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RNA Biology Jun 2017Spliceosomal snRNPs are complex particles that proceed through a fascinating maturation pathway. Several steps of this pathway are closely linked to nuclear non-membrane... (Review)
Review
Spliceosomal snRNPs are complex particles that proceed through a fascinating maturation pathway. Several steps of this pathway are closely linked to nuclear non-membrane structures called Cajal bodies. In this review, I summarize the last 20 y of research in this field. I primarily focus on snRNP biogenesis, specifically on the steps that involve Cajal bodies. I also evaluate the contribution of the Cajal body in snRNP quality control and discuss the role of snRNPs in Cajal body formation.
Topics: Animals; Coiled Bodies; Humans; Protein Binding; RNA Processing, Post-Transcriptional; Ribonucleoproteins, Small Nuclear; Spliceosomes; Transcription, Genetic
PubMed: 27627834
DOI: 10.1080/15476286.2016.1231359 -
Nature Communications Nov 2021Mutations in the cardiac splicing factor RBM20 lead to malignant dilated cardiomyopathy (DCM). To understand the mechanism of RBM20-associated DCM, we engineered...
Mutations in the cardiac splicing factor RBM20 lead to malignant dilated cardiomyopathy (DCM). To understand the mechanism of RBM20-associated DCM, we engineered isogenic iPSCs with DCM-associated missense mutations in RBM20 as well as RBM20 knockout (KO) iPSCs. iPSC-derived engineered heart tissues made from these cell lines recapitulate contractile dysfunction of RBM20-associated DCM and reveal greater dysfunction with missense mutations than KO. Analysis of RBM20 RNA binding by eCLIP reveals a gain-of-function preference of mutant RBM20 for 3' UTR sequences that are shared with amyotrophic lateral sclerosis (ALS) and processing-body associated RNA binding proteins (FUS, DDX6). Deep RNA sequencing reveals that the RBM20 R636S mutant has unique gene, splicing, polyadenylation and circular RNA defects that differ from RBM20 KO. Super-resolution microscopy verifies that mutant RBM20 maintains very limited nuclear localization potential; rather, the mutant protein associates with cytoplasmic processing bodies (DDX6) under basal conditions, and with stress granules (G3BP1) following acute stress. Taken together, our results highlight a pathogenic mechanism in cardiac disease through splicing-dependent and -independent pathways.
Topics: Cardiomyopathies; Cardiomyopathy, Dilated; DEAD-box RNA Helicases; DNA Helicases; Gain of Function Mutation; Gene Knockdown Techniques; Humans; Induced Pluripotent Stem Cells; Male; Mutation; Mutation, Missense; Poly-ADP-Ribose Binding Proteins; Proto-Oncogene Proteins; RNA Helicases; RNA Recognition Motif Proteins; RNA Splicing; RNA-Binding Proteins; Ribonucleoproteins
PubMed: 34732726
DOI: 10.1038/s41467-021-26623-y -
Scientific Reports Nov 2022A new class of deformation is presented for a planar loop structure made up of slender elastic bodies and joints. In demonstrating the circumferential shortening of the...
A new class of deformation is presented for a planar loop structure made up of slender elastic bodies and joints. In demonstrating the circumferential shortening of the multi-jointed elastic loop, diverse three-dimensional (3D) deformations emerge through piecewise deflections and discrete rotations. These 3D morphologies correspond to conformations of molecular ring systems. Through image processing, the 3D reconstructions of the deformed structures are characterized by number, geometry, and initial imperfections of the body segments. We elucidate from measurements that the conformational deformation without self-stress results from a cyclical assembly of compressive bending of elastic bodies with high shear rigidity. The mechanical insights gained may apply in controlling the polymorphism exhibited by the cyclical structures across scales.
Topics: Molecular Conformation; Image Processing, Computer-Assisted; Pressure
PubMed: 36411324
DOI: 10.1038/s41598-022-24355-7 -
Sensors (Basel, Switzerland) Dec 2023The Celestial Object Rendering TOol (CORTO) offers a powerful solution for generating synthetic images of celestial bodies, catering to the needs of space mission...
The Celestial Object Rendering TOol (CORTO) offers a powerful solution for generating synthetic images of celestial bodies, catering to the needs of space mission design, algorithm development, and validation. Through rendering, noise modeling, hardware-in-the-loop testing, and post-processing functionalities, CORTO creates realistic scenarios. It offers a versatile and comprehensive solution for generating synthetic images of celestial bodies, aiding the development and validation of image processing and navigation algorithms for space missions. This work illustrates its functionalities in detail for the first time. The importance of a robust validation pipeline to test the tool's accuracy against real mission images using metrics like normalized cross-correlation and structural similarity is also illustrated. CORTO is a valuable asset for advancing space exploration and navigation algorithm development and has already proven effective in various projects, including CubeSat design, lunar missions, and deep learning applications. While the tool currently covers a range of celestial body simulations, mainly focused on minor bodies and the Moon, future enhancements could broaden its capabilities to encompass additional planetary phenomena and environments.
