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Trends in Cell Biology Sep 2016Stress granules are assemblies of untranslating messenger ribonucleoproteins (mRNPs) that form from mRNAs stalled in translation initiation. Stress granules form through... (Review)
Review
Stress granules are assemblies of untranslating messenger ribonucleoproteins (mRNPs) that form from mRNAs stalled in translation initiation. Stress granules form through interactions between mRNA-binding proteins that link together populations of mRNPs. Interactions promoting stress granule formation include conventional protein-protein interactions as well as interactions involving intrinsically disordered regions (IDRs) of proteins. Assembly and disassembly of stress granules are modulated by various post-translational modifications as well as numerous ATP-dependent RNP or protein remodeling complexes, illustrating that stress granules represent an active liquid wherein energy input maintains their dynamic state. Stress granule formation modulates the stress response, viral infection, and signaling pathways. Persistent or aberrant stress granule formation contributes to neurodegenerative disease and some cancers.
Topics: Animals; Cytoplasmic Granules; Disease; Humans; Intrinsically Disordered Proteins; Models, Biological; Ribonucleoproteins; Stress, Physiological
PubMed: 27289443
DOI: 10.1016/j.tcb.2016.05.004 -
Molecular Cell Oct 2019Stress granules and P-bodies are cytosolic biomolecular condensates that dynamically form by the phase separation of RNAs and proteins. They participate in translational... (Review)
Review
Stress granules and P-bodies are cytosolic biomolecular condensates that dynamically form by the phase separation of RNAs and proteins. They participate in translational control and buffer the proteome. Upon stress, global translation halts and mRNAs bound to the translational machinery and other proteins coalesce to form stress granules (SGs). Similarly, translationally stalled mRNAs devoid of translation initiation factors shuttle to P-bodies (PBs). Here, we review the cumulative progress made in defining the protein components that associate with mammalian SGs and PBs. We discuss the composition of SG and PB proteomes, supported by a new user-friendly database (http://rnagranuledb.lunenfeld.ca/) that curates current literature evidence for genes or proteins associated with SGs or PBs. As previously observed, the SG and PB proteomes are biased toward intrinsically disordered regions and have a high propensity to contain primary sequence features favoring phase separation. We also provide an outlook on how the various components of SGs and PBs may cooperate to organize and form membraneless organelles.
Topics: Animals; Cytoplasmic Granules; Humans; Proteome; RNA, Messenger
PubMed: 31626750
DOI: 10.1016/j.molcel.2019.09.014 -
Cell Jan 2016Stress granules are mRNA-protein granules that form when translation initiation is limited, and they are related to pathological granules in various neurodegenerative...
Stress granules are mRNA-protein granules that form when translation initiation is limited, and they are related to pathological granules in various neurodegenerative diseases. Super-resolution microscopy reveals stable substructures, referred to as cores, within stress granules that can be purified. Proteomic analysis of stress granule cores reveals a dense network of protein-protein interactions and links between stress granules and human diseases and identifies ATP-dependent helicases and protein remodelers as conserved stress granule components. ATP is required for stress granule assembly and dynamics. Moreover, multiple ATP-driven machines affect stress granules differently, with the CCT complex inhibiting stress granule assembly, while the MCM and RVB complexes promote stress granule persistence. Our observations suggest that stress granules contain a stable core structure surrounded by a dynamic shell with assembly, disassembly, and transitions between the core and shell modulated by numerous protein and RNA remodeling complexes.
Topics: Adenosine Triphosphatases; Animals; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cytoplasmic Granules; DEAD-box RNA Helicases; Humans; Neurodegenerative Diseases; Proteome; RNA, Messenger; Repressor Proteins; Ribonucleoproteins; Saccharomyces cerevisiae Proteins; Sodium Azide; Yeasts
PubMed: 26777405
DOI: 10.1016/j.cell.2015.12.038 -
Cell Sep 2015Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic...
Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy-diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.
Topics: Amyloid; Cell Line, Tumor; Cytoplasmic Granules; DNA-Binding Proteins; HeLa Cells; Heterogeneous Nuclear Ribonucleoprotein A1; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Humans; Protein Aggregation, Pathological
PubMed: 26406374
DOI: 10.1016/j.cell.2015.09.015 -
Molecular Cell Nov 2017Stress granules are mRNA-protein assemblies formed from nontranslating mRNAs. Stress granules are important in the stress response and may contribute to some...
Stress granules are mRNA-protein assemblies formed from nontranslating mRNAs. Stress granules are important in the stress response and may contribute to some degenerative diseases. Here, we describe the stress granule transcriptome of yeast and mammalian cells through RNA-sequencing (RNA-seq) analysis of purified stress granule cores and single-molecule fluorescence in situ hybridization (smFISH) validation. While essentially every mRNA, and some noncoding RNAs (ncRNAs), can be targeted to stress granules, the targeting efficiency varies from <1% to >95%. mRNA accumulation in stress granules correlates with longer coding and UTR regions and poor translatability. Quantifying the RNA-seq analysis by smFISH reveals that only 10% of bulk mRNA molecules accumulate in mammalian stress granules and that only 185 genes have more than 50% of their mRNA molecules in stress granules. These results suggest that stress granules may not represent a specific biological program of messenger ribonucleoprotein (mRNP) assembly, but instead form by condensation of nontranslating mRNPs in proportion to their length and lack of association with ribosomes.
Topics: Cell Line, Tumor; Cytoplasmic Granules; Humans; RNA, Fungal; RNA, Messenger; Saccharomyces cerevisiae; Transcriptome
PubMed: 29129640
DOI: 10.1016/j.molcel.2017.10.015 -
ELife Sep 2016Stress granules are non-membrane bound RNA-protein (RNP) assemblies that form when translation initiation is limited and contain a biphasic structure with stable core...
