failure of the viral antagonism during infection, the resulting antiviral granules exhibit properties different from those of the canonical stress granules.
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Kim, Yeonju, Jaecheul Yu, Soyeon Jeong, Jeongmi Kim, Seongjae Park, Hyokwan Bae, Sung-Keun Rhee, Tatsuya Unno, Shou-Qing Ni, and Taeho Lee. "Differences in the Effects of Calcium and Magnesium Ions on the Anammox Granular Properties to Alleviate Salinity Stress." Applied Sciences 12, no. 1 (December 21, 2021): 19. http://dx.doi.org/10.3390/app12010019.
Full textAbstract:
Divalent cations were known to alleviate salinity stress on anammox bacteria. Understanding the mechanism of reducing the salinity stress on anammox granules is essential for the application of the anammox process for saline wastewater treatment. In this study, the effect of Ca2+ and Mg2+ augmentation on the recovery of the activity of freshwater anammox granules affected by salinity stress was evaluated. At the condition of a salinity stress of 5 g NaCl/L, the specific anammox activity (SAA) of the granule decreased to 50% of that of the SAA without NaCl treatment. Augmentation of Ca2+ at the optimum concentration of 200 mg/L increased the SAA up to 78% of the original activity, while the augmentation of Mg2+ at the optimum concentration of 70 mg/L increased the SAA up to 71%. EPS production in the granules was increased by the augmentation of divalent cations compared with the granules affected by salinity stress. In the soluble EPS, the ratio of protein to polysaccharides was higher in the granules augmented by Ca2+ than with Mg2+, and the functional groups of the EPS differed from each other. The amount of Na+ sequestered in the soluble EPS was increased by the augmentation of divalent cations, which seems to contribute to the alleviation of salinity stress. Ca. Kuenenia-like anammox bacteria, which were known to be salinity stress-tolerant, were predominant in the granules and there was no significant difference in the microbial community of the granules by the salinity stress treatment. Our results suggest that the alleviation effect of the divalent cations on the salinity stress on the anammox granules might be associated with the increased production of different EPS rather than in changes to the anammox bacteria.
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Shin, H. S., K. H. Lim, and H. S. Park. "Effect of Shear Stress on Granulation in Oxygen Aerobic Upflow Sludge Bed Reactors." Water Science and Technology 26, no. 3-4 (August 1, 1992): 601–5. http://dx.doi.org/10.2166/wst.1992.0440.
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Aerobic upflow sludge blanket(AUSB) process is a new biological wastewater treatment method applying the concept of the self-immobilization to activated sludge. Two sets of AUSB system with different mixing velocities of 3 rpm(R1) and 6 rpm(R2) were operated for high-rate treatment of synthetic wastewater. The COD removal efficiency in R2 was higher than R1 at the same loading rate up to 7 kg/m3·day. However, in R1, the sludge bulking was observed at the end of the experiment. The chocolate colored granules were formed about 5 days after the start-up. The morphological study on the granular sludge consortia was made with both scanning electron and optical microscopes. The granules were 0.5-2.5 mm in diameter and mainly consisted of bacteria with pili-like appendages and filamentous bacteria, which were thought to be Sphaerotilus natans and Beggiatoa. In R1, the long multicellular filaments causing bulking were prevalent in the granule, while in R2 overgrowth of filamentous bacteria was prevented with appropriate shear stress resulting in higher MLSS density. Experimental results indicated that granulation could be controlled by physical stress on granular sludge.
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Chadwick, Benjamin J., Brittain Elizabeth Ross, and Xiaorong Lin. "Molecular Dissection of Crz1 and Its Dynamic Subcellular Localization in Cryptococcus neoformans." Journal of Fungi 9, no. 2 (February 14, 2023): 252. http://dx.doi.org/10.3390/jof9020252.
