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Seminars in Cell & Developmental Biology May 2024
Topics: Stress Granules; Processing Bodies; Protein Biosynthesis; RNA, Messenger; Models, Theoretical; Cytoplasmic Granules; Stress, Physiological
PubMed: 38232687
DOI: 10.1016/j.semcdb.2024.01.003 -
Seminars in Cell & Developmental Biology 2024Stress granules and P-bodies are conserved cytoplasmic biomolecular condensates whose assembly and composition are well documented, but whose clearance mechanisms remain... (Review)
Review
Stress granules and P-bodies are conserved cytoplasmic biomolecular condensates whose assembly and composition are well documented, but whose clearance mechanisms remain controversial or poorly described. Such understanding could provide new insight into how cells regulate biomolecular condensate formation and function, and identify therapeutic strategies in disease states where aberrant persistence of stress granules in particular is implicated. Here, I review and compare the contributions of chaperones, the cytoskeleton, post-translational modifications, RNA helicases, granulophagy and the proteasome to stress granule and P-body clearance. Additionally, I highlight the potentially vital role of RNA regulation, cellular energy, and changes in the interaction networks of stress granules and P-bodies as means of eliciting clearance. Finally, I discuss evidence for interplay of distinct clearance mechanisms, suggest future experimental directions, and suggest a simple working model of stress granule clearance.
Topics: Processing Bodies; Stress Granules; Cytoplasmic Granules; RNA Helicases; Cytoplasm
PubMed: 38278052
DOI: 10.1016/j.semcdb.2024.01.002 -
Proceedings of the National Academy of... Apr 2023Many biomolecular condensates appear to form through liquid-liquid phase separation (LLPS). Individual condensate components can often undergo LLPS in vitro, capturing...
Many biomolecular condensates appear to form through liquid-liquid phase separation (LLPS). Individual condensate components can often undergo LLPS in vitro, capturing some features of the native structures. However, natural condensates contain dozens of components with different concentrations, dynamics, and contributions to compartment formation. Most biochemical reconstitutions of condensates have not benefited from quantitative knowledge of these cellular features nor attempted to capture natural complexity. Here, we build on prior quantitative cellular studies to reconstitute yeast RNA processing bodies (P bodies) from purified components. Individually, five of the seven highly concentrated P-body proteins form homotypic condensates at cellular protein and salt concentrations, using both structured domains and intrinsically disordered regions. Combining the seven proteins together at their cellular concentrations with RNA yields phase-separated droplets with partition coefficients and dynamics of most proteins in reasonable agreement with cellular values. RNA delays the maturation of proteins within and promotes the reversibility of, P bodies. Our ability to quantitatively recapitulate the composition and dynamics of a condensate from its most concentrated components suggests that simple interactions between these components carry much of the information that defines the physical properties of the cellular structure.
Topics: Processing Bodies; Saccharomyces cerevisiae; RNA
PubMed: 36972455
DOI: 10.1073/pnas.2214064120 -
Nature Communications Aug 2023Ethylene plays essential roles in rice growth, development and stress adaptation. Translational control of ethylene signaling remains unclear in rice. Here, through...
Ethylene plays essential roles in rice growth, development and stress adaptation. Translational control of ethylene signaling remains unclear in rice. Here, through analysis of an ethylene-response mutant mhz9, we identified a glycine-tyrosine-phenylalanine (GYF) domain protein MHZ9, which positively regulates ethylene signaling at translational level in rice. MHZ9 is localized in RNA processing bodies. The C-terminal domain of MHZ9 interacts with OsEIN2, a central regulator of rice ethylene signaling, and the N-terminal domain directly binds to the OsEBF1/2 mRNAs for translational inhibition, allowing accumulation of transcription factor OsEIL1 to activate the downstream signaling. RNA-IP seq and CLIP-seq analyses reveal that MHZ9 associates with hundreds of RNAs. Ribo-seq analysis indicates that MHZ9 is required for the regulation of ~ 90% of genes translationally affected by ethylene. Our study identifies a translational regulator MHZ9, which mediates translational regulation of genes in response to ethylene, facilitating stress adaptation and trait improvement in rice.
