Regulation of ELAV/Hu RNA-binding proteins by phosphorylation

2014 ◽  
Vol 42 (4) ◽  
pp. 1147-1151 ◽  
Author(s):  
Ulrike Bräuer ◽  
Emanuela Zaharieva ◽  
Matthias Soller
Keyword(s):  
Cellular Localization ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Sequence Motifs ◽  
Functional Diversification ◽  
Embryonic Lethal ◽  
Hu Proteins ◽  
Abnormal Visual

ELAV (embryonic lethal/abnormal visual system)/Hu proteins comprise a family of highly related neuronal RBPs (RNA-binding proteins) involved in many aspects of mRNA processing. Although they bind to highly similar short sequence motifs, they have acquired diverse functions suggesting that cellular signalling is important for their functional diversification. Indeed, ELAV/Hu proteins harbour many phosphorylatable amino acids. In the present article, we review our current knowledge about phosphorylation of ELAV/Hu proteins and how phosphorylation affects cellular localization of ELAV/Hu proteins and their binding to RNA.

scholarly journals Concentration and localization of co-expressed ELAV/Hu proteins control specificity of mRNA processing

2015 ◽  
pp. MCB.00473-15 ◽  
Author(s):  
Emanuela Zaharieva ◽  
Irmgard U. Haussmann ◽  
Ulrike Bräuer ◽  
Matthias Soller
Keyword(s):  
Cellular Localization ◽  
Binding Proteins ◽  
Target Genes ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Processing ◽  
Hu Proteins ◽  
Sex Lethal ◽  
Specific Regulation

Neuronally co-expressed ELAV/Hu proteins comprise a family of highly related RNA binding proteins, which bind to very similar cognate sequences. How this redundancy is linked to in vivo function and how gene specific regulation is achieved, has not been clear. Analysis of mutants inDrosophilaELAV/Hu family proteins ELAV, FNE and RBP9, and genetic interactions among them, indicates mostly independent roles in neuronal development and function, but convergence in the regulation of synaptic plasticity. Conversely, ELAV, FNE, RBP9 and human HuR bind ELAV target RNA in vitro with similar affinity. Likewise, all can regulate alternative splicing of ELAV target genes in non-neuronal wing-disc cells and substitute ELAV in eye development with artificially increased expression, but can also substantially restore ELAV's biological functions, when expressed under the control of theelavgene. Furthermore, ELAV related Sex-lethal can regulate ELAV targets and ELAV/Hu proteins can interfere with sexual differentiation. An ancient relationship to Sex-lethal is revealed by gonadal expression of RBP9 providing a maternal failsafe for dosage compensation. Our results indicate that highly related ELAV/Hu RNA binding proteins select targets for mRNA processing based on expression levels and sub-cellular localization, but only minimally by altered RNA binding specificity.

scholarly journals Targeting the RNA-Binding Protein HuR as Potential Thera-Peutic Approach for Neurological Disorders: Focus on Amyo-Trophic Lateral Sclerosis (ALS), Spinal Muscle Atrophy (SMA) and Multiple Sclerosis

2021 ◽  
Vol 22 (19) ◽  
pp. 10394
Author(s):  
Vittoria Borgonetti ◽  
Elisabetta Coppi ◽  
Nicoletta Galeotti
Keyword(s):  
Neurological Disorders ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Demyelinating Diseases ◽  
Double Chain ◽  
Embryonic Lethal ◽  
Hu Proteins ◽  
Abnormal Visual ◽  
Lateral Sclerosis

The importance of precise co- and post-transcriptional processing of RNA in the regulation of gene expression has become increasingly clear. RNA-binding proteins (RBPs) are a class of proteins that bind single- or double-chain RNA, with different affinities and selectivity, thus regulating the various functions of RNA and the fate of the cells themselves. ELAV (embryonic lethal/abnormal visual system)/Hu proteins represent an important family of RBPs and play a key role in the fate of newly transcribed mRNA. ELAV proteins bind AU-rich element (ARE)-containing transcripts, which are usually present on the mRNA of proteins such as cytokines, growth factors, and other proteins involved in neuronal differentiation and maintenance. In this review, we focused on a member of ELAV/Hu proteins, HuR, and its role in the development of neurodegenerative disorders, with a particular focus on demyelinating diseases.

scholarly journals A unique ribonucleoprotein complex assembles preferentially on ecdysone-responsive sites in Drosophila melanogaster.

