Artykuły w czasopismach: „Granule Disassembly”

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Gwon, Youngdae, Brian A. Maxwell, Regina-Maria Kolaitis, Peipei Zhang, Hong Joo Kim i J. Paul Taylor. "Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner". Science 372, nr 6549 (24.06.2021): 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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Jakobson, Christopher M., i Daniel F. Jarosz. "Metabolites control stress granule disassembly". Nature Cell Biology 23, nr 10 (październik 2021): 1053–55. http://dx.doi.org/10.1038/s41556-021-00768-w.

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Panas, Marc D., Pavel Ivanov i Paul Anderson. "Mechanistic insights into mammalian stress granule dynamics". Journal of Cell Biology 215, nr 3 (7.11.2016): 313–23. http://dx.doi.org/10.1083/jcb.201609081.

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The accumulation of stalled translation preinitiation complexes (PICs) mediates the condensation of stress granules (SGs). Interactions between prion-related domains and intrinsically disordered protein regions found in SG-nucleating proteins promote the condensation of ribonucleoproteins into SGs. We propose that PIC components, especially 40S ribosomes and mRNA, recruit nucleators that trigger SG condensation. With resolution of stress, translation reinitiation reverses this process and SGs disassemble. By cooperatively modulating the assembly and disassembly of SGs, ribonucleoprotein condensation can influence the survival and recovery of cells exposed to unfavorable environmental conditions.

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Dang, Yongjun, Nancy Kedersha, Woon-Kai Low, Daniel Romo, Myriam Gorospe, Randal Kaufman, Paul Anderson i Jun O. Liu. "Eukaryotic Initiation Factor 2α-independent Pathway of Stress Granule Induction by the Natural Product Pateamine A". Journal of Biological Chemistry 281, nr 43 (2.09.2006): 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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Xie, Wen, i Robert B. Denman. "Protein Methylation and Stress Granules: Posttranslational Remodeler or Innocent Bystander?" Molecular Biology International 2011 (24.02.2011): 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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Chen, Wenjun, Yabing Hu, Charles F. Lang, Jordan S. Brown, Sierra Schwabach, Xiaoyan Song, Ying Zhang i in. "The Dynamics of P Granule Liquid Droplets Are Regulated by the Caenorhabditis elegans Germline RNA Helicase GLH-1 via Its ATP Hydrolysis Cycle". Genetics 215, nr 2 (3.04.2020): 421–34. http://dx.doi.org/10.1534/genetics.120.303052.

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P granules are phase-separated liquid droplets that play important roles in the maintenance of germ cell fate in Caenorhabditis elegans. Both the localization and formation of P granules are highly dynamic, but mechanisms that regulate such processes remain poorly understood. Here, we show evidence that the VASA-like germline RNA helicase GLH-1 couples distinct steps of its ATPase hydrolysis cycle to control the formation and disassembly of P granules. In addition, we found that the phenylalanine-glycine-glycine repeats in GLH-1 promote its localization at the perinucleus. Proteomic analyses of the GLH-1 complex with a GLH-1 mutation that interferes with P granule disassembly revealed transient interactions of GLH-1 with several Argonautes and RNA-binding proteins. Finally, we found that defects in recruiting the P granule component PRG-1 to perinuclear foci in the adult germline correlate with the fertility defects observed in various GLH-1 mutants. Together, our results highlight the versatile roles of an RNA helicase in controlling the formation of liquid droplets in space and time.

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Hird, S. N., J. E. Paulsen i S. Strome. "Segregation of germ granules in living Caenorhabditis elegans embryos: cell-type-specific mechanisms for cytoplasmic localisation". Development 122, nr 4 (1.04.1996): 1303–12. http://dx.doi.org/10.1242/dev.122.4.1303.

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Germ granules are ribonucleoprotein particles that are thought to function in germline specification in invertebrates and possibly in vertebrates. In Caenorhabditis elegans, these structures, termed P granules, are partitioned to the germline P cells during the early embryonic divisions. By injecting a fluorescently labelled anti-P-granule antibody into the C. elegans germline syncitium, we followed P-granule segregation in live embryos using laser-scanning confocal microscopy. We show that, in early P cells (P0 and P1), P-granule partitioning is achieved primarily by their migration through the cytoplasm towards the site of formation of the germline daughter cell. A different mechanism appears to operate in later P cells (P2 and P3): P granules associate with the nucleus and move with it toward the site of formation of the germline daughter cell, where they are then deposited. At each division, there is also disassembly or degradation of those P granules that remain in the cytoplasm destined for the somatic daughter cell. Microfilaments, microtubules and the product of the gene mes-1 are required for the normal pattern of P-granule segregation in P2.

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Chandler, D. E., M. Whitaker i J. Zimmerberg. "High molecular weight polymers block cortical granule exocytosis in sea urchin eggs at the level of granule matrix disassembly." Journal of Cell Biology 109, nr 3 (1.09.1989): 1269–78. http://dx.doi.org/10.1083/jcb.109.3.1269.

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Recently, we have shown that high molecular weight polymers inhibit cortical granule exocytosis at total osmolalities only slightly higher than that of sea water (Whitaker, M., and J. Zimmerberg. 1987. J. Physiol. 389:527-539). In this study, we visualize the step at which this inhibition occurs. Lytechinus pictus and Strongylocentrotus purpuratus eggs were exposed to 0.8 M stachyose or 40% (wt/vol) dextran (average molecular mass of 10 kD) in artificial sea water, activated with 60 microM of the calcium ionophore A23187, and then either fixed with glutaraldehyde and embedded or quick-frozen and freeze-fractured. Stachyose (2.6 osmol/kg) appears to inhibit cortical granule exocytosis by eliciting formation of a granule-free zone (GFZ) in the egg cortex which pushes granules away from the plasma membrane thus preventing their fusion. In contrast, 40% dextran (1.58 osmol/kg) does not result in a GFZ and cortical granules undergo fusion. In some specimens, the pores joining granule and plasma membranes are relatively small; in other cases, the exocytotic pocket has been stabilized in an omega configuration and the granule matrix remains intact. These observations suggest that high molecular weight polymers block exocytosis because of their inability to enter the granule matrix: they retard the water entry that is needed for matrix dispersal.

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Maxwell, Brian A., Youngdae Gwon, Ashutosh Mishra, Junmin Peng, Haruko Nakamura, Ke Zhang, Hong Joo Kim i J. Paul Taylor. "Ubiquitination is essential for recovery of cellular activities after heat shock". Science 372, nr 6549 (24.06.2021): eabc3593. http://dx.doi.org/10.1126/science.abc3593.

