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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 -
RNA Biology May 2012In eukaryotic cells, components of messenger ribonucleoproteins (mRNPs) are often detected in cytoplasmic granules, such as processing bodies (P-bodies) and stress...
In eukaryotic cells, components of messenger ribonucleoproteins (mRNPs) are often detected in cytoplasmic granules, such as processing bodies (P-bodies) and stress granules (SGs) where translationally repressed mRNAs accumulate. RAP55A, which is an RNA binding component of mRNPs, acts as a translational repressor and localizes to P-bodies and SGs. We found here that a homologous protein RAP55B also localized to P-bodies when expressed in human cultured cells. When RAP55A or RAP55B was highly expressed in the cells, they induced the formation of SG-like large cytoplasmic mRNP granules that contained both P-body and SG components, indicating that RAP55 is important for the assembly of cytoplasmic mRNP granules. In addition, we found that RAP55A associated with protein arginine methyltransferases PRMT1 and PRMT5. Multiple arginine residues of RAP55A were indeed asymmetrically dimethylated in the cell and PRMT1 was shown to be a component of large mRNP granules induced by RAP55A overexpression. Although PRMT1 did not accumulate in P-bodies, siRNA-mediated knockdown of PRMT1 impaired the localization of RAP55A to P-bodies, while other components were still retained in these structures. Thus, our data indicate that RAP55 is important for the assembly of cytoplasmic mRNP granules and that PRMT1 is required for RAP55A to localize to P-bodies.
Topics: Amino Acid Motifs; Amino Acid Sequence; Arginine; Cytoplasmic Granules; Gene Knockdown Techniques; HeLa Cells; Humans; Methylation; Molecular Sequence Data; Peptide Fragments; Protein Binding; Protein Isoforms; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein Transport; Protein-Arginine N-Methyltransferases; RNA, Small Interfering; Repressor Proteins; Ribonucleoproteins; Sequence Analysis, DNA
PubMed: 22614839
DOI: 10.4161/rna.19527 -
Frontiers in Molecular Neuroscience 2023Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of... (Review)
Review
Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.
Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result in the formation of ribonucleoprotein (RNP) condensates, which are critical for RNA processing, mRNA transport, stability, stress granule assembly, and translation. Stress granules, neuronal transport granules, and processing bodies are examples of cytoplasmic RNP condensates, while the nucleolus and Cajal bodies are representative nuclear RNP condensates. In neurons, RNP condensates promote long-range mRNA transport and local translation in the dendrites and axon, and are essential for spatiotemporal regulation of gene expression, axonal integrity and synaptic function. Mutations of RBPs and/or pathologic mislocalization and aggregation of RBPs are hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. ALS/FTD-linked mutations of RBPs alter the strength and reversibility of multivalent interactions with other RBPs and RNAs, resulting in aberrant phase transitions. These aberrant RNP condensates have detrimental functional consequences on mRNA stability, localization, and translation, and ultimately lead to compromised axonal integrity and synaptic function in disease. Pathogenic protein aggregation is dependent on various factors, and aberrant dynamically arrested RNP condensates may serve as an initial nucleation step for pathologic aggregate formation. Recent studies have focused on identifying mechanisms by which neurons resolve phase transitioned condensates to prevent the formation of pathogenic inclusions/aggregates. The present review focuses on the phase separation of neurodegenerative disease-linked RBPs, physiological functions of RNP condensates, and the pathologic role of aberrant phase transitions in neurodegenerative disease, particularly ALS/FTD. We also examine cellular mechanisms that contribute to the resolution of aberrant condensates in neurons, and potential therapeutic approaches to resolve aberrantly phase transitioned condensates at a molecular level.
PubMed: 37720552
DOI: 10.3389/fnmol.2023.1242925 -
ADAD2 interacts with RNF17 in P-bodies to repress the Ping-pong cycle in pachytene piRNA biogenesis.The Journal of Cell Biology May 2023Pachytene piRNA biogenesis is a hallmark of the germline, distinct from another wave of pre-pachytene piRNA biogenesis with regard to the lack of a secondary...
