Zeitschriftenartikel: „RNP granule“

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Aoki, Scott T., Aaron M. Kershner, Craig A. Bingman, Marvin Wickens und Judith Kimble. „PGL germ granule assembly protein is a base-specific, single-stranded RNase“. Proceedings of the National Academy of Sciences 113, Nr. 5 (19.01.2016): 1279–84. http://dx.doi.org/10.1073/pnas.1524400113.

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Cellular RNA-protein (RNP) granules are ubiquitous and have fundamental roles in biology and RNA metabolism, but the molecular basis of their structure, assembly, and function is poorly understood. Using nematode “P-granules” as a paradigm, we focus on the PGL granule scaffold protein to gain molecular insights into RNP granule structure and assembly. We first identify a PGL dimerization domain (DD) and determine its crystal structure. PGL-1 DD has a novel 13 α-helix fold that creates a positively charged channel as a homodimer. We investigate its capacity to bind RNA and discover unexpectedly that PGL-1 DD is a guanosine-specific, single-stranded endonuclease. Discovery of the PGL homodimer, together with previous results, suggests a model in which the PGL DD dimer forms a fundamental building block for P-granule assembly. Discovery of the PGL RNase activity expands the role of RNP granule assembly proteins to include enzymatic activity in addition to their job as structural scaffolds.

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Krüger, Timothy, Mario Hofweber und 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, Nr. 13 (Juli 2013): 2098–111. http://dx.doi.org/10.1091/mbc.e13-01-0068.

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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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Hanazawa, Momoyo, Masafumi Yonetani und Asako Sugimoto. „PGL proteins self associate and bind RNPs to mediate germ granule assembly in C. elegans“. Journal of Cell Biology 192, Nr. 6 (14.03.2011): 929–37. http://dx.doi.org/10.1083/jcb.201010106.

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Germ granules are germ lineage–specific ribonucleoprotein (RNP) complexes, but how they are assembled and specifically segregated to germ lineage cells remains unclear. Here, we show that the PGL proteins PGL-1 and PGL-3 serve as the scaffold for germ granule formation in Caenorhabditis elegans. Using cultured mammalian cells, we found that PGL proteins have the ability to self-associate and recruit RNPs. Depletion of PGL proteins from early C. elegans embryos caused dispersal of other germ granule components in the cytoplasm, suggesting that PGL proteins are essential for the architecture of germ granules. Using a structure–function analysis in vivo, we found that two functional domains of PGL proteins contribute to germ granule assembly: an RGG box for recruiting RNA and RNA-binding proteins and a self-association domain for formation of globular granules. We propose that self-association of scaffold proteins that can bind to RNPs is a general mechanism by which large RNP granules are formed.

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Van Treeck, Briana, David S. W. Protter, Tyler Matheny, Anthony Khong, Christopher D. Link und Roy Parker. „RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome“. Proceedings of the National Academy of Sciences 115, Nr. 11 (26.02.2018): 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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An, Haiyan, und Tatyana A. Shelkovnikova. „Stress granules regulate paraspeckles: RNP granule continuum at work“. Cell Stress 3, Nr. 12 (09.12.2019): 385–87. http://dx.doi.org/10.15698/cst2019.12.207.

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6

Davis, Michael, Andrea Montalbano, Megan P. Wood und Jennifer A. Schisa. „Biphasic adaptation to osmotic stress in the C. elegans germ line“. American Journal of Physiology-Cell Physiology 312, Nr. 6 (01.06.2017): 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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An, Haiyan, Jing Tong Tan und Tatyana A. Shelkovnikova. „Stress granules regulate stress-induced paraspeckle assembly“. Journal of Cell Biology 218, Nr. 12 (21.10.2019): 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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Corbet, Giulia Ada, und Roy Parker. „RNP Granule Formation: Lessons from P-Bodies and Stress Granules“. Cold Spring Harbor Symposia on Quantitative Biology 84 (2019): 203–15. http://dx.doi.org/10.1101/sqb.2019.84.040329.

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9

Kim, Younghoon, Christian Eckmann, Clifford P. Brangwynne und Sua Myong. „DEAD Box Helicases in Rnp Granule“. Biophysical Journal 106, Nr. 2 (Januar 2014): 71a. http://dx.doi.org/10.1016/j.bpj.2013.11.471.