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Across lower eukaryotes, the transcription factor Crz1 is dephosphorylated by calcineurin, which facilitates Crz1 translocation to the nucleus to regulate gene expression. In the fungal pathogen Cryptococcus neoformans, calcineurin–Crz1 signaling maintains calcium homeostasis, thermotolerance, cell wall integrity, and morphogenesis. How Crz1 distinguishes different stressors and differentially regulates cellular responses is poorly understood. Through monitoring Crz1 subcellular localization over time, we found that Crz1 transiently localizes to granules after exposure to high temperature or calcium. These granules also host the phosphatase calcineurin and Pub1, a ribonucleoprotein stress granule marker, suggesting a role of stress granules in modulating calcineurin–Crz1 signaling. Additionally, we constructed and analyzed an array of Crz1 truncation mutants. We identified the intrinsically disordered regions in Crz1 contribute to proper stress granule localization, nuclear localization, and function. Our results provide the groundwork for further determination of the mechanisms behind the complex regulation of Crz1.
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Pevere, A., P. d'Abzac, E. van Hullebusch, P. N. L. Lens, and G. Guibaud. "Effect of substrate feeding on viscosity evolution of anaerobic granular sludges." Water Science and Technology 62, no. 1 (July 1, 2010): 132–39. http://dx.doi.org/10.2166/wst.2010.286.
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This work aims to describe the effect of the feeding regime of anaerobic activity tests on the limit viscosity (μlim) evolution of the granules. Batch experiments were performed with 3 different sources of substrate: acetate, peptone, and glucose. Despite, the substrate origin was shown to affect the μlim evolution of granules, no clear relationship was found between the μlim evolution, type of substrate and other granule physico-chemical characteristics (i.e. pH; % of Volatile Suspended Solid; concentration of exopolymeric substances, divalent cations, P and S). The origin of granules and the substrate feeding regime modify the surface shape of the granules and may change granule–granule interactions under a shear stress, thus affecting the evolution of the μlim value during long term reactor operation.
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Biancon, Giulia, Poorval Joshi, Joshua T. Zimmer, Torben Hunck, Yimeng Gao, Mark D. Lessard, Edward Courchaine, et al. "U2AF1 Mutations Enhance Stress Granule Response in Myeloid Malignancies." Blood 138, Supplement 1 (November 5, 2021): 321. http://dx.doi.org/10.1182/blood-2021-149618.
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Abstract Somatic mutations in splicing factor genes are drivers of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The splicing factors U2AF1 and U2AF2 form the U2AF heterodimer that is critical in the 3' splice site (3'SS) recognition and in the recruitment of U2 small nuclear ribonucleoproteins for the activation of the spliceosome complex. U2AF1 carries hotspot mutations in its two RNA binding motifs; yet the molecular mechanisms affecting the splicing process and promoting clonal advantage remain unclear, albeit necessary to develop effective targeted therapies. We applied a multi-omics approach comparing the activities of two U2AF1 mutants (S34F and Q157R) in MDS/AML cell lines and primary samples. Using a novel approach of fractionated enhanced crosslinking immunoprecipitation coupled with deep RNA-sequencing (freCLIP-seq), we mapped transcriptome-wide binding at nucleotide resolution and we identified conformational changes in mutant vs wild-type U2AF1 binding. Specifically, we observed an emergent peak in position -3 of the 3'SS for the S34F mutant and in position +1 for the Q157R mutant, matching the critical positions observed by differential splicing analysis on RNA-seq data. Altered U2AF1-RNA binding compromised U2AF2-RNA interactions, resulting predominantly in exon exclusion and intron retention. Combined binding-splicing analysis showed that while the Q157R mutant mainly exhibits loss of binding, the S34F mutant follows a gain-of-binding pattern, where splicing progression appears impaired by increased mutant binding. Functional analysis of genes affected by both binding and splicing alterations revealed that U2AF1 mutants alter RNA granule biology, affecting in particular stress granule-enriched transcripts and proteins. Stress granules are membrane-less cytoplasmic assemblies of RNAs and RNA binding proteins that improve cellular adaptation in response to stress conditions. Increased stress granule formation has been linked to tumorigenesis as a strategy exploited by cancer cells to regulate gene expression and signal transduction, enhancing their fitness under stress. To probe how aberrant binding and splicing of stress granule components affected stress granule biology, we assessed stress granule formation in U2AF1 mutant vs wild-type cells at steady state and after stress induction with sodium arsenite treatment. Immunofluorescent