Roles for myosin Va in RNA transport and turnover

2012 ◽  
Vol 40 (6) ◽  
pp. 1416-1420 ◽  
Author(s):  
Mary W. McCaffrey ◽  
Andrew J. Lindsay
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Class V ◽  
Processing Bodies ◽  
Surface Receptors ◽  
P Bodies ◽  
Myosin Va ◽  
Myosin Vb ◽  
Actin Cables ◽  
The Brain

Mammals express three class V myosins. Myosin Va is widely expressed, but enriched in the brain, testes and melanocytes, myosin Vb is expressed ubiquitously, and myosin Vc is believed to be epithelium-specific. Myosin Va is the best characterized of the three and plays a key role in the transport of cargo to the plasma membrane. Its cargo includes cell-surface receptors, pigment and organelles such as the endoplasmic reticulum. It is also emerging that RNA and RNA-BPs (RNA-binding proteins) make up another class of myosin Va cargo. It has long been established that the yeast class V myosin, Myo4p, transports mRNAs along actin cables into the growing bud, and now several groups have reported a similar role for class V myosins in higher eukaryotes. Myosin Va has also been implicated in the assembly and maintenance of P-bodies (processing bodies), cytoplasmic foci that are involved in mRNA storage and degradation. The present review examines the evidence that myosin Va plays a role in the transport and turnover of mRNA.

scholarly journals Competitive binding of CUGBP1 and HuR to occludin mRNA controls its translation and modulates epithelial barrier function

2013 ◽  
Vol 24 (2) ◽  
pp. 85-99 ◽  
Author(s):  
Ting-Xi Yu ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Liu ◽  
Lan Xiao ◽  
...  
Keyword(s):  
Barrier Function ◽  
Untranslated Region ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Monolayer ◽  
Intestinal Epithelial ◽  
Processing Bodies ◽  
Epithelial Barrier Function ◽  
P Bodies ◽  
The Stability

RNA-binding proteins CUG-binding protein 1 (CUGBP1) and HuR are highly expressed in epithelial tissues and modulate the stability and translation of target mRNAs. Here we present evidence that CUGBP1 and HuR jointly regulate the translation of occludin and play a crucial role in the maintenance of tight junction (TJ) integrity in the intestinal epithelial cell monolayer. CUGBP1 and HuR competed for association with the same occludin 3′-untranslated region element and regulated occludin translation competitively and in opposite directions. CUGBP1 overexpression decreased HuR binding to occludin mRNA, repressed occludin translation, and compromised the TJ barrier function, whereas HuR overexpression inhibited CUGBP1 association with occludin mRNA and promoted occludin translation, thereby enhancing the barrier integrity. Repression of occludin translation by CUGBP1 was due to the colocalization of CUGBP1 and tagged occludin RNA in processing bodies (P-bodies), and this colocalization was prevented by HuR overexpression. These findings indicate that CUGBP1 represses occludin translation by increasing occludin mRNA recruitment to P-bodies, whereas HuR promotes occludin translation by blocking occludin mRNA translocation to P-bodies via the displacement of CUGBP1.

scholarly journals Insights into the multifaceted role of circular RNAs: implications for Parkinson’s disease pathogenesis and diagnosis

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Epaminondas Doxakis
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Clinical Manifestations ◽  
Alpha Synuclein ◽  
Circular Rnas ◽  
Age Related ◽  
And Function ◽  
The Brain

AbstractParkinson’s disease (PD) is a complex, age-related, neurodegenerative disease whose etiology, pathology, and clinical manifestations remain incompletely understood. As a result, care focuses primarily on symptoms relief. Circular RNAs (circRNAs) are a large class of mostly noncoding RNAs that accumulate with aging in the brain and are increasingly shown to regulate all aspects of neuronal and glial development and function. They are generated by the spliceosome through the backsplicing of linear RNA. Although their biological role remains largely unknown, they have been shown to regulate transcription and splicing, act as decoys for microRNAs and RNA binding proteins, used as templates for translation, and serve as scaffolding platforms for signaling components. Considering that they are stable, diverse, and detectable in easily accessible biofluids, they are deemed promising biomarkers for diagnosing diseases. CircRNAs are differentially expressed in the brain of patients with PD, and growing evidence suggests that they regulate PD pathogenetic processes. Here, the biogenesis, expression, degradation, and detection of circRNAs, as well as their proposed functions, are reviewed. Thereafter, research linking circRNAs to PD-related processes, including aging, alpha-synuclein dysregulation, neuroinflammation, and oxidative stress is highlighted, followed by recent evidence for their use as prognostic and diagnostic biomarkers for PD.