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Abolhassani-Dadras, S., G. H. Vázquez-Nin, O. M. Echeverría und S. Fakan. „The use of an internal standard in the application of quantitative image-EELS in biology“. Proceedings, annual meeting, Electron Microscopy Society of America 54 (11.08.1996): 50–51. http://dx.doi.org/10.1017/s0424820100162715.

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The energy filtering transmission electron microscope (EFTEM) is employed to examine the possibility of using ribosomes as internal standard for a quantitative in-situ study of phosphorus content of nuclear constituents in a biological section. The problems that can arise from different steps of such an experimental approach are discussed.Salivary gland cells from fourth instar larvae of Chironomus thummi are selected as test specimens because of their appropriate structure. The nucleus of these cells contains two types of granules, one of which (known as Balbiani ring granule, Brg) has an RNA size known from radioactive phosphorus labelling and subsequent isolation, allowing one to estimate its phosphorus content. The other type of granule (known as small RNP granule) has been recently discovered and its phosphorus content is not known. The EFTEM method is used to verify the phosphorus content of these two nuclear constituents.

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Tauber, Devin, Gabriel Tauber und Roy Parker. „Mechanisms and Regulation of RNA Condensation in RNP Granule Formation“. Trends in Biochemical Sciences 45, Nr. 9 (September 2020): 764–78. http://dx.doi.org/10.1016/j.tibs.2020.05.002.

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12

Noble, Scott L., Brittany L. Allen, Lai Kuan Goh, Kristen Nordick und Thomas C. Evans. „Maternal mRNAs are regulated by diverse P body–related mRNP granules during early Caenorhabditis elegans development“. Journal of Cell Biology 182, Nr. 3 (11.08.2008): 559–72. http://dx.doi.org/10.1083/jcb.200802128.

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Processing bodies (P bodies) are conserved mRNA–protein (mRNP) granules that are thought to be cytoplasmic centers for mRNA repression and degradation. However, their specific functions in vivo remain poorly understood. We find that repressed maternal mRNAs and their regulators localize to P body–like mRNP granules in the Caenorhabditis elegans germ line. Surprisingly, several distinct types of regulated granules form during oocyte and embryo development. 3′ untranslated region elements direct mRNA targeting to one of these granule classes. The P body factor CAR-1/Rap55 promotes association of repressed mRNA with granules and contributes to repression of Notch/glp-1 mRNA. However, CAR-1 controls Notch/glp-1 only during late oogenesis, where it functions with the RNA-binding regulators PUF-5, PUF-6, and PUF-7. The P body protein CGH-1/Rck/Dhh1 differs from CAR-1 in control of granule morphology and promotes mRNP stability in arrested oocytes. Therefore, a system of diverse and regulated RNP granules elicits stage-specific functions that ensure proper mRNA control during early development.

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De Graeve, Fabienne, und Florence Besse. „Neuronal RNP granules: from physiological to pathological assemblies“. Biological Chemistry 399, Nr. 7 (27.06.2018): 623–35. http://dx.doi.org/10.1515/hsz-2018-0141.

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Abstract Neuronal cells rely on macro- and micro-cellular compartmentalization to rapidly process information, and respond locally to external stimuli. Such a cellular organization is achieved via the assembly of neuronal ribonucleoprotein (RNP) granules, dynamic membrane-less organelles enriched in RNAs and associated regulatory proteins. In this review, we discuss how these high-order structures transport mRNAs to dendrites and axons, and how they contribute to the spatio-temporal regulation of localized mRNA translation. We also highlight how recent biophysical studies have shed light on the mechanisms underlying neuronal RNP granule dynamic assembly, remodeling and maturation, in both physiological and pathological contexts.

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Ivanov, P. „RNP stress-granule formation is inhibited by microtubule disruption“. Cell Biology International 27, Nr. 3 (2003): 207–8. http://dx.doi.org/10.1016/s1065-6995(02)00341-4.

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15

Lehtiniemi, Tiina, und Noora Kotaja. „Germ granule-mediated RNA regulation in male germ cells“. Reproduction 155, Nr. 2 (Februar 2018): R77—R91. http://dx.doi.org/10.1530/rep-17-0356.