staining followed by confocal imaging demonstrated that U2AF1 mutations enhance stress granule formation upon arsenite stress in both cell lines and primary samples. RNA turnover analysis by TimeLapse-seq confirmed that U2AF1 S34F and Q157R mutations promote stability/synthesis of transcripts that are enriched in stress granules and determine degradation/shutdown of transcripts that are depleted in stress granules, providing a molecular explanation for the increase in stress granules observed by imaging. Finally, we were able to corroborate our observations by single-cell RNA-seq in patient-derived U2AF1-mutant MDS blasts, establishing the causal link between U2AF1 mutations and upregulation of stress granule components. Collectively, this multi-omics analysis identified biological processes directly influenced by mutant U2AF1 binding and splicing, laying the foundation for a new paradigm where splicing factor mutations enhance stress granule formation by acting on the availability of their RNA and protein components. The enhanced formation of stress granules potentially fosters the stress adaptation of U2AF1-mutant cells, contributing to their clonal advantage in MDS/AML. Stress granule perturbations may therefore represent a novel therapeutic vulnerability in U2AF1-mutant MDS/AML patients and possibly in patients carrying other splicing factor mutations. Disclosures Hunck: Boehringer Ingelheim: Other: Fellowship.
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Brownsword, Matthew J., Nicole Doyle, Michèle Brocard, Nicolas Locker, and Helena J. Maier. "Infectious Bronchitis Virus Regulates Cellular Stress Granule Signaling." Viruses 12, no. 5 (May 14, 2020): 536. http://dx.doi.org/10.3390/v12050536.
Full textAbstract:
Viruses must hijack cellular translation machinery to express viral genes. In many cases, this is impeded by cellular stress responses. These stress responses result in the global inhibition of translation and the storage of stalled mRNAs, into RNA-protein aggregates called stress granules. This results in the translational silencing of the majority of mRNAs excluding those beneficial for the cell to resolve the specific stress. For example, the expression of antiviral factors is maintained during viral infection. Here we investigated stress granule regulation by Gammacoronavirus infectious bronchitis virus (IBV), which causes the economically important poultry disease, infectious bronchitis. Interestingly, we found that IBV is able to inhibit multiple cellular stress granule signaling pathways, whilst at the same time, IBV replication also results in the induction of seemingly canonical stress granules in a proportion of infected cells. Moreover, IBV infection uncouples translational repression and stress granule formation and both processes are independent of eIF2α phosphorylation. These results provide novel insights into how IBV modulates cellular translation and antiviral stress signaling.
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Bryantsev, Anton L., Svetlana Yu Kurchashova, Sergey A. Golyshev, Vladimir Yu Polyakov, Herman F. Wunderink, Bart Kanon, Karina R. Budagova, Alexander E. Kabakov, and Harm H. Kampinga. "Regulation of stress-induced intracellular sorting and chaperone function of Hsp27 (HspB1) in mammalian cells." Biochemical Journal 407, no. 3 (October 12, 2007): 407–17. http://dx.doi.org/10.1042/bj20070195.
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In vitro, small Hsps (heat-shock proteins) have been shown to have chaperone function capable of keeping unfolded proteins in a form competent for Hsp70-dependent refolding. However, this has never been confirmed in living mammalian cells. In the present study, we show that Hsp27 (HspB1) translocates into the nucleus upon heat shock, where it forms granules that co-localize with IGCs (interchromatin granule clusters). Although heat-induced changes in the oligomerization status of Hsp27 correlate with its phosphorylation and nuclear translocation, Hsp27 phosphorylation alone is not sufficient for effective nuclear translocation of HspB1. Using firefly luciferase as a heat-sensitive reporter protein, we demonstrate that HspB1 expression in HspB1-deficient fibroblasts enhances protein refolding after heat shock. The positive effect of HspB1 on refolding is completely diminished by overexpression of Bag-1 (Bcl-2-associated athanogene), the negative regulator of Hsp70, consistent with the idea of HspB1 being the substrate holder for Hsp70. Although HspB1 and luciferase both accumulate in nuclear granules after heat shock, our results suggest that this is not related to the refolding activity of HspB1. Rather, granular accumulation may reflect a situation of failed refolding where the substrate is stored for subsequent degradation. Consistently, we found 20S proteasomes concentrated in nuclear granules of HspB1 after heat shock. We conclude that HspB1 contributes to an increased chaperone capacity of cells by binding unfolded proteins that are hereby kept competent for refolding by Hsp70 or that are sorted to nuclear granules if such refolding fails.