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Eukaryotic cells respond to stress through adaptive programs that include reversible shutdown of key cellular processes, the formation of stress granules, and a global increase in ubiquitination. The primary function of this ubiquitination is thought to be for tagging damaged or misfolded proteins for degradation. Here, working in mammalian cultured cells, we found that different stresses elicited distinct ubiquitination patterns. For heat stress, ubiquitination targeted specific proteins associated with cellular activities that are down-regulated during stress, including nucleocytoplasmic transport and translation, as well as stress granule constituents. Ubiquitination was not required for the shutdown of these processes or for stress granule formation but was essential for the resumption of cellular activities and for stress granule disassembly. Thus, stress-induced ubiquitination primes the cell for recovery after heat stress.

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Hofmann, Sarah, Nancy Kedersha, Paul Anderson i Pavel Ivanov. "Molecular mechanisms of stress granule assembly and disassembly". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1868, nr 1 (styczeń 2021): 118876. http://dx.doi.org/10.1016/j.bbamcr.2020.118876.

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Reineke, Lucas C., Jon D. Dougherty, Philippe Pierre i Richard E. Lloyd. "Large G3BP-induced granules trigger eIF2α phosphorylation". Molecular Biology of the Cell 23, nr 18 (15.09.2012): 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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Williams, Erin R. "Turning off cellular stress". Science Signaling 12, nr 581 (14.05.2019): eaax9738. http://dx.doi.org/10.1126/scisignal.aax9738.

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Finnen, Renée L., Mingzhao Zhu, Jing Li, Daniel Romo i Bruce W. Banfield. "Herpes Simplex Virus 2 Virion Host Shutoff Endoribonuclease Activity Is Required To Disrupt Stress Granule Formation". Journal of Virology 90, nr 17 (22.06.2016): 7943–55. http://dx.doi.org/10.1128/jvi.00947-16.

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ABSTRACTWe previously established that cells infected with herpes simplex virus 2 (HSV-2) are disrupted in their ability to form stress granules (SGs) in response to oxidative stress and that this disruption is mediated by virion host shutoff protein (vhs), a virion-associated endoribonuclease. Here, we test the requirement for vhs endoribonuclease activity in disruption of SG formation. We analyzed the ability of HSV-2 vhs carrying the point mutation D215N, which ablates its endoribonuclease activity, to disrupt SG formation in both transfected and infected cells. We present evidence that ablation of vhs endoribonuclease activity results in defects in vhs-mediated disruption of SG formation. Furthermore, we demonstrate that preformed SGs can be disassembled by HSV-2 infection in a manner that requires vhs endoribonuclease activity and that, befitting this ability to promote SG disassembly, vhs is able to localize to SGs. Together these data indicate that endoribonuclease activity must be maintained in order for vhs to disrupt SG formation. We propose a model whereby vhs-mediated destruction of SG mRNA promotes SG disassembly and may also prevent SG assembly.IMPORTANCEStress granules (SGs) are transient cytoplasmic structures that form when a cell is exposed to stress. SGs are emerging as potential barriers to viral infection, necessitating a more thorough understanding of their basic biology. We identified virion host shutoff protein (vhs) as a herpes simplex virus 2 (HSV-2) protein capable of disrupting SG formation. As mRNA is a central component of SGs and the best-characterized activity of vhs is as an endoribonuclease specific for mRNAin vivo, we investigated the requirement for vhs endoribonuclease activity in disruption of SG formation. Our studies demonstrate that endoribonuclease activity is required for vhs to disrupt SG formation and, more specifically, that SG disassembly can be driven by vhs endoribonuclease activity. Notably, during the course of these studies we discovered that there is an ordered departure of SG components during their disassembly and, furthermore, that vhs itself has the capacity to localize to SGs.

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Liu, I.-Chun, Sheng-Wen Chiu, Hsin-Yi Lee i Jun-Yi Leu. "The histone deacetylase Hos2 forms an Hsp42-dependent cytoplasmic granule in quiescent yeast cells". Molecular Biology of the Cell 23, nr 7 (kwiecień 2012): 1231–42. http://dx.doi.org/10.1091/mbc.e11-09-0752.

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One of many physiological adjustments in quiescent cells is spatial regulation of specific proteins and RNA important for the entry to or exit from the stationary phase. By examining the localization of epigenetic-related proteins in Saccharomyces cerevisiae, we observed the formation of a reversible cytosolic “stationary-phase granule” (SPG) by Hos2, a nuclear histone deacetylase. In the stationary phase, hos2 mutants display reduced viability. Additionally, they exhibit a significant delay when recovering from stationary phase. Hos2 SPGs also contained Hst2, a Sir2 homologue, and several stress-related proteins, including Set3, Yca1, Hsp26, Hsp42, and some known components of stress granules. However, Hos2 SPG formation does not depend on the formation of stress granules or processing bodies. The absence or presence of glucose is sufficient to trigger assembly or disassembly of Hos2 SPGs. Among the identified components of Hos2 SPGs, Hsp42 is the first and last member observed in the Hos2 SPG assembly and disassembly processes. Hsp42 is also vital for the relocalization of the other components to Hos2 SPGs, suggesting that Hsp42 plays a central role in spatial regulation of proteins in quiescent cells.

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Castilla-Llorente, Virginia, i Andres Ramos. "PolyQ-mediated regulation of mRNA granules assembly". Biochemical Society Transactions 42, nr 4 (1.08.2014): 1246–50. http://dx.doi.org/10.1042/bst20140099.

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RNA granules have been observed in different organisms, cell types and under different conditions, and their formation is crucial for the mRNA life cycle. However, very little is known about the molecular mechanisms governing their assembly and disassembly. The aggregation-prone LSCRs (low-sequence-complexity regions), and in particular, the polyQ/N-rich regions, have been extensively studied under pathological conditions due to their role in neurodegenerative diseases. In the present review, we discuss recent in vitro, in vivo and computational data that, globally, suggest a role for polyQ/N regions in RNA granule assembly.

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Kotani, Tomoya, Kyota Yasuda, Ryoma Ota i Masakane Yamashita. "Cyclin B1 mRNA translation is temporally controlled through formation and disassembly of RNA granules". Journal of Cell Biology 202, nr 7 (23.09.2013): 1041–55. http://dx.doi.org/10.1083/jcb.201302139.

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Temporal control of messenger RNA (mRNA) translation is an important mechanism for regulating cellular, neuronal, and developmental processes. However, mechanisms that coordinate timing of translational activation remain largely unresolved. Full-grown oocytes arrest meiosis at prophase I and deposit dormant mRNAs. Of these, translational control of cyclin B1 mRNA in response to maturation-inducing hormone is important for normal progression of oocyte maturation, through which oocytes acquire fertility. In this study, we found that dormant cyclin B1 mRNA forms granules in the cytoplasm of zebrafish and mouse oocytes. Real-time imaging of translation revealed that the granules disassemble at the time of translational activation during maturation. Formation of cyclin B1 RNA granules requires binding of the mRNA to Pumilio1 protein and depends on actin filaments. Disruption of cyclin B1 RNA granules accelerated the timing of their translational activation after induction of maturation, whereas stabilization hindered translational activation. Thus, our results suggest that RNA granule formation is critical for the regulation of timing of translational activation.