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Germ cells have exceptionally diverse transcriptomes. Furthermore, the progress of spermatogenesis is accompanied by dramatic changes in gene expression patterns, the most drastic of them being near-to-complete transcriptional silencing during the final steps of differentiation. Therefore, accurate RNA regulatory mechanisms are critical for normal spermatogenesis. Cytoplasmic germ cell-specific ribonucleoprotein (RNP) granules, known as germ granules, participate in posttranscriptional regulation in developing male germ cells. Particularly, germ granules provide platforms for the PIWI-interacting RNA (piRNA) pathway and appear to be involved both in piRNA biogenesis and piRNA-targeted RNA degradation. Recently, other RNA regulatory mechanisms, such as the nonsense-mediated mRNA decay pathway have also been associated to germ granules providing new exciting insights into the function of germ granules. In this review article, we will summarize our current knowledge on the role of germ granules in the control of mammalian male germ cell’s transcriptome and in the maintenance of fertility.

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Mittag, Tanja, und Roy Parker. „Multiple Modes of Protein–Protein Interactions Promote RNP Granule Assembly“. Journal of Molecular Biology 430, Nr. 23 (November 2018): 4636–49. http://dx.doi.org/10.1016/j.jmb.2018.08.005.

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17

An, Haiyan, Camille Rabesahala de Meritens und Tatyana A. Shelkovnikova. „Connecting the “dots”: RNP granule network in health and disease“. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1868, Nr. 8 (Juli 2021): 119058. http://dx.doi.org/10.1016/j.bbamcr.2021.119058.

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18

Burke, James M., Evan T. Lester, Devin Tauber und Roy Parker. „RNase L promotes the formation of unique ribonucleoprotein granules distinct from stress granules“. Journal of Biological Chemistry 295, Nr. 6 (02.01.2020): 1426–38. http://dx.doi.org/10.1074/jbc.ra119.011638.

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Stress granules (SGs) are ribonucleoprotein (RNP) assemblies that form in eukaryotic cells as a result of limited translation in response to stress. SGs form during viral infection and are thought to promote the antiviral response because many viruses encode inhibitors of SG assembly. However, the antiviral endoribonuclease RNase L also alters SG formation, whereby only small punctate SG-like bodies that we term RNase L–dependent bodies (RLBs) form during RNase L activation. How RLBs relate to SGs and their mode of biogenesis is unknown. Herein, using immunofluorescence, live-cell imaging, and MS-based analyses, we demonstrate that RLBs represent a unique RNP granule with a protein and RNA composition distinct from that of SGs in response to dsRNA lipofection in human cells. We found that RLBs are also generated independently of SGs and the canonical dsRNA-induced SG biogenesis pathway, because RLBs did not require protein kinase R, phosphorylation of eukaryotic translation initiation factor 2 subunit 1 (eIF2α), the SG assembly G3BP paralogs, or release of mRNAs from ribosomes via translation elongation. Unlike the transient interactions between SGs and P-bodies, RLBs and P-bodies extensively and stably interacted. However, despite both RLBs and P-bodies exhibiting liquid-like properties, they remained distinct condensates. Taken together, these observations reveal that RNase L promotes the formation of a unique RNP complex that may have roles during the RNase L–mediated antiviral response.

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Protter, David S. W., Bhalchandra S. Rao, Briana Van Treeck, Yuan Lin, Laura Mizoue, Michael K. Rosen und Roy Parker. „Intrinsically Disordered Regions Can Contribute Promiscuous Interactions to RNP Granule Assembly“. Cell Reports 22, Nr. 6 (Februar 2018): 1401–12. http://dx.doi.org/10.1016/j.celrep.2018.01.036.

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20

Zhang, Yi, Jiayu Gu und 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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Nielsen, Finn C., Jacob Nielsen, Mette A. Kristensen, Grete Koch und Jan Christiansen. „Cytoplasmic trafficking of IGF-II mRNA-binding protein by conserved KH domains“. Journal of Cell Science 115, Nr. 10 (15.05.2002): 2087–97. http://dx.doi.org/10.1242/jcs.115.10.2087.

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The IGF-II mRNA-binding proteins (IMPs), which are composed of two RNA recognition motifs, (RRM) and four hnRNP K homology (KH) domains, have been implicated in subcytoplasmic localization of mRNAs during embryogenesis. The IMP family originated via two gene duplications before the divergence of vertebrates, and IMP homologues consisting of only the four KH motifs have been identified in Drosophila and Caenorhabditis elegans. Here we characterise the trafficking of GFP-IMP1 fusion proteins and determine the structural determinants for proper cytoplasmic localization. GFP-IMP1 is present in large 200-700 nm RNP granules, which are distributed along microtubules. In motile cells, GFP-IMP1 is transported towards the leading edge into the cortical region of the lamellipodia where it is connected to microfilaments. Granules travel in an ATP-dependent fashion at an average speed of 0.12 μm/s (range 0.04-0.22 μm/s), and cells switch from a delocalized to a localized pattern within 15-20 minutes. Both granule formation and localization are unaffected by removal of the two RRMs, whereas deletion of the KH domains, which mediate RNA-binding, impairs these functions. We conclude that IMP1 localization is associated with motility and that the major functions of IMP1 are carried out by the phylogenetically conserved KH domains.