scholarly journals CUGBP1 and HuR regulate E-cadherin translation by altering recruitment of E-cadherin mRNA to processing bodies and modulate epithelial barrier function

2016 ◽  
Vol 310 (1) ◽  
pp. C54-C65 ◽  
Author(s):  
Ting-Xi Yu ◽  
Bei-Lin Gu ◽  
Jun-Kai Yan ◽  
Jie Zhu ◽  
Wei-Hui Yan ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Intestinal Barrier ◽  
Primary Component ◽  
Epithelial Barrier ◽  
Barrier Dysfunction ◽  
Processing Bodies ◽  
Epithelial Barrier Function ◽  
Epithelial Barrier Dysfunction ◽  
E Cadherin

The effectiveness and stability of epithelial barrier depend on apical junctional complexes, which consist of tight junctions (TJs) and adherens junctions (AJs). E-cadherin is the primary component of AJs, and it is essential for maintenance of cell-to-cell interactions and regulates the epithelial barrier. However, the exact mechanism underlying E-cadherin expression, particularly at the posttranscriptional level, remains largely unknown. RNA-binding proteins CUG-binding protein 1 (CUGBP1) and HU antigen R (HuR) are highly expressed in the intestinal epithelial tissues and modulate the stability and translation of target mRNAs. Here, we present evidence that CUGBP1 and HuR interact directly with the 3′-untranslated region of E-cadherin mRNA and regulate E-cadherin translation. CUGBP1 overexpression in Caco-2 cells inhibited E-cadherin translation by increasing the recruitment of E-cadherin mRNA to processing bodies (PBs), thus resulting in an increase in paracellular permeability. Overexpression of HuR exhibited an opposite effect on E-cadherin expression by preventing the translocation of E-cadherin mRNA to PBs and therefore prevented CUGBP1-induced repression of E-cadherin expression. Elevation of HuR also abolished the CUGBP1-induced epithelial barrier dysfunction. These findings indicate that CUGBP1 and HuR negate each other's effects in regulating E-cadherin translation by altering the recruitment of E-cadherin mRNA to PBs and play an important role in the regulation of intestinal barrier integrity under various pathophysiological conditions.

scholarly journals miR-503 represses CUG-binding protein 1 translation by recruiting CUGBP1 mRNA to processing bodies

2012 ◽  
Vol 23 (1) ◽  
pp. 151-162 ◽  
Author(s):  
Yu-Hong Cui ◽  
Lan Xiao ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Liu ◽  
...  
Keyword(s):  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Mrna Levels ◽  
Intestinal Epithelial ◽  
Coding Region ◽  
Processing Bodies ◽  
Target Mrnas ◽  
Repressive Effect

microRNAs (miRNAs) and RNA-binding proteins (RBPs) jointly regulate gene expression at the posttranscriptional level and are involved in many aspects of cellular functions. The RBP CUG-binding protein 1 (CUGBP1) destabilizes and represses the translation of several target mRNAs, but the exact mechanism that regulates CUGBP1 abundance remains elusive. In this paper, we show that miR-503, computationally predicted to associate with three sites of the CUGBP1 mRNA, represses CUGBP1 expression. Overexpression of an miR-503 precursor (pre-miR-503) reduced the de novo synthesis of CUGBP1 protein, whereas inhibiting miR-503 by using an antisense RNA (antagomir) enhanced CUGBP1 biosynthesis and elevated its abundance; neither intervention changed total CUGBP1 mRNA levels. Studies using heterologous reporter constructs revealed a greater repressive effect of miR-503 through the CUGBP1 coding region sites than through the single CUGBP1 3′-untranslated region target site. CUGBP1 mRNA levels in processing bodies (P-bodies) increased in cells transfected with pre-miR-503, while silencing P-body resident proteins Ago2, RCK, or LSm4 decreased miR-503–mediated repression of CUGBP1 expression. Decreasing the levels of cellular polyamines reduced endogenous miR-503 levels and promoted CUGBP1 expression, an effect that was prevented by ectopic miR-503 overexpression. Repression of CUGBP1 by miR-503 in turn altered the expression of CUGBP1 target mRNAs and thus increased the sensitivity of intestinal epithelial cells to apoptosis. These findings identify miR-503 as both a novel regulator of CUGBP1 expression and a modulator of intestinal epithelial homoeostasis.