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Saitoh, Atsushi, Yuki Takada, Mayu Horie i Tomoya Kotani. "Pumilio1 phosphorylation precedes translational activation of its target mRNA in zebrafish oocytes". Zygote 26, nr 5 (październik 2018): 372–80. http://dx.doi.org/10.1017/s0967199418000369.

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SummaryTranslational regulation of mRNAs is crucial for promoting various cellular and developmental processes. Pumilio1 (Pum1) has been shown to play key roles in translational regulation of target mRNAs in many systems of diverse organisms. In zebrafish immature oocytes, Pum1 was shown to bind to cyclin B1 mRNA and promote the formation of cyclin B1 RNA granules. This Pum1-mediated RNA granule formation seemed critical to determine the timing of translational activation of cyclin B1 mRNA during oocyte maturation, leading to activation of maturation/M-phase-promoting factor (MPF) at the appropriate timing. Despite its fundamental importance, the mechanisms of translational regulation by Pum1 remain elusive. In this study, we examined the phosphorylation of Pum1 as a first step to understand the mechanisms of Pum1-mediated translation. SDS-PAGE analyses and phosphatase treatments showed that Pum1 was phosphorylated at multiple sites during oocyte maturation. This phosphorylation began in an early period after induction of oocyte maturation, which preceded the polyadenylation of cyclin B1 mRNA. Interestingly, depolymerization of actin filaments in immature oocytes caused phosphorylation of Pum1, disassembly of cyclin B1 RNA granules, and polyadenylation of cyclin B1 mRNA but not translational activation of the mRNA. Overexpression of the Pum1 N-terminus prevented the phosphorylation of Pum1, disassembly of cyclin B1 RNA granules, and translational activation of the mRNA even after induction of oocyte maturation. These results suggest that Pum1 phosphorylation in the early period of oocyte maturation is one of the key processes for promoting the disassembly of cyclin B1 RNA granules and translational activation of target mRNA.

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Mazroui, Rachid, Sergio Di Marco, Randal J. Kaufman i Imed-Eddine Gallouzi. "Inhibition of the Ubiquitin-Proteasome System Induces Stress Granule Formation". Molecular Biology of the Cell 18, nr 7 (lipiec 2007): 2603–18. http://dx.doi.org/10.1091/mbc.e06-12-1079.

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The inhibition of the ubiquitin-dependent proteasome system (UPS) via specific drugs is one type of approach used to combat cancer. Although it has been suggested that UPS inhibition prevents the rapid decay of AU-rich element (ARE)-containing messages, very little is known about the cellular mechanisms leading to this effect. Here we establish a link between the inhibition of UPS activity, the formation of cytoplasmic stress granules (SGs), and mRNA metabolism. The assembly of the SGs requires the phosphorylation of the translation initiation factor eIF2α by a mechanism involving the stress kinase GCN2. On prolonged UPS inhibition and despite the maintenance of eIF2α phosphorylation, SGs disassemble and translation recovers in an Hsp72 protein-dependent manner. The formation of these SGs coincides with the disassembly of processing bodies (PBs), known as mRNA decay entities. As soon as the SGs assemble, they recruit ARE-containing messages such as p21cip1 mRNA, which are stabilized under these conditions. Hence, our findings suggest that SGs could be considered as one of the players that mediate the early response of the cell to proteasome inhibitors by interfering temporarily with mRNA decay pathways.

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Li, Chi Ho, Takbum Ohn, Pavel Ivanov, Sarah Tisdale i Paul Anderson. "eIF5A Promotes Translation Elongation, Polysome Disassembly and Stress Granule Assembly". PLoS ONE 5, nr 4 (1.04.2010): e9942. http://dx.doi.org/10.1371/journal.pone.0009942.

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Merkle, Carrie J., i Douglas E. Chandler. "Cortical granule matrix disassembly during exocytosis in sea urchin eggs". Developmental Biology 148, nr 2 (grudzień 1991): 429–41. http://dx.doi.org/10.1016/0012-1606(91)90262-2.

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Lee, Jason E., Peter I. Cathey, Haoxi Wu, Roy Parker i Gia K. Voeltz. "Endoplasmic reticulum contact sites regulate the dynamics of membraneless organelles". Science 367, nr 6477 (30.01.2020): eaay7108. http://dx.doi.org/10.1126/science.aay7108.

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Tethered interactions between the endoplasmic reticulum (ER) and other membrane-bound organelles allow for efficient transfer of ions and/or macromolecules and provide a platform for organelle fission. Here, we describe an unconventional interface between membraneless ribonucleoprotein granules, such as processing bodies (P-bodies, or PBs) and stress granules, and the ER membrane. We found that PBs are tethered at molecular distances to the ER in human cells in a tunable fashion. ER-PB contact and PB biogenesis were modulated by altering PB composition, ER shape, or ER translational capacity. Furthermore, ER contact sites defined the position where PB and stress granule fission occurs. We thus suggest that the ER plays a fundamental role in regulating the assembly and disassembly of membraneless organelles.

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Wöll, Stefan, Reinhard Windoffer i Rudolf E. Leube. "p38 MAPK-dependent shaping of the keratin cytoskeleton in cultured cells". Journal of Cell Biology 177, nr 5 (29.05.2007): 795–807. http://dx.doi.org/10.1083/jcb.200703174.

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Plasticity of the resilient keratin intermediate filament cytoskeleton is an important prerequisite for epithelial tissue homeostasis. Here, the contribution of stress-activated p38 MAPK to keratin network organization was examined in cultured cells. It was observed that phosphorylated p38 colocalized with keratin granules that were rapidly formed in response to orthovanadate. The same p38p recruitment was noted during mitosis, in various stress situations and in cells producing mutant keratins. In all these situations keratin 8 became phosphorylated on S73, a well-known p38 target site. To demonstrate that p38-dependent keratin phosphorylation determines keratin organization, p38 activity was pharmacologically and genetically modulated: up-regulation induced keratin granule formation, whereas down-regulation prevented keratin filament network disassembly. Furthermore, transient p38 inhibition also inhibited keratin filament precursor formation and mutant keratin granule dissolution. Collectively, the rapid and reversible effects of p38 activity on keratin phosphorylation and organization in diverse physiological, stress, and pathological situations identify p38-dependent signalling as a major intermediate filament–regulating pathway.