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Decker, Carolyn J., und Roy Parker. „CAR-1 and Trailer hitch: driving mRNP granule function at the ER?“ Journal of Cell Biology 173, Nr. 2 (24.04.2006): 159–63. http://dx.doi.org/10.1083/jcb.200601153.

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The targeting of messenger RNAs (mRNAs) to specific subcellular sites for local translation plays an important role in diverse cellular and developmental processes in eukaryotes, including axis formation, cell fate determination, spindle pole regulation, cell motility, and neuronal synaptic plasticity. Recently, a new conserved class of Lsm proteins, the Scd6 family, has been implicated in controlling mRNA function. Depletion or mutation of members of the Scd6 family, Caenorhabditis elegans CAR-1 and Drosophila melanogaster trailer hitch, lead to a variety of developmental phenotypes, which in some cases can be linked to alterations in the endoplasmic reticulum (ER). Scd6/Lsm proteins are RNA binding proteins and are found in RNP complexes associated with translational control of mRNAs, and these complexes can colocalize with the ER. These findings raise the possibility that localization and translational regulation of mRNAs at the ER plays a role in controlling the organization of this organelle.

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Huang, S., T. J. Deerinck, M. H. Ellisman und D. L. Spector. „In vivo analysis of the stability and transport of nuclear poly(A)+ RNA.“ Journal of Cell Biology 126, Nr. 4 (15.08.1994): 877–99. http://dx.doi.org/10.1083/jcb.126.4.877.

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We have studied the distribution of poly(A)+ RNA in the mammalian cell nucleus and its transport through nuclear pores by fluorescence and electron microscopic in situ hybridization. Poly(A)+ RNA was detected in the nucleus as a speckled pattern which includes interchromatin granule clusters and perichromatin fibrils. When cells are fractionated by detergent and salt extraction as well as DNase I digestion, the majority of the nuclear poly(A)+ RNA was found to remain associated with the nonchromatin RNP-enriched fraction of the nucleus. After inhibition of RNA polymerase II transcription for 5-10 h, a stable population of poly(A)+ RNA remained in the nucleus and was reorganized into fewer and larger interchromatin granule clusters along with pre-mRNA splicing factors. This stable population of nuclear RNA may play an important role in nuclear function. Furthermore, we have observed that, in actively transcribing cells, the regions of poly(A)+ RNA which reached the nuclear pore complexes appeared as narrow concentrations of RNA suggesting a limited or directed pathway of movement. All of the observed nuclear pores contained poly(A)+ RNA staining suggesting that they are all capable of exporting RNA. In addition, we have directly visualized, for the first time in mammalian cells, the transport of poly(A)+ RNA through the nuclear pore complexes.

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Hofweber, Mario, und Dorothee Dormann. „Friend or foe—Post-translational modifications as regulators of phase separation and RNP granule dynamics“. Journal of Biological Chemistry 294, Nr. 18 (26.12.2018): 7137–50. http://dx.doi.org/10.1074/jbc.tm118.001189.

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Bakthavachalu, Baskar, Joern Huelsmeier, Indulekha P. Sudhakaran, Jens Hillebrand, Amanjot Singh, Arnas Petrauskas, Devasena Thiagarajan et al. „RNP-Granule Assembly via Ataxin-2 Disordered Domains Is Required for Long-Term Memory and Neurodegeneration“. Neuron 98, Nr. 4 (Mai 2018): 754–66. http://dx.doi.org/10.1016/j.neuron.2018.04.032.

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Murakami, Tetsuro, Seema Qamar, Julie Qiaojin Lin, Gabriele S. Kaminski Schierle, Eric Rees, Akinori Miyashita, Ana R. Costa et al. „ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function“. Neuron 88, Nr. 4 (November 2015): 678–90. http://dx.doi.org/10.1016/j.neuron.2015.10.030.