Pachytene piRNA biogenesis is a hallmark of the germline, distinct from another wave of pre-pachytene piRNA biogenesis with regard to the lack of a secondary amplification process known as the Ping-pong cycle. However, the underlying molecular mechanism and the venue for the suppression of the Ping-pong cycle remain elusive. Here, we showed that a testis-specific protein, ADAD2, interacts with a TDRD family member protein RNF17 and is associated with P-bodies. Importantly, ADAD2 directs RNF17 to repress Ping-pong activity in pachytene piRNA biogenesis. The P-body localization of RNF17 requires the intrinsically disordered domain of ADAD2. Deletion of Adad2 or Rnf17 causes the mislocalization of each other and subsequent Ping-pong activity derepression, secondary piRNAs overproduced, and disruption of P-body integrity at the meiotic stage, thereby leading to spermatogenesis arrested at the round spermatid stage. Collectively, by identifying the ADAD2-dependent mechanism, our study reveals a novel function of P-bodies in suppressing Ping-pong activity in pachytene piRNA biogenesis.
Topics: Male; Meiotic Prophase I; Piwi-Interacting RNA; Processing Bodies; RNA, Small Interfering; Spermatogenesis
PubMed: 36930220
DOI: 10.1083/jcb.202206067 -
Current Genetics Feb 2020The eukaryotic cell is subdivided into distinct functional domains by the presence of both membrane-bound and membraneless organelles. The latter include cytoplasmic... (Review)
Review
The eukaryotic cell is subdivided into distinct functional domains by the presence of both membrane-bound and membraneless organelles. The latter include cytoplasmic granules, like the Processing-body (P-body), that are induced in response to stress and contain specific sets of mRNAs and proteins. Although P-bodies have been evolutionarily conserved, we do not yet understand the full extent of their biological functions in the cell. Early studies suggested that these structures might be sites of mRNA decay as the first protein constituents identified were enzymes involved in mRNA processing. However, more recent work indicates that this is not likely to be the primary function of these granules and has even suggested that P-bodies are sites of long-term mRNA storage. Interestingly, P-bodies and other ribonucleoprotein granules have been found to also contain a variety of signaling molecules, including protein kinases and phosphatases key to the normal control of cell growth and survival. Therefore, P-bodies could have a role in the modulation of cell signaling during particular types of stress. This review discusses both the general implications of such a proposal and one particular example that illustrates how the granule recruitment of a protein kinase can impact overall cell physiology.
Topics: Cytoplasmic Granules; Eukaryotic Cells; Gene Expression Regulation; Organelles; RNA Processing, Post-Transcriptional; RNA Stability; RNA, Messenger; Signal Transduction; Vault Ribonucleoprotein Particles
PubMed: 31317215
DOI: 10.1007/s00294-019-01016-3 -
Proceedings of the National Academy of... Jun 2019
PubMed: 31182577
DOI: 10.1073/pnas.1908132116 -
Biochimica Et Biophysica Acta May 2009Processing bodies (P-bodies) are cytoplasmic domains that have been implicated in critical steps of the regulation of gene expression, including mRNA decay and...
Processing bodies (P-bodies) are cytoplasmic domains that have been implicated in critical steps of the regulation of gene expression, including mRNA decay and post-transcriptional gene silencing. Previously, we reported that PCBP2 (Poly-(rC) Binding Protein 2), a facilitator of IRES-mediated translation, is a novel P-body component. Interestingly, PCBP2 is recruited to only a subset of Dcp1a-positive P-bodies, which may reflect functional diversity among these structures. In this study, we examined the selective P-body localization of PCBP2 in detail. Co-localization studies between Dcp1a and PCBP2 revealed that PCBP2 is present in approximately 40% of P-bodies. While PCBP2 was more likely to reside in larger P-bodies, P-body size did not seem to be the sole determinant, and puromycin-induced enlargement of P-bodies only modestly increased the percentage of PCBP2-positive P-bodies. Photobleaching experiments demonstrated that the accumulation of PCBP2 to specific P-bodies is a dynamic process, which does not involve the protein's transcription-dependent nucleo-cytoplasmic shuttling activity. Finally, we found that PCBP1, a close relative of PCBP2, localizes to P-bodies in a similar manner to PCBP2. Taken together, these results establish the compositional diversity among P-bodies, and that PCBP2, probably in complex with other mRNP factors, may dynamically recognize such differences and accumulate to specific P-bodies.