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McInerney, Gerald M., Nancy L. Kedersha, Randal J. Kaufman, Paul Anderson i Peter Liljeström. "Importance of eIF2α Phosphorylation and Stress Granule Assembly in Alphavirus Translation Regulation". Molecular Biology of the Cell 16, nr 8 (sierpień 2005): 3753–63. http://dx.doi.org/10.1091/mbc.e05-02-0124.

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Alphavirus infection results in the shutoff of host protein synthesis in favor of viral translation. Here, we show that during Semliki Forest virus (SFV) infection, the translation inhibition is largely due to the activation of the cellular stress response via phosphorylation of eukaryotic translation initiation factor 2α subunit (eIF2α). Infection of mouse embryo fibroblasts (MEFs) expressing a nonphosphorylatable mutant of eIF2α does not result in efficient shutoff, despite efficient viral protein production. Furthermore, we show that the SFV translation enhancer element counteracts the translation inhibition imposed by eIF2α phosphorylation. In wild-type MEFs, viral infection induces the transient formation of stress granules (SGs) containing the cellular TIA-1/R proteins. These SGs are disassembled in the vicinity of viral RNA replication, synchronously with the switch from cellular to viral gene expression. We propose that phosphorylation of eIF2α and the consequent SG assembly is important for shutoff to occur and that the localized SG disassembly and the presence of the enhancer aid the SFV mRNAs to elude general translational arrest.

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Sacco-Bubulya, Paula, i David L. Spector. "Disassembly of interchromatin granule clusters alters the coordination of transcription and pre-mRNA splicing". Journal of Cell Biology 156, nr 3 (4.02.2002): 425–36. http://dx.doi.org/10.1083/jcb.200107017.

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To examine the involvement of interchromatin granule clusters (IGCs) in transcription and pre-mRNA splicing in mammalian cell nuclei, the serine-arginine (SR) protein kinase cdc2-like kinase (Clk)/STY was used as a tool to manipulate IGC integrity in vivo. Both immunofluorescence and transmission electron microscopy analyses of cells overexpressing Clk/STY indicate that IGC components are completely redistributed to a diffuse nuclear localization, leaving no residual structure. Conversely, overexpression of a catalytically inactive mutant, Clk/STY(K190R), causes retention of hypophosphorylated SR proteins in nuclear speckles. Our data suggest that the protein–protein interactions responsible for the clustering of interchromatin granules are disrupted when SR proteins are hyperphosphorylated and stabilized when SR proteins are hypophosphorylated. Interestingly, cells without intact IGCs continue to synthesize nascent transcripts. However, both the accumulation of splicing factors at sites of pre-mRNA synthesis as well as pre-mRNA splicing are dramatically reduced, demonstrating that IGC disassembly perturbs coordination between transcription and pre-mRNA splicing in mammalian cell nuclei.

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Stark, F., R. Golla i V. T. Nachmias. "Formation and contraction of a microfilamentous shell in saponin-permeabilized platelets." Journal of Cell Biology 112, nr 5 (1.03.1991): 903–13. http://dx.doi.org/10.1083/jcb.112.5.903.

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To study the mechanism of granule centralization in platelets, we permeabilized with saponin in either EGTA (5 mM) or calcium (1 or 10 microM). Under all conditions, platelets retained 40-50% of their total actin and greater than 70% of their actin-binding protein (ABP) but lost greater than 80% of talin and myosin to the supernatant. Thin sections of platelets permeabilized in EGTA showed a microfilament network under the residual plasma membrane and throughout the cytoplasm. Platelets permeabilized in calcium contained a microfilament shell partly separated from the residual membrane. The shell stained brightly for F-actin. A less dense microfilament shell was also seen in sections of ADP-stimulated intact platelets subsequently permeabilized in EGTA. In the presence of 1 mM ATP gamma S and calcium, myosin was retained (70%) and was localized by indirect immunofluorescence in bright central spots that also stained intensely for F-actin. Electron micrographs showed centralized granules surrounded by a closely packed mass of microfilaments much like the structures seen in thrombin-stimulated intact platelets subsequently permeabilized in EGTA. Permeabilization in calcium, ATP, and okadaic acid, produced the same configuration of centralized granules and packed microfilaments; myosin was retained and the myosin regulatory light chain became phosphorylated. Microtubule coil disassembly before permeabilization did not inhibit granule centralization. These results suggest a possible mechanism for granule centralization in these models. The cytoskeletal network first separates from some of its connections to the plasma membrane by a calcium-dependent mechanism not involving ABP proteolysis. Phosphorylated myosin interacts with the microfilaments to contract the shell moving the granules to the platelet's center.

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Zhang, Yi, Jiayu Gu i Qiming Sun. "Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis". Cells 10, nr 9 (30.08.2021): 2247. http://dx.doi.org/10.3390/cells10092247.

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Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.

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Cereghetti, Gea, Caroline Wilson-Zbinden, Vera M. Kissling, Maren Diether, Alexandra Arm, Haneul Yoo, Ilaria Piazza i in. "Reversible amyloids of pyruvate kinase couple cell metabolism and stress granule disassembly". Nature Cell Biology 23, nr 10 (październik 2021): 1085–94. http://dx.doi.org/10.1038/s41556-021-00760-4.

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Fritsch, Anatol W., Andrés F. Diaz-Delgadillo, Omar Adame-Arana, Carsten Hoege, Matthäus Mittasch, Moritz Kreysing, Mark Leaver, Anthony A. Hyman, Frank Jülicher i Christoph A. Weber. "Local thermodynamics govern formation and dissolution of Caenorhabditis elegans P granule condensates". Proceedings of the National Academy of Sciences 118, nr 37 (10.09.2021): e2102772118. http://dx.doi.org/10.1073/pnas.2102772118.

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Membraneless compartments, also known as condensates, provide chemically distinct environments and thus spatially organize the cell. A well-studied example of condensates is P granules in the roundworm Caenorhabditis elegans that play an important role in the development of the germline. P granules are RNA-rich protein condensates that share the key properties of liquid droplets such as a spherical shape, the ability to fuse, and fast diffusion of their molecular components. An outstanding question is to what extent phase separation at thermodynamic equilibrium is appropriate to describe the formation of condensates in an active cellular environment. To address this question, we investigate the response of P granule condensates in living cells to temperature changes. We observe that P granules dissolve upon increasing the temperature and recondense upon lowering the temperature in a reversible manner. Strikingly, this temperature response can be captured by in vivo phase diagrams that are well described by a Flory–Huggins model at thermodynamic equilibrium. This finding is surprising due to active processes in a living cell. To address the impact of such active processes on intracellular phase separation, we discuss temperature heterogeneities. We show that, for typical estimates of the density of active processes, temperature represents a well-defined variable and that mesoscopic volume elements are at local thermodynamic equilibrium. Our findings provide strong evidence that P granule assembly and disassembly are governed by phase separation based on local thermal equilibria where the nonequilibrium nature of the cytoplasm is manifested on larger scales.