1993 ◽  
Vol 13 (9) ◽  
pp. 5323-5330 ◽  
Author(s):  
S A Amero ◽  
M J Matunis ◽  
E L Matunis ◽  
J W Hockensmith ◽  
G Raychaudhuri ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Polytene Chromosomes ◽  
Cell Extract ◽  
Sequence Motifs ◽  
Drosophila Cell ◽  
Rnase Digestion

The protein on ecdysone puffs (PEP) is associated preferentially with active ecdysone-inducible puffs on Drosophila polytene chromosomes and contains sequence motifs characteristic of transcription factors and RNA-binding proteins (S. A. Amero, S. C. R. Elgin, and A. L. Beyer, Genes Dev. 5:188-200, 1991). PEP is associated with RNA in vivo, as demonstrated here by the sensitivity of PEP-specific chromosomal immunostaining in situ to RNase digestion and by the immunopurification of PEP in Drosophila cell extract with heterogeneous nuclear ribonucleoprotein (hnRNP) complexes. As revealed by sequential immunostaining, PEP is found on a subset of chromosomal sites bound by the HRB (heterogeneous nuclear RNA-binding) proteins, which are basic Drosophila hnRNPs. These observations lead us to suggest that a unique, PEP-containing hnRNP complex assembles preferentially on the transcripts of ecdysone-regulated genes in Drosophila melanogaster presumably to expedite the transcription and/or processing of these transcripts.

Functional diversity of the hnRNPs: past, present and perspectives

2010 ◽  
Vol 430 (3) ◽  
pp. 379-392 ◽  
Author(s):  
Siew Ping Han ◽  
Yue Hang Tang ◽  
Ross Smith
Keyword(s):  
Translational Regulation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Functional Divergence ◽  
Nucleic Acid Metabolism ◽  
Heterogeneous Nuclear Ribonucleoproteins ◽  
Nascent Transcripts

The hnRNPs (heterogeneous nuclear ribonucleoproteins) are RNA-binding proteins with important roles in multiple aspects of nucleic acid metabolism, including the packaging of nascent transcripts, alternative splicing and translational regulation. Although they share some general characteristics, they vary greatly in terms of their domain composition and functional properties. Although the traditional grouping of the hnRNPs as a collection of proteins provided a practical framework, which has guided much of the research on them, this approach is becoming increasingly incompatible with current knowledge about their structural and functional divergence. Hence, we review the current literature to examine hnRNP diversity, and discuss how this impacts upon approaches to the classification of RNA-binding proteins in general.

scholarly journals Trypanosoma brucei RNA Binding Proteins p34 and p37 Mediate NOPP44/46 Cellular Localization via the Exportin 1 Nuclear Export Pathway

2007 ◽  
Vol 6 (12) ◽  
pp. 2206-2213 ◽  
Author(s):  
Kristina Hellman ◽  
Kimberly Prohaska ◽  
Noreen Williams
Keyword(s):  
Amino Acid ◽  
Trypanosoma Brucei ◽  
Nuclear Export ◽  
Cellular Localization ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Nuclear Export Signal ◽  
Amino Acid Sequences ◽  
Protein Levels