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Percipalle, Piergiorgio, Jian Zhao, Brian Pope, Alan Weeds, Uno Lindberg und Bertil Daneholt. „Actin Bound to the Heterogeneous Nuclear Ribonucleoprotein Hrp36 Is Associated with Balbiani Ring mRNA from the Gene to Polysomes“. Journal of Cell Biology 153, Nr. 1 (02.04.2001): 229–36. http://dx.doi.org/10.1083/jcb.153.1.229.

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In the salivary glands of the dipteran Chironomus tentans, a specific messenger ribonucleoprotein (mRNP) particle, the Balbiani ring (BR) granule, can be visualized during its assembly on the gene and during its nucleocytoplasmic transport. We now show with immunoelectron microscopy that actin becomes associated with the BR particle concomitantly with transcription and is present in the particle in the nucleoplasm. DNase I affinity chromatography experiments with extracts from tissue culture cells indicate that both nuclear and cytoplasmic actin are bound to the heterogeneous RNP (hnRNP) protein hrp36, but not to the hnRNP proteins hrp23 and hrp45. The interaction is likely to be direct as purified actin binds to recombinant hrp36 in vitro. Furthermore, it is demonstrated by cross linking that nuclear as well as cytoplasmic actin are bound to hrp36 in vivo. It is known that hrp36 is added cotranscriptionally along the BR mRNA molecule and accompanies the RNA through the nuclear pores and into polysomes. We conclude that actin is likely to be bound to the BR transcript via hrp36 during the transfer of the mRNA from the gene all the way into polysomes.

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Shorter, James, und J. Paul Taylor. „Disease mutations in the prion-like domains of hnRNPA1 and hnRNPA2/B1 introduce potent steric zippers that drive excess RNP granule assembly“. Rare Diseases 1, Nr. 1 (Januar 2013): e25200. http://dx.doi.org/10.4161/rdis.25200.

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Tian, Siran, Harrison A. Curnutte und Tatjana Trcek. „RNA Granules: A View from the RNA Perspective“. Molecules 25, Nr. 14 (08.07.2020): 3130. http://dx.doi.org/10.3390/molecules25143130.

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RNA granules are ubiquitous. Composed of RNA-binding proteins and RNAs, they provide functional compartmentalization within cells. They are inextricably linked with RNA biology and as such are often referred to as the hubs for post-transcriptional regulation. Much of the attention has been given to the proteins that form these condensates and thus many fundamental questions about the biology of RNA granules remain poorly understood: How and which RNAs enrich in RNA granules, how are transcripts regulated in them, and how do granule-enriched mRNAs shape the biology of a cell? In this review, we discuss the imaging, genetic, and biochemical data, which have revealed that some aspects of the RNA biology within granules are carried out by the RNA itself rather than the granule proteins. Interestingly, the RNA structure has emerged as an important feature in the post-transcriptional control of granule transcripts. This review is part of the Special Issue in the Frontiers in RNA structure in the journal Molecules.

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Lindquist, Michael E., Aaron W. Lifland, Thomas J. Utley, Philip J. Santangelo und James E. Crowe. „Respiratory Syncytial Virus Induces Host RNA Stress Granules To Facilitate Viral Replication“. Journal of Virology 84, Nr. 23 (15.09.2010): 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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Tatavarty, Vedakumar, Marius F. Ifrim, Mikhail Levin, George Korza, Elisa Barbarese, Ji Yu und John H. Carson. „Single-molecule imaging of translational output from individual RNA granules in neurons“. Molecular Biology of the Cell 23, Nr. 5 (März 2012): 918–29. http://dx.doi.org/10.1091/mbc.e11-07-0622.

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Dendritic RNAs are localized and translated in RNA granules. Here we use single-molecule imaging to count the number of RNA molecules in each granule and to record translation output from each granule using Venus fluorescent protein as a reporter. For RNAs encoding activity-regulated cytoskeletal-associated protein (ARC) or fragile X mental retardation protein (FMRP), translation events are spatially clustered near individual granules, and translational output from individual granules is either sporadic or bursty. The probability of bursty translation is greater for Venus-FMRP RNA than for Venus-ARC RNA and is increased in Fmr1-knockout neurons compared to wild-type neurons. Dihydroxyphenylglycine (DHPG) increases the rate of sporadic translation and decreases bursty translation for Venus-FMRP and Venus-ARC RNAs. Single-molecule imaging of translation in individual granules provides new insight into molecular, spatial, and temporal regulation of translation in granules.