PubMed: 38067968
DOI: 10.3390/s23239595 -
Frontiers in Cellular and Infection... 2019Regulation of RNA homeostasis or "RNAstasis" is a central step in eukaryotic gene expression. From transcription to decay, cellular messenger RNAs (mRNAs) associate with... (Review)
Review
Regulation of RNA homeostasis or "RNAstasis" is a central step in eukaryotic gene expression. From transcription to decay, cellular messenger RNAs (mRNAs) associate with specific proteins in order to regulate their entire cycle, including mRNA localization, translation and degradation, among others. The best characterized of such RNA-protein complexes, today named membraneless organelles, are Stress Granules (SGs) and Processing Bodies (PBs) which are involved in RNA storage and RNA decay/storage, respectively. Given that SGs and PBs are generally associated with repression of gene expression, viruses have evolved different mechanisms to counteract their assembly or to use them in their favor to successfully replicate within the host environment. In this review we summarize the current knowledge about the viral regulation of SGs and PBs, which could be a potential novel target for the development of broad-spectrum antiviral therapies.
Topics: Animals; Cytoplasmic Granules; Gene Expression Regulation; Gene Expression Regulation, Viral; Host-Pathogen Interactions; Humans; Organelles; Signal Transduction; Stress, Physiological; Virus Diseases; Virus Physiological Phenomena; Virus Replication; Viruses
PubMed: 31681621
DOI: 10.3389/fcimb.2019.00336 -
Viruses Jun 2016The general stress and innate immune responses are closely linked and overlap at many levels. The outcomes of these responses serve to reprogram host expression patterns... (Review)
Review
The general stress and innate immune responses are closely linked and overlap at many levels. The outcomes of these responses serve to reprogram host expression patterns to prevent viral invasions. In turn, viruses counter attack these cell responses to ensure their replication. The mechanisms by which viruses attempt to control host cell responses are as varied as the number of different virus families. One of the most recurrent strategies used by viruses to control the antiviral response of the cell is to hijack the translation machinery of the host, such that viral proteins are preferentially synthesized, while the expression of the stress and antiviral responses of the cell are blocked at the translation level. Here, we will review how rotaviruses, an important agent of acute severe gastroenteritis in children, overcome the stress responses of the cell to establish a productive infectious cycle.
Topics: Gene Expression Regulation; Host-Pathogen Interactions; Humans; Immunity, Innate; Protein Biosynthesis; Rotavirus; Rotavirus Infections; Stress, Physiological; Virus Replication
PubMed: 27338442
DOI: 10.3390/v8060162 -
Cell Reports Jan 2023Membraneless condensates, such as stress granules (SGs) and processing bodies (P-bodies), have attracted wide attention due to their unique feature of rapid response to...
Membraneless condensates, such as stress granules (SGs) and processing bodies (P-bodies), have attracted wide attention due to their unique feature of rapid response to stress without first requiring nuclear feedback. In this study, we identify diaphanous-related formin 3 (DIAPH3), an actin nucleator, as a scaffold protein to initiate liquid-liquid phase separation (LLPS) and form abundant cytosolic phase-separated DIAPH3 granules (D-granules) in mammalian cells such as HeLa, HEK293, and fibroblasts under various stress conditions. Neither mRNAs nor known stress-associated condensate markers, such as G3BP1, G3BP2, and TIA1 for SGs and DCP1A for P-bodies, are detected in D-granules. Using overexpression and knockout of DIAPH3, pharmacological interventions, and optogenetics, we further demonstrate that stress-induced D-granules spatially sequester DIAPH3 within the condensation to inhibit the assembly of actin filaments in filopodia. This study reveals that D-granules formed by LLPS act as a regulatory hub for actin cytoskeletal remodeling in response to stress.
Topics: Animals; Humans; DNA Helicases; Actins; HEK293 Cells; Poly-ADP-Ribose Binding Proteins; RNA Helicases; RNA Recognition Motif Proteins; Actin Cytoskeleton; Mammals; Formins
PubMed: 36640348
DOI: 10.1016/j.celrep.2022.111986 -
Trends in Plant Science Jul 2023The SERRATE (SE) protein is involved in the processing of RNA polymerase II (RNAPII) transcripts. It is associated with different complexes engaged in different aspects... (Review)
Review
The SERRATE (SE) protein is involved in the processing of RNA polymerase II (RNAPII) transcripts. It is associated with different complexes engaged in different aspects of plant RNA metabolism, including assemblies involved in transcription, splicing, polyadenylation, miRNA biogenesis, and RNA degradation. SE stability and interactome properties can be influenced by phosphorylation. SE exhibits an intriguing liquid-liquid phase separation property that may be important in the assembly of different RNA-processing bodies. Therefore, we propose that SE seems to participate in the coordination of different RNA-processing steps and can direct the fate of transcripts, targeting them for processing or degradation when they cannot be properly processed or are synthesized in excess.
Topics: Arabidopsis Proteins; Arabidopsis; Calcium-Binding Proteins; RNA Processing, Post-Transcriptional; Serrate-Jagged Proteins; RNA; MicroRNAs; RNA, Plant; Gene Expression Regulation, Plant
PubMed: 37019716
DOI: 10.1016/j.tplants.2023.03.009 -
Journal of Experimental Neuroscience 2015As more evidence points to a clear role for astrocytes in synaptic processing, synaptogenesis and cognition, continuing research on astrocytic function could lead to... (Review)
Review
As more evidence points to a clear role for astrocytes in synaptic processing, synaptogenesis and cognition, continuing research on astrocytic function could lead to strategies for neurodegenerative disease prevention. Reactive astrogliosis results in astrocyte proliferation early in injury and disease states and is considered neuroprotective, indicating a role for astrocytes in disease etiology. This review describes the different types of human cortical astrocytes and the current evidence regarding adult cortical astrogenesis in injury and degenerative disease. A role for disrupted astrogenesis as a cause of cortical degeneration, with a focus on the tauopathies and synucleinopathies, will also be considered.
PubMed: 26568684
DOI: 10.4137/JEN.S25520 -
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