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Moujaber, Ossama, and Ursula Stochaj. "Cytoplasmic RNA Granules in Somatic Maintenance." Gerontology 64, no. 5 (2018): 485–94. http://dx.doi.org/10.1159/000488759.
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Cytoplasmic RNA granules represent subcellular compartments that are enriched in protein-bound RNA species. RNA granules are produced by evolutionary divergent eukaryotes, including yeast, mammals, and plants. The functions of cytoplasmic RNA granules differ widely. They are dictated by the cell type and physiological state, which in turn is determined by intrinsic cell properties and environmental factors. RNA granules provide diverse cellular functions. However, all of the granules contribute to aspects of RNA metabolism. This is exemplified by transcription, RNA storage, silencing, and degradation, as well as mRNP remodeling and regulated translation. Several forms of cytoplasmic mRNA granules are linked to normal physiological processes. For instance, they may coordinate protein synthesis and thereby serve as posttranscriptional “operons”. RNA granules also participate in cytoplasmic mRNA trafficking, a process particularly well understood for neurons. Many forms of RNA granules support the preservation of somatic cell performance under normal and stress conditions. On the other hand, severe insults or disease can cause the formation and persistence of RNA granules that contribute to cellular dysfunction, especially in the nervous system. Neurodegeneration and many other diseases linked to RNA granules are associated with aging. Nevertheless, information related to the impact of aging on the various types of RNA granules is presently very limited. This review concentrates on cytoplasmic RNA granules and their role in somatic cell maintenance. We summarize the current knowledge on different types of RNA granules in the cytoplasm, their assembly and function under normal, stress, or disease conditions. Specifically, we discuss processing bodies, neuronal granules, stress granules, and other less characterized cytoplasmic RNA granules. Our focus is primarily on mammalian and yeast models, because they have been critical to unravel the physiological role of various RNA granules. RNA granules in plants and pathogens are briefly described. We conclude our viewpoint by summarizing the emerging concepts for RNA granule biology and the open questions that need to be addressed in future studies.
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ErLin, Sun, Wei WenJie, Wang LiNing, Lu BingXin, Lei MingDe, Sun Yan, and Han RuiFa. "Musashi-1 maintains blood–testis barrier structure during spermatogenesis and regulates stress granule formation upon heat stress." Molecular Biology of the Cell 26, no. 10 (May 15, 2015): 1947–56. http://dx.doi.org/10.1091/mbc.e14-11-1497.
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In mouse testes, Musashi-1 (Msi-1) was predominantly expressed in the cytoplasm and nuclei of Sertoli cells. Here we demonstrate that knockdown of Msi-1 in Sertoli cells altered the levels and distribution of blood–testis barrier (BTB)-associated proteins. Moreover, Msi-1 knockdown in vivo disrupted BTB functional structure and spermatogenesis. In addition, we report a novel role of Msi-1 in regulating Sertoli cells survival following heat-induced injury. Endogenous Msi-1 protein in heat-treated Sertoli cells was recruited to stress granules. The formation of stress granules was considerably disrupted, and apoptosis was significantly up-regulated in Msi-1–knockdown Sertoli cells after heat treatment. p-ERK1/2 acted downstream of stress granule formation, and inhibition of p-ERK1/2 signaling triggered Sertoli cell apoptosis upon heat stress. In conclusion, we demonstrate that Msi-1 is critical for constructing a functional BTB structure and maintaining spermatogenesis. We also note a role for Msi-1 in regulating Sertoli cell fate following heat-induced injury, likely through the induction of stress granule formation and subsequent activation of p-ERK1/2 signaling.