scholarly journals Stress Granule-Mediated Oxidized RNA Decay in P-Body: Hypothetical Role of ADAR1, Tudor-SN, and STAU1

2021 ◽  
Vol 8 ◽  
Author(s):  
Ravi Kumar Alluri ◽  
Zhongwei Li ◽  
Keith R. McCrae
Keyword(s):  
Oxidative Stress ◽  
Inverted Repeat ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Relevant Literature ◽  
Stress Granule ◽  
P Bodies ◽  
Docking Mechanism

Reactive oxygen species (ROS) generated under oxidative stress (OS) cause oxidative damage to RNA. Recent studies have suggested a role for oxidized RNA in several human disorders. Under the conditions of oxidative stress, mRNAs released from polysome dissociation accumulate and initiate stress granule (SG) assembly. SGs are highly enriched in mRNAs, containing inverted repeat (IR) Alus in 3′ UTRs, AU-rich elements, and RNA-binding proteins. SGs and processing bodies (P-bodies) transiently interact through a docking mechanism to allow the exchange of RNA species. However, the types of RNA species exchanged, and the mechanisms and outcomes of exchange are still unknown. Specialized RNA-binding proteins, including adenosine deaminase acting on RNA (ADAR1-p150), with an affinity toward inverted repeat Alus, and Tudor staphylococcal nuclease (Tudor-SN) are specifically recruited to SGs under OS along with an RNA transport protein, Staufen1 (STAU1), but their precise biochemical roles in SGs and SG/P-body docking are uncertain. Here, we critically review relevant literature and propose a hypothetical mechanism for the processing and decay of oxidized-RNA in SGs/P-bodies, as well as the role of ADAR1-p150, Tudor-SN, and STAU1.

scholarly journals Proteomic analysis of Dhh1 complexes reveals a role for Hsp40 chaperone Ydj1 in yeast P-body assembly

2015 ◽  
Author(s):  
Gregory A. Cary ◽  
Dani B.N. Vinh ◽  
Patrick May ◽  
Rolf Kuestner ◽  
Aimee M. Dudley
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Active Role ◽  
Low Complexity ◽  
Mitochondrial Rna ◽  
P Bodies ◽  
Glucose Depletion ◽  
Catalytic Rnas ◽  
Rnp Granules

P-bodies (PB) are ribonucleoprotein (RNP) complexes that aggregate into cytoplasmic foci when cells are exposed to stress. While the conserved mRNA decay and translational repression machineries are known components of PB, how and why cells assemble RNP complexes into large foci remain unclear. Using mass spectrometry to analyze proteins immunoisolated with the core PB protein Dhh1, we show that a considerable number of proteins contain low-complexity (LC) sequences, similar to proteins highly represented in mammalian RNP granules. We also show that the Hsp40 chaperone Ydj1, which contains an LC domain and controls prion protein aggregation, is required for the formation of Dhh1-GFP foci upon glucose depletion. New classes of proteins that reproducibly co-enrich with Dhh1-GFP during PB induction include proteins involved in nucleotide or amino acid metabolism, glycolysis, tRNA aminoacylation, and protein folding. Many of these proteins have been shown to form foci in response to other stresses. Finally, analysis of RNA associated with Dhh1-GFP shows enrichment of mRNA encoding the PB protein Pat1 and catalytic RNAs along with their associated mitochondrial RNA-binding proteins, suggesting an active role for RNA in PB function. Thus, global characterization of PB composition has uncovered proteins and RNA that are important for PB assembly.

scholarly journals Single-molecule imaging of mRNA localization and regulation during the integrated stress response

2018 ◽  
Author(s):  
Johannes H. Wilbertz ◽  
Franka Voigt ◽  
Ivana Horvathova ◽  
Gregory Roth ◽  
Yinxiu Zhan ◽  
...  
Keyword(s):  
Stress Response ◽  
Single Molecule ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Localization ◽  
Mrna Degradation ◽  
Integrated Stress Response ◽  
Cellular Space ◽  
Processing Bodies ◽  
Functional Consequence