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Jayabalan, Aravinth Kumar, Srivathsan Adivarahan, Aakash Koppula, Rachy Abraham, Mona Batish, Daniel Zenklusen, Diane E. Griffin i Anthony K. L. Leung. "Stress granule formation, disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity". Proceedings of the National Academy of Sciences 118, nr 6 (5.02.2021): e2021719118. http://dx.doi.org/10.1073/pnas.2021719118.

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While biomolecular condensates have emerged as an important biological phenomenon, mechanisms regulating their composition and the ways that viruses hijack these mechanisms remain unclear. The mosquito-borne alphaviruses cause a range of diseases from rashes and arthritis to encephalitis, and no licensed drugs are available for treatment or vaccines for prevention. The alphavirus virulence factor nonstructural protein 3 (nsP3) suppresses the formation of stress granules (SGs)—a class of cytoplasmic condensates enriched with translation initiation factors and formed during the early stage of infection. nsP3 has a conserved N-terminal macrodomain that hydrolyzes ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds the essential SG component G3BP1. Here, we show that macrodomain hydrolase activity reduces the ADP-ribosylation of G3BP1, disassembles virus-induced SGs, and suppresses SG formation. Expression of nsP3 results in the formation of a distinct class of condensates that lack translation initiation factors but contain G3BP1 and other SG-associated RNA-binding proteins. Expression of ADP-ribosylhydrolase–deficient nsP3 results in condensates that retain translation initiation factors as well as RNA-binding proteins, similar to SGs. Therefore, our data reveal that ADP-ribosylation controls the composition of biomolecular condensates, specifically the localization of translation initiation factors, during alphavirus infection.

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Mitchell, Troy, Andrea Lo, Michael R. Logan, Paige Lacy i Gary Eitzen. "Primary granule exocytosis in human neutrophils is regulated by Rac-dependent actin remodeling". American Journal of Physiology-Cell Physiology 295, nr 5 (listopad 2008): C1354—C1365. http://dx.doi.org/10.1152/ajpcell.00239.2008.

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The actin cytoskeleton regulates exocytosis in all secretory cells. In neutrophils, Rac2 GTPase has been shown to control primary (azurophilic) granule exocytosis. In this report, we propose that Rac2 is required for actin cytoskeletal remodeling to promote primary granule exocytosis. Treatment of neutrophils with low doses (≤10 μM) of the actin-depolymerizing drugs latrunculin B (Lat B) or cytochalasin B (CB) enhanced both formyl peptide receptor- and Ca2+ionophore-stimulated exocytosis. Higher concentrations of CB or Lat B, or stabilization of F-actin with jasplakinolide (JP), inhibited primary granule exocytosis measured as myeloperoxidase release but did not affect secondary granule exocytosis determined by lactoferrin release. These results suggest an obligatory role for F-actin disassembly before primary granule exocytosis. However, lysates from secretagogue-stimulated neutrophils showed enhanced actin polymerization activity in vitro. Microscopic analysis showed that resting neutrophils contain significant cortical F-actin, which was redistributed to sites of primary granule translocation when stimulated. Exocytosis and actin remodeling was highly polarized when cells were primed with CB; however, polarization was reduced by Lat B preincubation, and both polarization and exocytosis were blocked when F-actin was stabilized with JP. Treatment of cells with the small molecule Rac inhibitor NSC23766 also inhibited actin remodeling and primary granule exocytosis induced by Lat B/fMLF or CB/fMLF, but not by Ca2+ionophore. Therefore, we propose a role for F-actin depolymerization at the cell cortex coupled with Rac-dependent F-actin polymerization in the cell cytoplasm to promote primary granule exocytosis.

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Tolay, Nazife, i Alexander Buchberger. "Role of the Ubiquitin System in Stress Granule Metabolism". International Journal of Molecular Sciences 23, nr 7 (26.03.2022): 3624. http://dx.doi.org/10.3390/ijms23073624.

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Eukaryotic cells react to various stress conditions with the rapid formation of membrane-less organelles called stress granules (SGs). SGs form by multivalent interactions between RNAs and RNA-binding proteins and are believed to protect stalled translation initiation complexes from stress-induced degradation. SGs contain hundreds of different mRNAs and proteins, and their assembly and disassembly are tightly controlled by post-translational modifications. The ubiquitin system, which mediates the covalent modification of target proteins with the small protein ubiquitin (‘ubiquitylation’), has been implicated in different aspects of SG metabolism, but specific functions in SG turnover have only recently emerged. Here, we summarize the evidence for the presence of ubiquitylated proteins at SGs, review the functions of different components of the ubiquitin system in SG formation and clearance, and discuss the link between perturbed SG clearance and the pathogenesis of neurodegenerative disorders. We conclude that the ubiquitin system plays an important, medically relevant role in SG biology.

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32

Lowenstein, Charles J., i Hiromasa Tsuda. "N-Ethylmaleimide-sensitive factor: a redox sensor in exocytosis". Biological Chemistry 387, nr 10/11 (1.10.2006): 1377–83. http://dx.doi.org/10.1515/bc.2006.173.

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AbstractVascular injury triggers endothelial exocytosis of granules, releasing pro-inflammatory and pro-thrombotic mediators into the blood. Nitric oxide (NO) and reactive oxygen species (ROS) limit vascular inflammation and thrombosis by inhibiting endothelial exocytosis. NO decreases exocytosis by regulating the activity of theN-ethylmaleimide-sensitive factor (NSF), a central component of the exocytic machinery. NO nitrosylates specific cysteine residues of NSF, thereby inhibiting NSF disassembly of the soluble NSF attachment protein receptor (SNARE). NO also modulates exocytosis of other cells; for example, NO regulates platelet activation by inhibiting α-granule secretion from platelets. Other radicals besides NO can regulate exocytosis as well. For example, H2O2inhibits exocytosis by oxidizing NSF. Using site-directed mutagenesis, we have defined the critical cysteine residues of NSF, and found that one particular cysteine residue, C264, renders NSF sensitive to oxidative stress. Since radicals such as NO and H2O2inhibit NSF and decrease exocytosis, NSF may act as a redox sensor, modulating exocytosis in response to changes in oxidative stress.

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33

Cereghetti, Gea, Caroline Wilson-Zbinden, Vera M. Kissling, Maren Diether, Alexandra Arm, Haneul Yoo, Ilaria Piazza i in. "Author Correction: Reversible amyloids of pyruvate kinase couple cell metabolism and stress granule disassembly". Nature Cell Biology 24, nr 1 (26.10.2021): 123. http://dx.doi.org/10.1038/s41556-021-00799-3.