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Drake, Kyle D., Emily Formato, and Leonard Zon. "Abstract A012: g3bp1-mediated stress granule formation drives melanoma initiation in zebrafish." Molecular Cancer Therapeutics 23, no. 11_Supplement (November 14, 2024): A012. http://dx.doi.org/10.1158/1538-8514.rnadrivers24-a012.
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Abstract Stress granules confer cancer cells the ability to withstand harsh biological conditions and impart tumorigenic translational states through mRNA sequestration. Despite advances in in vitro knowledge, mechanistic understanding of the endogenous influence of stress granules during tumorigenesis in vivo remains understudied. To address this, we use a zebrafish melanoma model where oncogenic human BRAF V600E is driven by the melanocyte master regulator mitfa in a p53 -/- background. Through vector-based genetic engineering, endogenous melanoma induction in these zebrafish can be developmentally staged from single cell to tumor. BRAF V600E ::p53 -/- melanocytes form a cancerized field (CF), from which a subset upregulate the melanocyte master regulator mitfa, creating a cancer precursor zone (CPZ). Transformation of CPZ cells to an embryonic, neural crest-like state facilitates their formation of an early tumor patch that inevitable develops into an overt tumor. Single cell RNAseq analysis of cells representing each melanoma stage showed that CPZ cells upregulate core stress granule markers, including g3bp1, tia1, tia1l, and nufip2. Immunostaining of g3bp1 in CF, CPZ, patch, and tumor cells revealed a significant induction of stress granules from the CF to CPZ transition (2 vs 10 stress granules/cell; N=3; p=0.034) that persists during the patch and tumor stage, indicating cell stress accompanies melanoma initiation and progression. Genetic disruption of g3bp1 through cell autonomous, melanocyte-specific CRISPR editing in zebrafish (N=10-13) causes delayed CPZ onset (P=0.012) and fewer CPZs to form (P=0.021). In turn, g3bp1-edited zebrafish have delayed tumor formation (P=0.026) and develop fewer tumors (P=0.006). To decipher the RNAs sequestered by stress granules during melanomagenesis, we performed RIPseq for G3BP1 in human A375 melanoma cells stressed with sodium arsenite. RNAs significantly bound to G3BP1 upon stress induction include major tumor suppressors, such as CDKN2A, RBM5, BIK, and RHOB. Together, these results suggest that endogenous g3bp1-mediated stress granule formation in melanoma initiating cells is tumorigenic in vivo and operates through the sequestration of tumor suppressive RNAs. Citation Format: Kyle D Drake, Emily Formato, Leonard Zon. g3bp1-mediated stress granule formation drives melanoma initiation in zebrafish [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A012.
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Byun, Wan Gi, Jihye Lee, Seungtaek Kim, and Seung Bum Park. "Harnessing stress granule formation by small molecules to inhibit the cellular replication of SARS-CoV-2." Chemical Communications 57, no. 93 (2021): 12476–79. http://dx.doi.org/10.1039/d1cc05508a.
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Small-molecule enhancers of cellular stress granules were identified by observing molecular crowding of proteins and RNAs in a time-dependent manner. Hit molecules inhibited the replication of SARS-CoV-2 by inducing stress granule formation.
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Khong, Anthony, Tyler Matheny, Saumya Jain, Sarah F. Mitchell, Joshua R. Wheeler, and Roy Parker. "The Stress Granule Transcriptome Reveals Principles of mRNA Accumulation in Stress Granules." Molecular Cell 68, no. 4 (November 2017): 808–20. http://dx.doi.org/10.1016/j.molcel.2017.10.015.
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An, Haiyan, and Tatyana A. Shelkovnikova. "Stress granules regulate paraspeckles: RNP granule continuum at work." Cell Stress 3, no. 12 (December 9, 2019): 385–87. http://dx.doi.org/10.15698/cst2019.12.207.
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Bi, Shilin, Hua Lian, Huiya Zhang, Zexiang Liu, Yong Chen, and Jian Zhang. "Response of Anaerobic Granular Sludge Reactor to Plant Polyphenol Stress: Floc Disintegration and Microbial Inhibition." Fermentation 10, no. 5 (May 17, 2024): 262. http://dx.doi.org/10.3390/fermentation10050262.
