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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 -
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 -
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 -
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 -
Journal of Leukocyte Biology Mar 2020Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or... (Review)
Review
Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or effective therapeutic approaches. The role of neutrophil granule exocytosis in multiple steps leading to recruitment and cell injury led each of our laboratories to develop molecular inhibitors that interfere with specific molecular regulators of secretion. This review summarizes neutrophil granule formation and contents, the role granule cargo plays in neutrophil functional responses and neutrophil-mediated diseases, and the mechanisms of granule release that provide the rationale for development of our exocytosis inhibitors. We present evidence for the inhibition of granule exocytosis in vitro and in vivo by those inhibitors and summarize animal data indicating that inhibition of neutrophil exocytosis is a viable therapeutic strategy.
Topics: Animals; Cytoplasmic Granules; Disease; Exocytosis; Humans; Molecular Targeted Therapy; Neutrophils; SNARE Proteins
PubMed: 31990103
DOI: 10.1002/JLB.3RI0120-645R -
The FEBS Journal Jul 2022Neutrophil granulocytes form the first line of host defense against invading pathogens and tissue injury. They are rapidly recruited from the blood to the affected... (Review)
Review
Neutrophil granulocytes form the first line of host defense against invading pathogens and tissue injury. They are rapidly recruited from the blood to the affected sites, where they deploy an impressive arsenal of effectors to eliminate invading microbes and damaged cells. This capacity is endowed in part by readily mobilizable proteins acquired during granulopoiesis and stored in multiple types of cytosolic granules with each granule type containing a unique cargo. Once released, granule proteins contribute to killing bacteria within the phagosome or the extracellular milieu, but are also capable of inflicting collateral tissue damage. Neutrophil-driven inflammation underlies many common diseases. Research over the last decade has documented neutrophil heterogeneity and functional versatility far beyond their antimicrobial function. Emerging evidence indicates that neutrophils utilize granule proteins to interact with innate and adaptive immune cells and orchestrate the inflammatory response. Granule proteins have been identified as important modulators of neutrophil trafficking, reverse transendothelial migration, phagocytosis, neutrophil life span, neutrophil extracellular trap formation, efferocytosis, cytokine activity, and autoimmunity. Hence, defining their roles within the inflammatory locus is critical for minimizing damage to the neighboring tissue and return to homeostasis. Here, we provide an overview of recent advances in the regulation of degranulation, granule protein functions, and signaling in modulating neutrophil-mediated immunity. We also discuss how targeting granule proteins and/or signaling could be harnessed for therapeutic benefits.
Topics: Cytoplasmic Granules; Extracellular Traps; Humans; Immunity, Innate; Inflammation; Neutrophils; Phagocytosis
PubMed: 33683814
DOI: 10.1111/febs.15803 -
Gerontology 2018Cytoplasmic RNA granules represent subcellular compartments that are enriched in protein-bound RNA species. RNA granules are produced by evolutionary divergent... (Review)
Review
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.
Topics: Aging; Animals; Cytoplasmic Granules; Homeostasis; Humans; Mitochondria; Neoplasms; Neurons; Parasites; RNA; RNA Processing, Post-Transcriptional; Ribonucleoproteins; Stress, Physiological; Virus Diseases
PubMed: 29847814
DOI: 10.1159/000488759 -
Viruses Jun 2016Poxviruses are large double-stranded DNA viruses that form viral factories in the cytoplasm of host cells. These viruses encode their own transcription machinery, but... (Review)
Review
Poxviruses are large double-stranded DNA viruses that form viral factories in the cytoplasm of host cells. These viruses encode their own transcription machinery, but rely on host translation for protein synthesis. Thus, poxviruses have to cope with and, in most cases, reprogram host translation regulation. Granule structures, called antiviral granules (AVGs), have been observed surrounding poxvirus viral factories. AVG formation is associated with abortive poxvirus infection, and AVGs contain proteins that are typically found in stress granules (SGs). With certain mutant poxviruses lack of immunoregulatory factor(s), we can specifically examine the mechanisms that drive the formation of these structures. In fact, cytoplasmic macromolecular complexes form during many viral infections and contain sensing molecules that can help reprogram transcription. More importantly, the similarity between AVGs and cytoplasmic structures formed during RNA and DNA sensing events prompts us to reconsider the cause and consequence of these AVGs. In this review, we first summarize recent findings regarding how poxvirus manipulates host translation. Next, we compare and contrast SGs and AVGs. Finally, we review recent findings regarding RNA- and especially DNA-sensing bodies observed during viral infection.
Topics: Animals; Cytoplasmic Granules; Host-Pathogen Interactions; Humans; Poxviridae; Protein Biosynthesis; Stress, Physiological; Transcription, Genetic; Virus Replication
PubMed: 27314378
DOI: 10.3390/v8060169