Topics: Oryza; Plant Proteins; Mutation; Ethylenes; RNA; Gene Expression Regulation, Plant
PubMed: 37542048
DOI: 10.1038/s41467-023-40429-0 -
Plant Science : An International... Jun 2015Abiotic and biotic stress conditions are vital determinants in the production of cereals, the major caloric source in human nutrition. Small RNAs, miRNAs and isomiRs are... (Review)
Review
Abiotic and biotic stress conditions are vital determinants in the production of cereals, the major caloric source in human nutrition. Small RNAs, miRNAs and isomiRs are central to post-transcriptional regulation of gene expression in a variety of cellular processes including development and stress responses. Several miRNAs have been identified using new technologies and have roles in stress responses in plants, including cereals. The overall knowledge about the cereal miRNA repertoire, as well as an understanding of complex miRNA mediated mechanisms of target regulation in response to stress conditions, is far from complete. Ongoing efforts that add to our understanding of complex miRNA machinery have implications in plant response to stress conditions. Additionally, sequence variants of miRNAs (isomiRNAs or isomiRs), regulation of their expression through dissection of upstream regulatory elements, the role of Processing-bodies (P-bodies) in miRNA exerted gene regulation and yet unveiled organellar plant miRNAs are newly emerging topics, which will contribute to the elucidation of the miRNA machinery and its role in cereal tolerance against abiotic and biotic stresses.
Topics: Adaptation, Physiological; Edible Grain; Gene Expression; Gene Expression Regulation, Plant; Genes, Plant; MicroRNAs; RNA, Plant; Stress, Physiological
PubMed: 25900561
DOI: 10.1016/j.plantsci.2015.02.008 -
Genes Aug 2023has been a premier model organism for over a century and many discoveries in flies have furthered our understanding of human disease. Flies have been successfully... (Review)
Review
has been a premier model organism for over a century and many discoveries in flies have furthered our understanding of human disease. Flies have been successfully applied to many aspects of health-based research spanning from behavioural addiction, to dysplasia, to RNA dysregulation and protein misfolding. Recently, tissues have been used to study biomolecular condensates and their role in multicellular systems. Identified in a wide range of plant and animal species, biomolecular condensates are dynamic, non-membrane-bound sub-compartments that have been observed and characterised in the cytoplasm and nuclei of many cell types. Condensate biology has exciting research prospects because of their diverse roles within cells, links to disease, and potential for therapeutics. In this review, we will discuss processing bodies (P bodies), a conserved biomolecular condensate, with a particular interest in how can be applied to advance our understanding of condensate biogenesis and their role in disease.
Topics: Animals; Humans; Drosophila; Processing Bodies; Cell Nucleus; Cytoplasm; RNA
PubMed: 37761815
DOI: 10.3390/genes14091675 -
Cell Biology International Apr 2021Processing bodies (PBs) are 100-300 nm cytoplasmic messenger ribonucleoprotein particle (mRNP) granules that regulate eukaryotic gene expression. These cytoplasmic... (Review)
Review
Processing bodies (PBs) are 100-300 nm cytoplasmic messenger ribonucleoprotein particle (mRNP) granules that regulate eukaryotic gene expression. These cytoplasmic compartments harbor messenger RNAs (mRNAs) and several proteins involved in mRNA decay, microRNA silencing, nonsense-mediated mRNA decay, and splicing. Though membrane-less, PB structures are maintained by RNA-protein and protein-protein interactions. PB proteins have intrinsically disordered regions and low complexity domains, which account for its liquid to liquid phase separation. In addition to being dynamic and actively involved in the exchange of materials with other mRNPs and organelles, they undergo changes on various cellular cues and environmental stresses, including viral infections. Interestingly, several PB proteins are individually implicated in cancer development, and no study has addressed the effects on PB dynamics after epigenetic modifications of cancer-associated PB genes. In the current review, we summarize modulations undergone by P bodies or P body components upon viral infections. Furthermore, we discuss the selective and widely investigated PB proteins that undergo methylation changes in cancer and their potential as biomarkers.