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Plant polyphenols are potential inhibitors for the anaerobic treatment of wastewater from the wood processing, pharmaceutical, and leather industries. Tannic acid (TA) was selected as a model compound to assess the inhibitory effect of plant polyphenols in simulated wastewater in this study. The influences of TA on methanogenic activity, sludge morphology, and the microbial community were investigated under glucose and sodium acetate as carbon substrates, respectively. The results show that a threshold concentration of TA above 1500 mg·L−1 that triggers significant methanogenesis depression and volatile fatty acids (VFAs) accumulation. In addition, granules might be weakened by TA addition, reflected in changes in extracellular polymeric substances (EPS) within the granules and an increase in floc in the effluent. The anaerobic granular sludge (AnGS) fed with sodium acetate was more sensitive than the presence of glucose as the substrate when facing the challenge of TA. The concentration of the mcrA gene in granular sludge decreased markedly in response to TA stress, providing direct evidence that a high concentration of TA caused the inhibition of specific gene expressions. This study provides details about the adverse impacts of TA stress on methane production, the microbial community, and granule integrity, deepening our understanding of the anaerobic treatment of plant polyphenols contained in wastewater.
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Dontsov, Alexander, and Mikhail Ostrovsky. "Retinal Pigment Epithelium Pigment Granules: Norms, Age Relations and Pathology." International Journal of Molecular Sciences 25, no. 7 (March 23, 2024): 3609. http://dx.doi.org/10.3390/ijms25073609.
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The retinal pigment epithelium (RPE), which ensures the normal functioning of the neural retina, is a pigmented single-cell layer that separates the retina from the Bruch’s membrane and the choroid. There are three main types of pigment granules in the RPE cells of the human eye: lipofuscin granules (LG) containing the fluorescent “age pigment” lipofuscin, melanoprotein granules (melanosomes, melanolysosomes) containing the screening pigment melanin and complex melanolipofuscin granules (MLG) containing both types of pigments simultaneously—melanin and lipofuscin. This review examines the functional role of pigment granules in the aging process and in the development of oxidative stress and associated pathologies in RPE cells. The focus is on the process of light-induced oxidative degradation of pigment granules caused by reactive oxygen species. The reasons leading to increased oxidative stress in RPE cells as a result of the oxidative degradation of pigment granules are considered. A mechanism is proposed to explain the phenomenon of age-related decline in melanin content in RPE cells. The essence of the mechanism is that when the lipofuscin part of the melanolipofuscin granule is exposed to light, reactive oxygen species are formed, which destroy the melanin part. As more melanolipofuscin granules are formed with age and the development of degenerative diseases, the melanin in pigmented epithelial cells ultimately disappears.
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Abdul Qadir Rahimoon. ""ABOUT STRESS TRANSMISSION THROUGH DISORDERED MEDIA CONFINED IN SILO GEOMETRY "." Bulletin of Toraighyrov University. Physics & Mathematics series, no. 1.2022 (March 28, 2022): 48–57. http://dx.doi.org/10.48081/wnvy4031.
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"Granular materials are found everywhere around us. A fundamental understanding of the behaviour of these materials is bound to have profound economic benefits. To understand the macroscopic behaviour of granular media and its relationship with the microscopic properties are major objectives of granular mechanics. However, presently macroscopic equations are empiric because of the complexities at the microscopic level. Granular media exhibit properties that are different from those of solids, liquids and gas and much of their behavior has not been fully understood. In this paper a brief survey of Physics of confined granular media has been presented. This is accomplished by reviewing the experimental and theoretical work done to determine the properties of static granular media and concerning theories presented to explain the properties. The apparent mass measurement at the bottom of a granular pile confined in a vertical tube decreases for denser granular packing. The denser granular packing comprising of two different diameters of granules augment the apparent mass instead. This anomalous behavior occurs when small granules are stacked on the large ones. In the case of anomalous increase, a percolation effect is found and correlated with the augment of apparent mass at the bottom of granular column. "
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Dauber, Bianca, David Poon, Theodore dos Santos, Brett A. Duguay, Ninad Mehta, Holly A. Saffran, and James R. Smiley. "The Herpes Simplex Virus Virion Host Shutoff Protein Enhances Translation of Viral True Late mRNAs Independently of Suppressing Protein Kinase R and Stress Granule Formation." Journal of Virology 90, no. 13 (April 20, 2016): 6049–57. http://dx.doi.org/10.1128/jvi.03180-15.