Topics: Argonaute Proteins; Cytoplasm; Cytoplasmic Vesicles; DNA-Binding Proteins; Endoribonucleases; Eukaryotic Initiation Factors; Fluorescence Recovery After Photobleaching; Fluorescent Dyes; HeLa Cells; Heterogeneous-Nuclear Ribonucleoproteins; Humans; Protein Synthesis Inhibitors; Puromycin; RNA-Binding Proteins; Recombinant Fusion Proteins; Trans-Activators
PubMed: 19230839
DOI: 10.1016/j.bbamcr.2009.02.002 -
Trends in Cancer Oct 2021Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under... (Review)
Review
Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies.
Topics: Cytoplasmic Granules; Cytoplasmic Ribonucleoprotein Granules; Neoplasms; Processing Bodies; Ribonucleoproteins; Stress Granules
PubMed: 34144941
DOI: 10.1016/j.trecan.2021.05.006 -
Advances in Experimental Medicine and... 2019In recent years, cytoplasmic RNA granules, which are micron-sized membrane-less entities formed by phase separation, have progressively gained recognition as essential... (Review)
Review
In recent years, cytoplasmic RNA granules, which are micron-sized membrane-less entities formed by phase separation, have progressively gained recognition as essential constituents of neuronal RNA metabolism. Stress granules form under adverse growth conditions in order to protect nontranslating mRNA, shift translation toward the production of prosurvival factors, as well as potentially serve as hubs for intracellular signaling. In contrast, processing bodies play a role in RNA degradation in both stressed and homeostatic conditions. Lastly, transport granules permit, as their name indicates, the transport of mRNA within neurons. All of these granule subtypes are required for proper neuronal function; thus, impairments in their regulation and/or composition are expected to be deleterious. Here, we review these cytoplasmic RNA granule subtypes and discuss how they have been implicated in some neurodegenerative diseases.
Topics: Cytoplasmic Granules; Humans; Neurodegenerative Diseases; RNA, Messenger
PubMed: 31811636
DOI: 10.1007/978-3-030-31434-7_8 -
Wiley Interdisciplinary Reviews. RNA 2011Degradation of messenger RNAs (mRNAs) plays an essential role in modulation of gene expression and in quality control of mRNA biogenesis. Nearly all major mRNA decay... (Review)
Review
Degradation of messenger RNAs (mRNAs) plays an essential role in modulation of gene expression and in quality control of mRNA biogenesis. Nearly all major mRNA decay pathways characterized thus far in eukaryotes are initiated by deadenylation, i.e., shortening of the mRNA 3(') poly(A) tail. Deadenylation is often a rate-limiting step for mRNA degradation and translational silencing, making it an important control point for both processes. In this review, we discuss the fundamental principles that govern mRNA deadenylation in eukaryotes. We use several major mRNA decay pathways in mammalian cells to illustrate mechanisms and regulation of deadenylation-dependent mRNA decay, including decay directed by adenine/uridine-rich elements (AREs) in the 3(') -untranslated region (UTR), the rapid decay mediated by destabilizing elements in protein-coding regions, the surveillance mechanism that detects and degrades nonsense-containing mRNA [i.e., nonsense-mediated decay (NMD)], the decay directed by miRNAs, and the default decay pathway for stable messages. Mammalian mRNA deadenylation involves two consecutive phases mediated by the PAN2-PAN3 and the CCR4-CAF1 complexes, respectively. Decapping takes place after deadenylation and may serve as a backup mechanism to trigger mRNA decay if initial deadenylation is compromised. In addition, we discuss how deadenylation impacts the dynamics of RNA processing bodies (P-bodies), where nontranslatable mRNAs can be degraded or stored. Possible models for mechanisms of various deadenylation-dependent mRNA decay pathways are also discussed.
Topics: Animals; Humans; Kinetics; Models, Biological; Poly A; Polyadenylation; RNA Processing, Post-Transcriptional; RNA Stability; RNA, Messenger; Signal Transduction
PubMed: 21957004
DOI: 10.1002/wrna.40