ABSTRACT We have previously identified and characterized two novel nuclear RNA binding proteins, p34 and p37, which have been shown to interact with a family of nucleolar phosphoproteins, NOPP44/46, in Trypanosoma brucei. These proteins are nearly identical, the major difference being an 18-amino-acid insert in the N terminus of p37. In order to characterize the interaction between p34 and p37 and NOPP44/46, we have utilized an RNA interference (RNAi) cell line that specifically targets p34 and p37. Within these RNAi cells, we detected a disruption of a higher-molecular-weight complex containing NOPP44/46, as well as a dramatic increase in nuclear NOPP44/46 protein levels. We demonstrated that no change occurred in NOPP44/46 mRNA steady-state levels or stability, nor was there a change in cellular protein levels. These results led us to investigate whether p34 and p37 regulate NOPP44/46 cellular localization. Examination of the p34 and p37 amino acid sequences revealed a leucine-rich nuclear export signal, which interacts with the nuclear export factor exportin 1. Immune capture experiments demonstrated that p34, p37, and NOPP44/46 associate with exportin 1. When these experiments were performed with p34/p37 RNAi cells, NOPP44/46 no longer associated with exportin 1. Sequential immune capture experiments demonstrated that p34, p37, NOPP44/46, and exportin 1 exist in a common complex. Inhibiting exportin 1-mediated nuclear export led to an increase in nuclear NOPP44/46 proteins, indicating that they are exported from the nucleus via this pathway. Together, our results demonstrate that p34 and p37 regulate NOPP44/46 cellular localization by facilitating their association with exportin 1.

scholarly journals Inferring Sequence-Structure Preferences of RNA-Binding Proteins with Convolutional Residual Networks

2018 ◽  
Author(s):  
Peter K. Koo ◽  
Praveen Anand ◽  
Steffan B. Paul ◽  
Sean R. Eddy
Keyword(s):  
Rna Structure ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Sequence Data ◽  
Synthetic Data ◽  
Sequence Motifs ◽  
Negative Effects ◽  
Interpretable Model ◽  
Saliency Analysis

AbstractTo infer the sequence and RNA structure specificities of RNA-binding proteins (RBPs) from experiments that enrich for bound sequences, we introduce a convolutional residual network which we call ResidualBind. ResidualBind significantly outperforms previous methods on experimental data from many RBP families. We interrogate ResidualBind to identify what features it has learned from high-affinity sequences with saliency analysis along with 1st-order and 2nd-orderin silicomutagenesis. We show that in addition to sequence motifs, ResidualBind learns a model that includes the number of motifs, their spacing, and both positive and negative effects of RNA structure context. Strikingly, ResidualBind learns RNA structure context, including detailed base-pairing relationships, directly from sequence data, which we confirm on synthetic data. ResidualBind is a powerful, flexible, and interpretable model that can uncovercis-recognition preferences across a broad spectrum of RBPs.

Regulation of the ELAV target ewg: insights from an evolutionary perspective

2008 ◽  
Vol 36 (3) ◽  
pp. 502-504 ◽  
Author(s):  
Matthias Soller ◽  
Min Li ◽  
Irmgard U. Haussmann
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Processing ◽  
Untranslated Regions ◽  
Cellular Environment ◽  
Specific Regulation ◽  
Abnormal Visual ◽  
Recent Sequencing

ELAV (embryonic lethal abnormal visual system)/Hu family proteins are prototype RNA-binding proteins with binding preferences for AU-rich regions. Due to frequent occurrence of AU-rich motifs in introns and untranslated regions, it is poorly understood how gene-specific RNA-binding proteins, such as ELAV/Hu family members, recognize their complement of target RNAs in a complex cellular environment. The powerful genetic tools of Drosophila make the fruitfly an excellent model to study alternative mRNA processing in vivo in a developing organism. Recent sequencing of 12 Drosophila genomes will provide a novel resource to enhance our understanding of how gene-specific regulation of mRNA processing is achieved by ELAV/Hu family proteins.