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ABSTRACTThe herpes simplex virus (HSV) virion host shutoff (vhs) RNase destabilizes cellular and viral mRNAs, suppresses host protein synthesis, dampens antiviral responses, and stimulates translation of viral mRNAs. vhs mutants display a host range phenotype: translation of viral true late mRNAs is severely impaired and stress granules accumulate in HeLa cells, while translation proceeds normally in Vero cells. We found that vhs-deficient virus activates the double-stranded RNA-activated protein kinase R (PKR) much more strongly than the wild-type virus does in HeLa cells, while PKR is not activated in Vero cells, raising the possibility that PKR might play roles in stress granule induction and/or inhibiting translation in restrictive cells. We tested this possibility by evaluating the effects of inactivating PKR. Eliminating PKR in HeLa cells abolished stress granule formation but had only minor effects on viral true late protein levels. These results document an essential role for PKR in stress granule formation by a nuclear DNA virus, indicate that induction of stress granules is the consequence rather than the cause of the translational defect, and are consistent with our previous suggestion that vhs promotes translation of viral true late mRNAs by preventing mRNA overload rather than by suppressing eIF2α phosphorylation.IMPORTANCEThe herpes simplex virus vhs RNase plays multiple roles during infection, including suppressing PKR activation, inhibiting the formation of stress granules, and promoting translation of viral late mRNAs. A key question is the extent to which these activities are mechanistically connected. Our results demonstrate that PKR is essential for stress granule formation in the absence of vhs, but at best, it plays a secondary role in suppressing translation of viral mRNAs. Thus, the ability of vhs to promote translation of viral mRNAs can be largely uncoupled from PKR suppression, demonstrating that this viral RNase modulates at least two distinct aspects of RNA metabolism.
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Krüger, Timothy, Mario Hofweber, and Susanne Kramer. "SCD6 induces ribonucleoprotein granule formation in trypanosomes in a translation-independent manner, regulated by its Lsm and RGG domains." Molecular Biology of the Cell 24, no. 13 (July 2013): 2098–111. http://dx.doi.org/10.1091/mbc.e13-01-0068.
Full textAbstract:
Ribonucleoprotein (RNP) granules are cytoplasmic, microscopically visible structures composed of RNA and protein with proposed functions in mRNA decay and storage. Trypanosomes have several types of RNP granules, but lack most of the granule core components identified in yeast and humans. The exception is SCD6/Rap55, which is essential for processing body (P-body) formation. In this study, we analyzed the role of trypanosome SCD6 in RNP granule formation. Upon overexpression, the majority of SCD6 aggregates to multiple granules enriched at the nuclear periphery that recruit both P-body and stress granule proteins, as well as mRNAs. Granule protein composition depends on granule distance to the nucleus. In contrast to findings in yeast and humans, granule formation does not correlate with translational repression and can also take place in the nucleus after nuclear targeting of SCD6. While the SCD6 Lsm domain alone is both necessary and sufficient for granule induction, the RGG motif determines granule type and number: the absence of an intact RGG motif results in the formation of fewer granules that resemble P-bodies. The differences in granule number remain after nuclear targeting, indicating translation-independent functions of the RGG domain. We propose that, in trypanosomes, a local increase in SCD6 concentration may be sufficient to induce granules by recruiting mRNA. Proteins that bind selectively to the RGG and/or Lsm domain of SCD6 could be responsible for regulating granule type and number.
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Kim, Kyongmin. "RNA Granules and Stress Granules in Virus Systems." Journal of Bacteriology and Virology 42, no. 3 (2012): 247. http://dx.doi.org/10.4167/jbv.2012.42.3.247.
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