Topics: Animals; Cytoplasm; Epigenesis, Genetic; Gene Expression Regulation; Humans; Methylation; MicroRNAs; Neoplasms; Organelles; Protein Processing, Post-Translational; RNA, Messenger; Ribonucleoproteins; Viruses
PubMed: 33325125
DOI: 10.1002/cbin.11527 -
Acta Biochimica Polonica 2016During reaction to stress caused by viral infection, RNA granules are formed in order to protect mRNA. Stress granules (SG) and processing bodies (PB) provide cell... (Review)
Review
During reaction to stress caused by viral infection, RNA granules are formed in order to protect mRNA. Stress granules (SG) and processing bodies (PB) provide cell homeostasis and mRNA stability. They are formed, for example, during polio virus and MRV (mammalian orthoreovirus) infections. Some viruses, such as influenza virus and HTLV-1 (Human T-lymphotropic virus 1), block the formation of granules. In addition, there are viruses like West Nile Virus, Hepatitis C Virus (HCV) or human Herpes viruses, which influence the functioning of the granules.
Topics: Animals; Cytoplasmic Granules; Flaviviridae; Homeostasis; Host-Pathogen Interactions; Humans; Picornaviridae; Protein Biosynthesis; Reoviridae; Retroviridae; Virus Diseases
PubMed: 26894234
DOI: 10.18388/abp.2015_1060 -
Nature Communications Jun 2022The formation of membraneless organelles can be a proteotoxic stress control mechanism that locally condenses a set of components capable of mediating protein...
The formation of membraneless organelles can be a proteotoxic stress control mechanism that locally condenses a set of components capable of mediating protein degradation decisions. The breadth of mechanisms by which cells respond to stressors and form specific functional types of membraneless organelles, is incompletely understood. We found that Bcl2-associated athanogene 2 (BAG2) marks a distinct phase-separated membraneless organelle, triggered by several forms of stress, particularly hyper-osmotic stress. Distinct from well-known condensates such as stress granules and processing bodies, BAG2-containing granules lack RNA, lack ubiquitin and promote client degradation in a ubiquitin-independent manner via the 20S proteasome. These organelles protect the viability of cells from stress and can traffic to the client protein, in the case of Tau protein, on the microtubule. Components of these ubiquitin-independent degradation organelles include the chaperone HSP-70 and the 20S proteasome activated by members of the PA28 (PMSE) family. BAG2 condensates did not co-localize with LAMP-1 or p62/SQSTM1. When the proteasome is inhibited, BAG2 condensates and the autophagy markers traffic to an aggresome-like structure.
Topics: Autophagy; Humans; Molecular Chaperones; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin
PubMed: 35654899
DOI: 10.1038/s41467-022-30751-4 -
Stem Cells (Dayton, Ohio) Jan 2021Mesenchymal stromal cells (MSCs) are widely used in clinical trials because of their ability to modulate inflammation. The success of MSCs has been variable over...
Mesenchymal stromal cells (MSCs) are widely used in clinical trials because of their ability to modulate inflammation. The success of MSCs has been variable over 25 years, most likely due to an incomplete understanding of their mechanism. After MSCs are injected, they traffic to the lungs and other tissues where they are rapidly cleared. Despite being cleared, MSCs suppress the inflammatory response in the long term. Using human cord tissue-derived MSCs (hCT-MSCs), we demonstrated that hCT-MSCs directly interact and reprogram monocytes and macrophages. After engaging hCT-MSCs, monocytes and macrophages engulfed cytoplasmic components of live hCT-MSCs, then downregulated gene programs for antigen presentation and costimulation, and functionally suppressed the activation of helper T cells. We determined that low-density lipoprotein receptor-related proteins on monocytes and macrophages mediated the engulfment of hCT-MSCs. Since a large amount of cellular information can be packaged in cytoplasmic RNA processing bodies (p-bodies), we generated p-body deficient hCT-MSCs and confirmed that they failed to reprogram monocytes and macrophages in vitro and in vivo. hCT-MSCs suppressed an inflammatory response caused by a nasal lipopolysaccharide challenge. Although both control and p-body deficient hCT-MSCs were engulfed by infiltrating lung monocytes and macrophages, p-body deficient hCT-MSCs failed to suppress inflammation and downregulate MHC-II. Overall, we identified a novel mechanism by which hCT-MSCs indirectly suppressed a T-cell response by directly interacting and reprogramming monocytes and macrophages via p-bodies. The results of this study suggest a novel mechanism for how MSCs can reprogram the inflammatory response and have long-term effects to suppress inflammation.
Topics: Animals; Cellular Reprogramming; Heterografts; Humans; Macrophages; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Monocytes
PubMed: 33166420
DOI: 10.1002/stem.3292