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Wang, Bo, Brian A. Maxwell, Joung Hyuck Joo, Youngdae Gwon, James Messing, Ashutosh Mishra, Timothy I. Shaw i in. "ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97". Molecular Cell 74, nr 4 (maj 2019): 742–57. http://dx.doi.org/10.1016/j.molcel.2019.03.027.

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35

Rennie, Madison, i Suzanne Scarlata. "Abstract 1791: The Lasting Effects of Stress Granule Dynamics: Assembly and Disassembly Upon Gαq Activation". Journal of Biological Chemistry 299, nr 3 (2023): S745. http://dx.doi.org/10.1016/j.jbc.2023.104360.

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36

Bartoli, Kristen M., Darryl L. Bishop i William S. Saunders. "The Role of Molecular Microtubule Motors and the Microtubule Cytoskeleton in Stress Granule Dynamics". International Journal of Cell Biology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/939848.

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Stress granules (SGs) are cytoplasmic foci that appear in cells exposed to stress-induced translational inhibition. SGs function as a triage center, where mRNAs are sorted for storage, degradation, and translation reinitiation. The underlying mechanisms of SGs dynamics are still being characterized, although many key players have been identified. The main components of SGs are stalled 48S preinitiation complexes. To date, many other proteins have also been found to localize in SGs and are hypothesized to function in SG dynamics. Most recently, the microtubule cytoskeleton and associated motor proteins have been demonstrated to function in SG dynamics. In this paper, we will discuss current literature examining the function of microtubules and the molecular microtubule motors in SG assembly, coalescence, movement, composition, organization, and disassembly.

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37

Stearns, M. E., i M. Wang. "Polarized pigment granule transport occurs in the absence of microtubules in squirrelfish erythrophores: studies of the effects of estramustine". Journal of Cell Science 87, nr 4 (1.05.1987): 565–80. http://dx.doi.org/10.1242/jcs.87.4.565.

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We have re-examined the involvement of microtubules in the process of pigment granule transport in squirrelfish erythrophores in situ (i.e. on scales). Light-microscopic studies revealed that following exposure to 5 microM-nocodazole for 1 h at 4 degrees C erythrophores retained an ability to aggregate and disperse their pigment uniformly, though at reduced rates. Serial thick-section stereo high-voltage electron-microscopic studies showed that the entire microtubule population was removed by drug treatment and that the microtubules were not reassembled as a result of pigment translocation processes in the presence of reduced levels of nocodazole (0.4 microM). Immunofluorescence microscopic studies confirmed that nocodazole (0.5-1 microM) produced rapid disassembly of the microtubules. Whole-mount electron-microscopic studies showed that the pigment granules were suspended in a cross-linking network of 3–10 nm filaments, which appeared to support ordered pigment transport in situ in the absence of microtubules. Drug inhibition studies showed that micromolar levels of estramustine, a novel anti-MAPs (microtubule-associated proteins) drug, reversibly inhibited pigment transport. The results suggest that an estramustine-sensitive cytomatrix component might produce polarized pigment transport in intact erythrophores.

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38

Tapper, H., i S. Grinstein. "Fc receptor-triggered insertion of secretory granules into the plasma membrane of human neutrophils: selective retrieval during phagocytosis." Journal of Immunology 159, nr 1 (1.07.1997): 409–18. http://dx.doi.org/10.4049/jimmunol.159.1.409.

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Abstract We studied the kinetics of secretion in human neutrophils stimulated by IgG-opsonized zymosan. Secretion of azurophilic and specific granules was quantified measuring the appearance of the granule markers CD63 and CD66b, respectively, at the cell surface. The kinetics of secretion was compared with the course of phagocytosis, revealed by the trapping of the fluid phase marker, Lucifer Yellow, in vacuoles containing zymosan particles. We found that secretion of both azurophilic and specific granules precedes phagosome sealing. An initial rapid phase of secretion was followed by a decrease in the amount of CD63 and CD66b at the cell surface. This subsequent disappearance of surface CD63 and CD66b was inhibited by cytochalasin B and probably represents internalization of the granular markers into the forming phagosome. The decrease in the amount of CD63 and CD66b exposed at the cell surface was not accompanied by a commensurate reduction in cell surface area, measured with the amphiphilic fluorescent dye FM1-43. These findings imply that CD63 and CD66b are selectively retrieved from the plasma membrane following secretion. Evidence is also presented that calcium is not the sole mediator of the rapid secretion of azurophilic and specific granules triggered by IgG-opsonized particles and that cytochalasin does not impair signaling of the calcium transient elicited by Fc receptors. Instead, actin disassembly appears to reduce the efficiency of the interaction between opsonized particles and their receptors, an effect that can be overcome by increasing the concentration of the stimulating particles.

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39

Liu, Lifeng, Eva Weiss, Marc D. Panas, Benjamin Götte, Stina Sellberg, Bastian Thaa i Gerald M. McInerney. "RNA processing bodies are disassembled during Old World alphavirus infection". Journal of General Virology 100, nr 10 (1.10.2019): 1375–89. http://dx.doi.org/10.1099/jgv.0.001310.

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RNA processing bodies (P-bodies) are non-membranous cytoplasmic aggregates of mRNA and proteins involved in mRNA decay and translation repression. P-bodies actively respond to environmental stresses, associated with another type of RNA granules, known as stress granules (SGs). Alphaviruses were previously shown to block SG induction at late stages of infection, which is important for efficient viral growth. In this study, we found that P-bodies were disassembled or reduced in number very early in infection with Semliki Forest virus (SFV) or chikungunya virus (CHIKV) in a panel of cell lines. Similar to SGs, reinduction of P-bodies by a second stress (sodium arsenite) was also blocked in infected cells. The disassembly of P-bodies still occurred in non-phosphorylatable eIF2α mouse embryonal fibroblasts (MEFs) that are impaired in SG assembly. Studies of translation status by ribopuromycylation showed that P-body disassembly is independent of host translation shutoff, which requires the phosphorylation of eIF2α in the SFV- or CHIKV-infected cells. Labelling of newly synthesized RNA with bromo-UTP showed that host transcription shutoff correlated with P-body disassembly at the same early stage (3–4 h) after infection. However, inhibition of global transcription with actinomycin D (ActD) failed to disassemble P-bodies as effectively as the viruses did. Interestingly, blocking nuclear import with importazole led to an efficient P-bodies loss. Our data reveal that P-bodies are disassembled independently from SG formation at early stages of Old World alphavirus infection and that nuclear import is involved in the dynamic of P-bodies.