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Piotrowska, Joanna, Spencer J. Hansen, Nogi Park, Katarzyna Jamka, Peter Sarnow und Kurt E. Gustin. „Stable Formation of Compositionally Unique Stress Granules in Virus-Infected Cells“. Journal of Virology 84, Nr. 7 (27.01.2009): 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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Gwon, Youngdae, Brian A. Maxwell, Regina-Maria Kolaitis, Peipei Zhang, Hong Joo Kim und 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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Buchan, J. Ross, Denise Muhlrad und Roy Parker. „P bodies promote stress granule assembly in Saccharomyces cerevisiae“. Journal of Cell Biology 183, Nr. 3 (03.11.2008): 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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Zhang, Xue, Fengchao Wang, Yi Hu, Runze Chen, Dawei Meng, Liang Guo, Hailong Lv, Jisong Guan und Yichang Jia. „In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model“. Brain 143, Nr. 5 (01.05.2020): 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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Fomicheva, Anastasia, und 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, Nr. 3 (27.01.2021): 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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Waselle, Laurent, Thierry Coppola, Mitsunori Fukuda, Mariella Iezzi, Aziz El-Amraoui, Christine Petit und Romano Regazzi. „Involvement of the Rab27 Binding Protein Slac2c/MyRIP in Insulin Exocytosis“. Molecular Biology of the Cell 14, Nr. 10 (Oktober 2003): 4103–13. http://dx.doi.org/10.1091/mbc.e03-01-0022.

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Rab27a is a GTPase associated with insulin-containing secretory granules of pancreatic β-cells. Selective reduction of Rab27a expression by RNA interference did not alter granule distribution and basal secretion but impaired exocytosis triggered by insulin secretagogues. Screening for potential effectors of the GTPase revealed that the Rab27a-binding protein Slac2c/MyRIP is associated with secretory granules of β-cells. Attenuation of Slac2c/MyRIP expression by RNA interference did not modify basal secretion but severely impaired hormone release in response to secretagogues. Although β-cells express Myosin-Va, a potential partner of Slac2c/MyRIP, no functional link between the two proteins could be demonstrated. In fact, overexpression of the Myosin-Va binding domain of Slac2c/MyRIP did not affect granule localization and hormone exocytosis. In contrast, overexpression of the actin-binding domain of Slac2c/MyRIP led to a potent inhibition of exocytosis without detectable alteration in granule distribution. This effect was prevented by point mutations that abolish actin binding. Taken together our data suggest that Rab27a and Slac2c/MyRIP are part of a complex mediating the interaction of secretory granules with cortical actin cytoskeleton and participate to the regulation of the final steps of insulin exocytosis.

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Chen, Wenjun, Yabing Hu, Charles F. Lang, Jordan S. Brown, Sierra Schwabach, Xiaoyan Song, Ying Zhang et al. „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 (03.04.2020): 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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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, Nr. 2 (28.03.2019): e201800257. http://dx.doi.org/10.26508/lsa.201800257.

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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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Barbarese, E., D. E. Koppel, M. P. Deutscher, C. L. Smith, K. Ainger, F. Morgan und J. H. Carson. „Protein translation components are colocalized in granules in oligodendrocytes“. Journal of Cell Science 108, Nr. 8 (01.08.1995): 2781–90. http://dx.doi.org/10.1242/jcs.108.8.2781.

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The intracellular distribution of various components of the protein translational machinery was visualized in mouse oligodendrocytes in culture using high resolution fluorescence in situ hybridization and immunofluorescence in conjunction with dual channel confocal laser scanning microscopy. Arginyl-tRNA synthetase, elongation factor 1a, ribosomal RNA, and myelin basic protein mRNA were all co-localized in granules in the processes, veins and membrane sheets of the cell. Colocalization was evaluated by dual channel cross correlation analysis to determine the correlation index (% colocalization) and correlation distance (granule radius), and by single granule ratiometric analysis to determine the distribution of the different components in individual granules. Most granules contained synthetase, elongation factor, ribosomal RNA and myelin basic protein mRNA. These results indicate that several different components of the protein synthetic machinery, including aminoacyl-tRNA synthetases, elongation factors, ribosomes and mRNAs, are colocalized in granules in oligodendrocytes. We propose that these granules are supramolecular complexes containing all of the necessary macromolecular components for protein translation and that they represent a heretofore undescribed subcellular organization of the protein synthetic machinery. This spatial organization may increase the efficiency of protein synthesis and may also provide a vehicle for transport and localization of specific mRNAs within the cell.