Stress granules are non-membrane bound RNA-protein (RNP) assemblies that form when translation initiation is limited and contain a biphasic structure with stable core structures surrounded by a less concentrated shell. The order of assembly and disassembly of these two structures remains unknown. Time course analysis of granule assembly suggests that core formation is an early event in granule assembly. Stress granule disassembly is also a stepwise process with shell dissipation followed by core clearance. Perturbations that alter liquid-liquid phase separations (LLPS) driven by intrinsically disordered protein regions (IDR) of RNA binding proteins in vitro have the opposite effect on stress granule assembly in vivo. Taken together, these observations argue that stress granules assemble through a multistep process initiated by stable assembly of untranslated mRNPs into core structures, which could provide sufficient high local concentrations to allow for a localized LLPS driven by IDRs on RNA binding proteins.
Topics: Arsenites; Cell Line, Tumor; Cell Survival; Cycloheximide; Cytoplasmic Granules; Digitonin; Glycols; HeLa Cells; Humans; Intrinsically Disordered Proteins; Peptide Chain Initiation, Translational; RNA, Messenger; Ribonucleoproteins; Saccharomyces cerevisiae; Sodium Compounds; Stress, Physiological; Time Factors
PubMed: 27602576
DOI: 10.7554/eLife.18413 -
Biochimica Et Biophysica Acta Jul 2015Cancer cells are exposed to adverse conditions in the tumor microenvironment, and utilize post-transcriptional control mechanisms to re-program gene expression in ways... (Review)
Review
Cancer cells are exposed to adverse conditions in the tumor microenvironment, and utilize post-transcriptional control mechanisms to re-program gene expression in ways that enhance cell survival. Stress granules and processing bodies are RNA-containing granules that contribute to this process by modulating cellular signaling pathways, metabolic machinery, and stress response programs. This review examines evidence implicating RNA granules in the pathogenesis of cancer and discusses their potential as targets for anticancer therapies. This article is part of a Special Issue entitled: Translation and Cancer.
Topics: Animals; Cytoplasmic Granules; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA, Neoplasm
PubMed: 25482014
DOI: 10.1016/j.bbagrm.2014.11.009 -
Genetics Mar 2022The transparency of Caenorhabditis elegans provides a unique window to observe and study the function of germ granules. Germ granules are specialized ribonucleoprotein... (Review)
Review
The transparency of Caenorhabditis elegans provides a unique window to observe and study the function of germ granules. Germ granules are specialized ribonucleoprotein (RNP) assemblies specific to the germline cytoplasm, and they are largely conserved across Metazoa. Within the germline cytoplasm, they are positioned to regulate mRNA abundance, translation, small RNA production, and cytoplasmic inheritance to help specify and maintain germline identity across generations. Here we provide an overview of germ granules and focus on the significance of more recent observations that describe how they further demix into sub-granules, each with unique compositions and functions.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cytoplasmic Granules; Gene Expression Regulation; Germ Cell Ribonucleoprotein Granules; Germ Cells
PubMed: 35239965
DOI: 10.1093/genetics/iyab195 -
Wiley Interdisciplinary Reviews. RNA May 2019In response to stress, cells must quickly reprogram gene expression to adapt and survive. This is achieved in part by altering levels of mRNAs and their translation into... (Review)
Review
In response to stress, cells must quickly reprogram gene expression to adapt and survive. This is achieved in part by altering levels of mRNAs and their translation into proteins. Recently, the formation of two stress-induced messenger ribonucleoprotein (mRNP) assemblies named stress granules and processing bodies has been postulated to directly impact gene expression during stress. These assemblies sequester and concentrate specific proteins and RNAs away from the larger cytoplasm during stress, thereby providing a layer of posttranscriptional gene regulation with the potential to directly impact mRNA levels, protein translation, and cell survival. The function of these granules has generally been ascribed either by the protein components concentrated into them or, more broadly, by global changes that occur during stress. Recent proteome- and transcriptome-wide studies have provided a more complete view of stress-induced mRNP granule composition in varied cell types and stress conditions. However, direct measurements of the phenotypic and functional consequences of stress granule and processing body formation are lacking. This leaves our understanding of their roles during stress incomplete. Continued study into the function of these granules will be an important part in elucidating how cells respond to and survive stressful environmental changes. This article is categorized under: Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Export and Localization > RNA Localization.
Topics: Cytoplasmic Granules; Eukaryotic Cells; Protein Biosynthesis; RNA Processing, Post-Transcriptional; Ribonucleoproteins; Stress, Physiological
PubMed: 30793528
DOI: 10.1002/wrna.1524 -
Development (Cambridge, England) Jan 2023A hallmark of all germ cells is the presence of germ granules: assemblies of proteins and RNA that lack a delineating membrane and are proposed to form via condensation....
A hallmark of all germ cells is the presence of germ granules: assemblies of proteins and RNA that lack a delineating membrane and are proposed to form via condensation. Germ granules across organisms share several conserved components, including factors required for germ cell fate determination and maintenance, and are thought to be linked to germ cell development. The molecular functions of germ granules, however, remain incompletely understood. In this Development at a Glance article, we survey germ granules across organisms and developmental stages, and highlight emerging themes regarding granule regulation, dynamics and proposed functions.
Topics: Animals; Caenorhabditis elegans; Germ Cell Ribonucleoprotein Granules; Germ Cells; RNA-Binding Proteins; RNA; Cytoplasmic Granules
PubMed: 36715566
DOI: 10.1242/dev.201037