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Arakawa, Masashi, Keisuke Tabata, Kotaro Ishida, Makiko Kobayashi, Arisa Arai, Tomohiro Ishikawa, Ryosuke Suzuki i in. "Flavivirus recruits the valosin-containing protein–NPL4 complex to induce stress granule disassembly for efficient viral genome replication". Journal of Biological Chemistry 298, nr 3 (marzec 2022): 101597. http://dx.doi.org/10.1016/j.jbc.2022.101597.

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Marmor-Kollet, Hagai, Aviad Siany, Nancy Kedersha, Naama Knafo, Natalia Rivkin, Yehuda M. Danino, Thomas G. Moens i in. "Spatiotemporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis". Molecular Cell 80, nr 5 (grudzień 2020): 876–91. http://dx.doi.org/10.1016/j.molcel.2020.10.032.

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Sahoo, Pabitra K., Amar N. Kar, Nitzan Samra, Marco Terenzio, Priyanka Patel, Seung Joon Lee, Sharmina Miller i in. "A Ca2+-Dependent Switch Activates Axonal Casein Kinase 2α Translation and Drives G3BP1 Granule Disassembly for Axon Regeneration". Current Biology 30, nr 24 (grudzień 2020): 4882–95. http://dx.doi.org/10.1016/j.cub.2020.09.043.

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Rabasco, Stefania, Alicia A. Lork, Emmanuel Berlin, Tho D. K. Nguyen, Carl Ernst, Nicolas Locker, Andrew G. Ewing i Nhu T. N. Phan. "Characterization of Stress Granule Protein Turnover in Neuronal Progenitor Cells Using Correlative STED and NanoSIMS Imaging". International Journal of Molecular Sciences 24, nr 3 (29.01.2023): 2546. http://dx.doi.org/10.3390/ijms24032546.

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Stress granules (SGs) are stress-induced biomolecular condensates which originate primarily from inactivated RNA translation machinery and translation initiation factors. SG formation is an important defensive mechanism for cell survival, while its dysfunction has been linked to neurodegenerative diseases. However, the molecular mechanisms of SG assembly and disassembly, as well as their impacts on cellular recovery, are not fully understood. More thorough investigations into the molecular dynamics of SG pathways are required to understand the pathophysiological roles of SGs in cellular systems. Here, we characterize the SG and cytoplasmic protein turnover in neuronal progenitor cells (NPCs) under stressed and non-stressed conditions using correlative STED and NanoSIMS imaging. We incubate NPCs with isotopically labelled (15N) leucine and stress them with the ER stressor thapsigargin (TG). A correlation of STED and NanoSIMS allows the localization of individual SGs (using STED), and their protein turnover can then be extracted based on the 15N/14N ratio (using NanoSIMS). We found that TG-induced SGs, which are highly dynamic domains, recruit their constituents predominantly from the cytoplasm. Moreover, ER stress impairs the total cellular protein turnover regimen, and this impairment is not restored after the commonly proceeded stress recovery period.

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44

Shiina, Nobuyuki, i Kei Nakayama. "RNA Granule Assembly and Disassembly Modulated by Nuclear Factor Associated with Double-stranded RNA 2 and Nuclear Factor 45". Journal of Biological Chemistry 289, nr 30 (11.06.2014): 21163–80. http://dx.doi.org/10.1074/jbc.m114.556365.

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Nahm, Minyeop, Su Min Lim, Young-Eun Kim, Jinseok Park, Min-Young Noh, Sanggon Lee, Ju Eun Roh i in. "ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics". Science Translational Medicine 12, nr 566 (21.10.2020): eaax3993. http://dx.doi.org/10.1126/scitranslmed.aax3993.

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Dysregulation of calcium ion homeostasis and abnormal protein aggregation have been proposed as major pathogenic hallmarks underpinning selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). Recently, mutations in annexin A11 (ANXA11), a gene encoding a Ca2+-dependent phospholipid-binding protein, have been identified in familial and sporadic ALS. However, the physiological and pathophysiological roles of ANXA11 remain unknown. Here, we report functions of ANXA11 related to intracellular Ca2+ homeostasis and stress granule dynamics. We analyzed the exome sequences of 500 Korean patients with sALS and identified nine ANXA11 variants in 13 patients. The amino-terminal variants p.G38R and p.D40G within the low-complexity domain of ANXA11 enhanced aggregation propensity, whereas the carboxyl-terminal ANX domain variants p.H390P and p.R456H altered Ca2+ responses. Furthermore, all four variants in ANXA11 underwent abnormal phase separation to form droplets with aggregates and led to the alteration of the biophysical properties of ANXA11. These functional defects caused by ALS-linked variants induced alterations in both intracellular Ca2+ homeostasis and stress granule disassembly. We also revealed that p.G228Lfs*29 reduced ANXA11 expression and impaired Ca2+ homeostasis, as caused by missense variants. Ca2+-dependent interaction and coaggregation between ANXA11 and ALS-causative RNA-binding proteins, FUS and hnRNPA1, were observed in motor neuron cells and brain from a patient with ALS-FUS. The expression of ALS-linked ANXA11 variants in motor neuron cells caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis. Together, our findings suggest that disease-associated ANXA11 mutations can contribute to ALS pathogenesis through toxic gain-of-function mechanisms involving abnormal protein aggregation.

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46

Haddad, Alex, Grant R. Bowman i Aaron P. Turkewitz. "New Class of Cargo Protein in Tetrahymena thermophila Dense Core Secretory Granules". Eukaryotic Cell 1, nr 4 (sierpień 2002): 583–93. http://dx.doi.org/10.1128/ec.1.4.583-593.2002.

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ABSTRACT Regulated exocytosis of dense core secretory granules releases biologically active proteins in a stimulus-dependent fashion. The packaging of the cargo within newly forming granules involves a transition: soluble polypeptides condense to form water-insoluble aggregates that constitute the granule cores. Following exocytosis, the cores generally disassemble to diffuse in the cell environment. The ciliates Tetrahymena thermophila and Paramecium tetraurelia have been advanced as genetically manipulatable systems for studying exocytosis via dense core granules. However, all of the known granule proteins in these organisms condense to form the architectural units of lattices that are insoluble both before and after exocytosis. Using an approach designed to detect new granule proteins, we have now identified Igr1p (induced during granule regeneration). By structural criteria, it is unrelated to the previously characterized lattice-forming proteins. It is distinct in that it is capable of dissociating from the insoluble lattice following secretion and therefore represents the first diffusible protein identified in ciliate granules.

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47

Fricke, Jens, Lily Y. Koo, Charles R. Brown i Peter L. Collins. "p38 and OGT Sequestration into Viral Inclusion Bodies in Cells Infected with Human Respiratory Syncytial Virus Suppresses MK2 Activities and Stress Granule Assembly". Journal of Virology 87, nr 3 (14.11.2012): 1333–47. http://dx.doi.org/10.1128/jvi.02263-12.