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Elbaum-Garfinkle, Shana, Younghoon Kim, Krzysztof Szczepaniak, Carlos Chih-Hsiung Chen, Christian R. Eckmann, Sua Myong und Clifford P. Brangwynne. „The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics“. Proceedings of the National Academy of Sciences 112, Nr. 23 (26.05.2015): 7189–94. http://dx.doi.org/10.1073/pnas.1504822112.

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P granules and other RNA/protein bodies are membrane-less organelles that may assemble by intracellular phase separation, similar to the condensation of water vapor into droplets. However, the molecular driving forces and the nature of the condensed phases remain poorly understood. Here, we show that the Caenorhabditis elegans protein LAF-1, a DDX3 RNA helicase found in P granules, phase separates into P granule-like droplets in vitro. We adapt a microrheology technique to precisely measure the viscoelasticity of micrometer-sized LAF-1 droplets, revealing purely viscous properties highly tunable by salt and RNA concentration. RNA decreases viscosity and increases molecular dynamics within the droplet. Single molecule FRET assays suggest that this RNA fluidization results from highly dynamic RNA–protein interactions that emerge close to the droplet phase boundary. We demonstrate than an N-terminal, arginine/glycine rich, intrinsically disordered protein (IDP) domain of LAF-1 is necessary and sufficient for both phase separation and RNA–protein interactions. In vivo, RNAi knockdown of LAF-1 results in the dissolution of P granules in the early embryo, with an apparent submicromolar phase boundary comparable to that measured in vitro. Together, these findings demonstrate that LAF-1 is important for promoting P granule assembly and provide insight into the mechanism by which IDP-driven molecular interactions give rise to liquid phase organelles with tunable properties.

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Olins, A. L., D. E. Olins und D. P. Bazett-Jones. „Balbiani ring hnRNP substructure visualized by selective staining and electron spectroscopic imaging.“ Journal of Cell Biology 117, Nr. 3 (01.05.1992): 483–91. http://dx.doi.org/10.1083/jcb.117.3.483.

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The Balbiani Rings (BR) in the polytene chromosomes of Chironomus salivary glands are intense sites of transcription. The nascent RNPs fold during transcription into 40-50-nm granules, containing in the mature transcript approximately 37-kb RNA. Using a new nucleic acid specific stain, osmium ammine B on Lowicryl sections, in combination with electron energy filtered imaging of sections containing BR granules, we demonstrate a RNA-rich particulate substructure (10-nm particle diameter; 10-12 particles per BR granule). Elemental imaging supports that these particles are enriched in phosphorus. The possible relationship of these RNA-rich particles to ribonucleosomes is discussed, as well as models for their arrangement in the mature BR granules.

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Källquist, Linda, Markus Hansson, Ann-Maj Persson, Hans Janssen, Jero Calafat, Hans Tapper und Inge Olsson. „The tetraspanin CD63 is involved in granule targeting of neutrophil elastase“. Blood 112, Nr. 8 (15.10.2008): 3444–54. http://dx.doi.org/10.1182/blood-2007-10-116285.

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Abstract Targeting mechanisms of neutrophil elastase (NE) and other luminal proteins stored in myeloperoxidase (MPO)–positive secretory lysosomes/primary granules of neutrophils are unknown. These granules contain an integral membrane protein, CD63, with an adaptor protein-3–dependent granule delivery system. Therefore, we hypothesized that CD63 cooperates in granule delivery of the precursor of NE (proNE). Supporting this hypothesis, an association was demonstrated between CD63 and proNE upon coexpression in COS cells. This also involved augmented cellular retention of proNE requiring intact large extracellular loop of CD63. Furthermore, depletion of CD63 in promyelocytic HL-60 cells with RNA interference or a CD63 mutant caused reduction of cellular NE. However, the proNE steady-state level was similar to wild type in CD63-depleted clones, making it feasible to examine possible effects of CD63 on NE trafficking. Thus, depletion of CD63 led to reduced processing of proNE into mature NE and reduced constitutive secretion. Furthermore, CD63-depleted cells showed a lack of morphologically normal granules, but contained MPO-positive cytoplasmic vacuoles with a lack of proNE and NE. Collectively, our data suggest that granule proteins may cooperate in targeting; CD63 can be involved in ER or Golgi export, cellular retention, and granule targeting of proNE before storage as mature NE.

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Fastenau, Caitlyn, Helen Cifuentes, Grant Kauwe und Tara Tracy. „THE ROLE OF CAPRIN-1 PROTEIN DYSREGULATION IN SYNAPSE DECLINE LEADING TO PROGRESSION OF TAUOPATHIES“. Innovation in Aging 3, Supplement_1 (November 2019): S835—S836. http://dx.doi.org/10.1093/geroni/igz038.3078.