AbstractBiological phase transitions form membrane-less organelles that generate distinct cellular environments. How molecules are partitioned between these compartments and the surrounding cellular space and the functional consequence of this localization is not well understood. Here, we report the localization of mRNA to stress granules(SGs) and processing bodies(PBs), which are distinct biomolecular condensates, and its effect on translation and mRNA degradation during the integrated stress response. Using single mRNA imaging in living human cells, we find that the interactions of mRNAs with SGs and PBs have different dynamics and that specific RNA binding proteins can anchor mRNAs within these compartments. During recovery from stress, mRNAs that were within SGs and PBs are translated and degraded at similar rates as their cytosolic counterparts.

scholarly journals An Algorithm to Quantify Inducible Protein Condensates In Eukaryotic Cells

2021 ◽  
Author(s):  
Jeremy C Hunn ◽  
Katherine M. Hutchinson ◽  
Joshua B Kelley ◽  
Daniel Reines
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Strain Differences ◽  
Growth Defect ◽  
Protein Distribution ◽  
Granule Formation ◽  
P Bodies ◽  
Subcellular Compartments ◽  
Manual Counting ◽  
Inducible Protein

Reorganization of cellular proteins into subcellular compartments, such as the rearrangement of RNA-binding proteins into cytoplasmic stress granules and P-bodies, is a well-recognized, widely studied physiological process currently under intense investigation. Using the assembly of a novel, inducible, nuclear granule formed from the east RNA-binding transcription termination factors Nab3 and Nrd1, we present a freely-accessible, high-throughput and unbiased algorithm written in MATLAB that detects and measures protein distribution, partitioning, and sequestration into subcellular compartments captured by fluorescence microscopy; an invaluable advancement to current image analysis methods which utilize experiment-specific custom scripts or subjective manual counting. Employing our algorithm, we quantified thousands of cells, ensuring rigorous examination of Nab3 granule formation across strains with reproducible statistical analyses. We document strain differences in Nab3 granule formation and an associated growth defect. Additionally, we applied our algorithm to immunofluorescent images of the inducible polymerization into filaments of an enzyme in human cells, demonstrating the algorithms versatility and adaptability.

scholarly journals Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

2019 ◽  
Author(s):  
Max Koppers ◽  
Roberta Cagnetta ◽  
Toshiaki Shigeoka ◽  
Lucia C.S. Wunderlich ◽  
Sixian Zhao ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Axon Growth ◽  
Mrna Translation ◽  
Local Translation ◽  
Simultaneous Exposure ◽  
Surface Receptors ◽  
Guidance Cue ◽  
Selective Translation ◽  
Specific Mrnas

AbstractDuring neuronal wiring, extrinsic cues trigger the local translation of specific mRNAs in axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors bind to distinct sets of mRNAs and RNA-binding proteins. Cue stimulation induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs in retinal axon growth cones. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by simultaneous exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and provide a general model for the rapid, localized and selective control of cue-induced translation.

scholarly journals RES complex is associated with intron definition and required for zebrafish early embryogenesis

2017 ◽  
Author(s):  
Juan P. Fernandez ◽  
Miguel A. Moreno-Mateos ◽  
Andre Gohr ◽  
Shun Hang Chan ◽  
Manuel Irimia ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Splicing ◽  
Vertebrate Development ◽  
Loss Of Function ◽  
Recognition Elements ◽  
Splicing Patterns ◽  
The Brain ◽  
Intron Definition

AbstractPre-mRNA splicing is a critical step of gene expression in eukaryotes. Transcriptome-wide splicing patterns are complex and primarily regulated by a diverse set of recognition elements and associated RNA-binding proteins. The retention and splicing (RES) complex is formed by three different proteins (Bud13p, Pml1p and Snu17p) and is involved in splicing in yeast. However, the importance of the RES complex for vertebrate splicing, the intronic features associated with its activity, and its role in development are unknown. In this study, we have generated loss-of-function mutants for the three components of the RES complex in zebrafish and showed that they are required during early development. The mutants showed a marked neural phenotype with increased cell death in the brain and a decrease in differentiated neurons. Transcriptomic analysis of bud13, snip1 (pml1) and rbmx2 (snu17) mutants revealed a global defect in intron splicing, with strong mis-splicing of a subset of introns. We found these RES-dependent introns were short, rich in GC and flanked by GC depleted exons, all of which are features associated with intron definition. Using these features we developed a predictive model that classifies RES dependent introns. Altogether, our study uncovers the essential role of the RES complex during vertebrate development and provides new insights into its function during splicing.

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