scholarly journals The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells

2013 ◽  
Vol 33 (6) ◽  
pp. 1233-1243 ◽  
Author(s):  
Yunling Wang ◽  
Gillian Vogel ◽  
Zhenbao Yu ◽  
Stéphane Richard
Keyword(s):  
Glial Cells ◽  
Rna Splicing ◽  
Cellular Localization ◽  
Binding Proteins ◽  
Rna Binding ◽  
Egf Receptor ◽  
Cell Function ◽  
Rna Binding Proteins ◽  
Glioblastoma Cells ◽  
Egfr Expression

Thequaking(qkI) gene encodes 3 major alternatively spliced isoforms that contain unique sequences at their C termini dictating their cellular localization. QKI-5 is predominantly nuclear, whereas QKI-6 is distributed throughout the cell and QKI-7 is cytoplasmic. The QKI isoforms are sequence-specific RNA binding proteins expressed mainly in glial cells modulating RNA splicing, export, and stability. Herein, we identify a new role for the QKI proteins in the regulation of microRNA (miRNA) processing. We observed that small interfering RNA (siRNA)-mediated QKI depletion of U343 glioblastoma cells leads to a robust increase in miR-7 expression. The processing from primary to mature miR-7 was inhibited in the presence QKI-5 and QKI-6 but not QKI-7, suggesting that the nuclear localization plays an important role in the regulation of miR-7 expression. The primary miR-7-1 was bound by the QKI isoforms in a QKI response element (QRE)-specific manner. We observed that the pri-miR-7-1 RNA was tightly bound to Drosha in the presence of the QKI isoforms, and this association was not observed in siRNA-mediated QKI or Drosha-depleted U343 glioblastoma cells. Moreover, the presence of the QKI isoforms led to an increase presence of pri-miR-7 in nuclear foci, suggesting that pri-miR-7-1 is retained in the nucleus by the QKI isoforms. miR-7 is known to target the epidermal growth factor (EGF) receptor (EGFR) 3′ untranslated region (3′-UTR), and indeed, QKI-deficient U343 cells had reduced EGFR expression and decreased ERK activation in response to EGF. Elevated levels of miR-7 are associated with cell cycle arrest, and it was observed that QKI-deficient U343 that harbor elevated levels of miR-7 exhibited defects in cell proliferation that were partially rescued by the addition of a miR-7 inhibitor. These findings suggest that the QKI isoforms regulate glial cell function and proliferation by regulating the processing of certain miRNAs.

scholarly journals Identifying the sequence specificities of circRNA-binding proteins based on a capsule network architecture

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhengfeng Wang ◽  
Xiujuan Lei
Keyword(s):  
Binding Sites ◽  
Network Architecture ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Circular Rnas ◽  
Sequence Motifs ◽  
Rna Motifs ◽  
Classification Framework ◽  
Bound Sequence

Abstract Background Circular RNAs (circRNAs) are widely expressed in cells and tissues and are involved in biological processes and human diseases. Recent studies have demonstrated that circRNAs can interact with RNA-binding proteins (RBPs), which is considered an important aspect for investigating the function of circRNAs. Results In this study, we design a slight variant of the capsule network, called circRB, to identify the sequence specificities of circRNAs binding to RBPs. In this model, the sequence features of circRNAs are extracted by convolution operations, and then, two dynamic routing algorithms in a capsule network are employed to discriminate between different binding sites by analysing the convolution features of binding sites. The experimental results show that the circRB method outperforms the existing computational methods. Afterwards, the trained models are applied to detect the sequence motifs on the seven circRNA-RBP bound sequence datasets and matched to known human RNA motifs. Some motifs on circular RNAs overlap with those on linear RNAs. Finally, we also predict binding sites on the reported full-length sequences of circRNAs interacting with RBPs, attempting to assist current studies. We hope that our model will contribute to better understanding the mechanisms of the interactions between RBPs and circRNAs. Conclusion In view of the poor studies about the sequence specificities of circRNA-binding proteins, we designed a classification framework called circRB based on the capsule network. The results show that the circRB method is an effective method, and it achieves higher prediction accuracy than other methods.

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