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Abstract Many neurodegenerative diseases are characterized by accumulation of proteins such as tau, a microtubule stabilization protein. Toxic tau forms tangles and affects neuronal synapse function, an early step of neurodegeneration. To focus on synapse function, we highlighted Caprin-1 protein. Through gene ontology, Caprin-1 is related to RNA granule proteins, important for transport and local translation in dendrites. Caprin-1 is of interest for neurodegeneration because it is a memory related protein, transports mRNA in RNA granules, and knock out mice demonstrate memory deficits. As we age, the performance of local translation in the dendrites is compromised and leads to synapse dysfunction. We hypothesize Caprin-1 binds to Tau and becomes disrupted. This leads to the dissolution of RNA granules, inhibition of mRNA transport in dendrites, suppression of translation, and failure of synapse. Early western blot data showed reduced Caprin-1 in PS19 Tau+, supporting our model that Caprin-1 is disrupted in disease models. Through immunohistochemistry, we investigated the localization of Caprin-1 in the mouse hippocampus. We observed Caprin-1 localization to dendrites of CA1 neurons in the hippocampus. Furthermore, Caprin-1 exhibited colocalization with Rps6, an RNA granule marker. This suggests Caprin-1 associates with RNA granules in mouse hippocampus. Finally, we investigated the localization of Caprin-1 in human iPSC-derived neurons. Similar to the mouse hippocampus, we observed localization of Caprin-1 to dendrites of human neurons. In future directions, we will examine whether pathogenic tau alters the association of Caprin-1 with RNA granules and the mechanisms by which pathogenic tau negatively effects synapse function.

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Dang, Yongjun, Nancy Kedersha, Woon-Kai Low, Daniel Romo, Myriam Gorospe, Randal Kaufman, Paul Anderson und 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 (02.09.2006): 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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Moujaber, Ossama, und Ursula Stochaj. „Cytoplasmic RNA Granules in Somatic Maintenance“. Gerontology 64, Nr. 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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Dougherty, M. K., C. Saul, L. Carman, M. D. Nelson und 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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Kotani, Tomoya, Kyota Yasuda, Ryoma Ota und 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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Canonne-Hergaux, François, Jero Calafat, Etienne Richer, Mathieu Cellier, Sergio Grinstein, Neils Borregaard und Philippe Gros. „Expression and subcellular localization of NRAMP1 in human neutrophil granules“. Blood 100, Nr. 1 (01.07.2002): 268–75. http://dx.doi.org/10.1182/blood.v100.1.268.

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Abstract Mutations at the Nramp1 gene cause susceptibility to infections with intracellular pathogens. In human blood, polymorphonuclear (PMN) leukocytes are the most abundant site ofNRAMP1 messenger RNA (mRNA) expression, suggesting that NRAMP1 plays an important role in the activity of these cells. By Northern blot analysis, NRAMP1 mRNA was only detected in most mature neutrophils from bone marrow (band and segmented cells). A high-affinity polyclonal rabbit antihuman NRAMP1 antibody directed against the amino terminus of the protein was produced and used to study cellular and subcellular localization of the protein in primary human neutrophils. Subcellular fractionation of granule populations together with immunoblotting studies with granule-specific markers indicate that NRAMP1 expression is primarily in tertiary granules. These granules are positive for the matrix enzyme gelatinase and the membrane subunit of the vacuolar H+/ATPase and can be recruited for exocytosis by treatment of neutrophils with phorbol myristate acetate. Immunogold studies by cryoelectron microscopy with primary neutrophils confirm that a majority (75%) of NRAMP1-positive granules are also positive for gelatinase, but they also suggest further heterogeneity in this granule population. Presence of NRAMP1 in tertiary granules is in agreement with the late-stage appearance ofNRAMP1 mRNA during neutrophil maturation in bone marrow. Finally, immunofluorescence studies of Candida albicans–containing phagosomes formed in neutrophils indicate that NRAMP1 is recruited from tertiary granules to the phagosomal membrane on phagocytosis, supporting a role for NRAMP1 in the antimicrobial defenses of human neutrophils.

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Dauber, Bianca, David Poon, Theodore dos Santos, Brett A. Duguay, Ninad Mehta, Holly A. Saffran und 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, Nr. 13 (20.04.2016): 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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