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ABSTRACTRespiratory syncytial virus (RSV) forms cytoplasmic inclusion bodies (IBs) that are thought to be sites of nucleocapsid accumulation and viral RNA synthesis. The present study found that IBs also were the sites of major sequestration of two proteins involved in cellular signaling pathways. These are phosphorylated p38 mitogen-activated protein kinase (MAPK) (p38-P), a key regulator of cellular inflammatory and stress responses, and O-linkedN-acetylglucosamine (OGN) transferase (OGT), an enzyme that catalyzes the posttranslational addition of OGN to protein targets to regulate cellular processes, including signal transduction, transcription, translation, and the stress response. The virus-induced sequestration of p38-P in IBs resulted in a substantial reduction in the accumulation of a downstream signaling substrate, MAPK-activated protein kinase 2 (MK2). Sequestration of OGT in IBs was associated with suppression of stress granule (SG) formation. Thus, while the RSV IBs are thought to play an essential role in viral replication, the present results show that they also play a role in suppressing the cellular response to viral infection. The sequestration of p38-P and OGT in IBs appeared to be reversible: oxidative stress resulting from arsenite treatment transformed large IBs into a scattering of smaller bodies, suggestive of partial disassembly, and this was associated with MK2 phosphorylation and OGN addition. Unexpectedly, the RSV M2-1 protein was found to localize in SGs that formed during oxidative stress. This protein was previously shown to be a viral transcription elongation factor, and the present findings provide the first evidence of possible involvement in SG activities during RSV infection.

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48

Bernstein, Audrey M., i Sidney W. Whiteheart. "Identification of a Cellubrevin/Vesicle Associated Membrane Protein 3 Homologue in Human Platelets". Blood 93, nr 2 (15.01.1999): 571–79. http://dx.doi.org/10.1182/blood.v93.2.571.

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Abstract Several studies suggest membrane trafficking events are mediated by integral, membrane proteins from both transport-vesicle and target membranes, called v- and t-SNAREs (SNAp REceptors), respectively. Previous experiments using antibodies to synaptobrevin/vesicle associated membrane protein (VAMP) 1, 2, or rat cellubrevin failed to detect these v-SNAREs in human platelets, although membrane proteins from these cells could support 20S complex formation. To identify v-SNAREs in platelets, we used a polymerase chain reaction (PCR) approach with degenerate primers to amplify potential VAMP-like v-SNAREs. A cDNA encoding a novel v-SNARE was isolated from a human megakaryocyte cDNA library. Termed human cellubrevin (Hceb), this protein has greater than 93% identity with human VAMP 1, 2, and rat cellubrevin over the conserved core region, but has a unique N–terminal domain. Northern blot analysis showed that the 2.5-kB mRNA encoding Hceb is expressed in every human tissue tested. Hceb from detergent-solubilized platelet membranes, participated in -SNAP–dependent 20S complex formation and adenosine triphosphate (ATP)-dependent disassembly, showing that Hceb can act as a v-SNARE in platelets. Immunofluorescence microscopy, using an anti-Hceb antibody showed a punctate, intracellular staining pattern in platelets, megakaryocytes, and HEK-293 cells. This same pattern was observed in surface-activated platelets even though all dense core and most -granule contents had been released. These data suggest that Hceb may reside on a platelet organelle that is not primarily involved in the exocytic pathway.

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49

Bernstein, Audrey M., i Sidney W. Whiteheart. "Identification of a Cellubrevin/Vesicle Associated Membrane Protein 3 Homologue in Human Platelets". Blood 93, nr 2 (15.01.1999): 571–79. http://dx.doi.org/10.1182/blood.v93.2.571.402k05_571_579.

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Several studies suggest membrane trafficking events are mediated by integral, membrane proteins from both transport-vesicle and target membranes, called v- and t-SNAREs (SNAp REceptors), respectively. Previous experiments using antibodies to synaptobrevin/vesicle associated membrane protein (VAMP) 1, 2, or rat cellubrevin failed to detect these v-SNAREs in human platelets, although membrane proteins from these cells could support 20S complex formation. To identify v-SNAREs in platelets, we used a polymerase chain reaction (PCR) approach with degenerate primers to amplify potential VAMP-like v-SNAREs. A cDNA encoding a novel v-SNARE was isolated from a human megakaryocyte cDNA library. Termed human cellubrevin (Hceb), this protein has greater than 93% identity with human VAMP 1, 2, and rat cellubrevin over the conserved core region, but has a unique N–terminal domain. Northern blot analysis showed that the 2.5-kB mRNA encoding Hceb is expressed in every human tissue tested. Hceb from detergent-solubilized platelet membranes, participated in -SNAP–dependent 20S complex formation and adenosine triphosphate (ATP)-dependent disassembly, showing that Hceb can act as a v-SNARE in platelets. Immunofluorescence microscopy, using an anti-Hceb antibody showed a punctate, intracellular staining pattern in platelets, megakaryocytes, and HEK-293 cells. This same pattern was observed in surface-activated platelets even though all dense core and most -granule contents had been released. These data suggest that Hceb may reside on a platelet organelle that is not primarily involved in the exocytic pathway.

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50

Hu, Rirong, Beituo Qian, Ang Li i Yanshan Fang. "Role of Proteostasis Regulation in the Turnover of Stress Granules". International Journal of Molecular Sciences 23, nr 23 (23.11.2022): 14565. http://dx.doi.org/10.3390/ijms232314565.

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RNA-binding proteins (RBPs) and RNAs can form dynamic, liquid droplet-like cytoplasmic condensates, known as stress granules (SGs), in response to a variety of cellular stresses. This process is driven by liquid–liquid phase separation, mediated by multivalent interactions between RBPs and RNAs. The formation of SGs allows a temporary suspension of certain cellular activities such as translation of unnecessary proteins. Meanwhile, non-translating mRNAs may also be sequestered and stalled. Upon stress removal, SGs are disassembled to resume the suspended biological processes and restore the normal cell functions. Prolonged stress and disease-causal mutations in SG-associated RBPs can cause the formation of aberrant SGs and/or impair SG disassembly, consequently raising the risk of pathological protein aggregation. The machinery maintaining protein homeostasis (proteostasis) includes molecular chaperones and co-chaperones, the ubiquitin-proteasome system, autophagy, and other components, and participates in the regulation of SG metabolism. Recently, proteostasis has been identified as a major regulator of SG turnover. Here, we summarize new findings on the specific functions of the proteostasis machinery in regulating SG disassembly and clearance, discuss the pathological and clinical implications of SG turnover in neurodegenerative disorders, and point to the unresolved issues that warrant future exploration.

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