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The Complex World of RNA-Protein Complexes—Emerging Players in Cellular Networks
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The Complex World of RNA-Protein Complexes—Emerging Players in Cellular Networks

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cellular Biophysics".

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Editor

Dr. Ágnes Tantos

E-Mail Website
Collection Editor
Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok körútja 2, 1117 Budapest, Hungary
Interests: protein-RNA interactions; histone methylation; liquid-liquid phase separation; intrinsically disordered proteins; histone lysine methyltransferases; long noncoding RNAs; RNA structure

Topical Collection Information

Dear Colleagues,

RNAs are involved in almost every cellular process—from gene expression regulation to molecular chaperoning. They are capable of forming various interactions with other RNA molecules, proteins, and DNA, which enables them to play central roles in the formation of cellular networks. Central to their proper function is the correct recognition of their native partners and the proper regulation of binding. Accumulating evidence shows that the RNA structure is essential in the molecular recognition of RNA binding proteins, and the immense effort invested in identifying the RNA–protein interaction networks of cells has produced an ever-growing amount of information on the structure–function relationship of RNAs and RNA–protein complexes. A clear understanding of the nature of RNA–protein binding is further complicated by the nonconventional interactions between RNA and protein that induce phase separation and the formation of membraneless organelles. Urgent questions regarding the recognition specificity, regulation of binding, and structural determinants of such processes from both RNA and protein must be elucidated.

Given the crucial roles of these interactions in the development of several diseases, RNAs are becoming attractive targets for drug development, offering new strategies to tackle difficult medical challenges; however, effective targeting requires detailed structural knowledge, which is relatively limited to date.

The aim of this Topical Collection is to provide an opportunity for researchers to present their latest results in the field of RNA–protein interactions in relation to the regulation of various cellular processes, and also to offer summaries on the most recent developments in the research field.

We look forward to your contribution.

Dr. Ágnes Tantos
Collection Editor

Manuscript Submission Information

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Keywords

  • RNA structure
  • RNA-protein complex
  • drug design
  • RNA biomarkers
  • membraneless organelles
  • non-coding RNA
  • RNA binding protein
  • RNA interactions

Published Papers (10 papers)

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2022

Jump to: 2021

22 pages, 3990 KiB  
Article
The RNA-Binding Landscape of HAX1 Protein Indicates Its Involvement in Translation and Ribosome Assembly
by Anna Balcerak, Ewelina Macech-Klicka, Maciej Wakula, Rafal Tomecki, Krzysztof Goryca, Malgorzata Rydzanicz, Mateusz Chmielarczyk, Malgorzata Szostakowska-Rodzos, Marta Wisniewska, Filip Lyczek, Aleksandra Helwak, David Tollervey, Grzegorz Kudla and Ewa A. Grzybowska
Cells 2022, 11(19), 2943; https://doi.org/10.3390/cells11192943 - 20 Sep 2022
Cited by 2 | Viewed by 2042
Abstract
HAX1 is a human protein with no known homologues or structural domains. Mutations in the HAX1 gene cause severe congenital neutropenia through mechanisms that are poorly understood. Previous studies reported the RNA-binding capacity of HAX1, but the role of this binding in physiology [...] Read more.
HAX1 is a human protein with no known homologues or structural domains. Mutations in the HAX1 gene cause severe congenital neutropenia through mechanisms that are poorly understood. Previous studies reported the RNA-binding capacity of HAX1, but the role of this binding in physiology and pathology remains unexplained. Here, we report the transcriptome-wide characterization of HAX1 RNA targets using RIP-seq and CRAC, indicating that HAX1 binds transcripts involved in translation, ribosome biogenesis, and rRNA processing. Using CRISPR knockouts, we find that HAX1 RNA targets partially overlap with transcripts downregulated in HAX1 KO, implying a role in mRNA stabilization. Gene ontology analysis demonstrated that genes differentially expressed in HAX1 KO (including genes involved in ribosome biogenesis and translation) are also enriched in a subset of genes whose expression correlates with HAX1 expression in four analyzed neoplasms. The functional connection to ribosome biogenesis was also demonstrated by gradient sedimentation ribosome profiles, which revealed differences in the small subunit:monosome ratio in HAX1 WT/KO. We speculate that changes in HAX1 expression may be important for the etiology of HAX1-linked diseases through dysregulation of translation. Full article
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20 pages, 2012 KiB  
Review
The Role of KH-Type Splicing Regulatory Protein (KSRP) for Immune Functions and Tumorigenesis
by Kim-Alicia Palzer, Vanessa Bolduan, Rudolf Käfer, Hartmut Kleinert, Matthias Bros and Andrea Pautz
Cells 2022, 11(9), 1482; https://doi.org/10.3390/cells11091482 - 28 Apr 2022
Cited by 9 | Viewed by 2939
Abstract
Post-transcriptional control of gene expression is one important mechanism that enables stringent and rapid modulation of cytokine, chemokines or growth factors expression, all relevant for immune or tumor cell function and communication. The RNA-binding protein KH-type splicing regulatory protein (KSRP) controls the mRNA [...] Read more.
Post-transcriptional control of gene expression is one important mechanism that enables stringent and rapid modulation of cytokine, chemokines or growth factors expression, all relevant for immune or tumor cell function and communication. The RNA-binding protein KH-type splicing regulatory protein (KSRP) controls the mRNA stability of according genes by initiation of mRNA decay and inhibition of translation, and by enhancing the maturation of microRNAs. Therefore, KSRP plays a pivotal role in immune cell function and tumor progression. In this review, we summarize the current knowledge about KSRP with regard to the regulation of immunologically relevant targets, and the functional role of KSRP on immune responses and tumorigenesis. KSRP is involved in the control of myeloid hematopoiesis. Further, KSRP-mediated mRNA decay of pro-inflammatory factors is necessary to keep immune homeostasis. In case of infection, functional impairment of KSRP is important for the induction of robust immune responses. In this regard, KSRP seems to primarily dampen T helper cell 2 immune responses. In cancer, KSRP has often been associated with tumor growth and metastasis. In summary, aside of initiation of mRNA decay, the KSRP-mediated regulation of microRNA maturation seems to be especially important for its diverse biological functions, which warrants further in-depth examination. Full article
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21 pages, 5257 KiB  
Article
Y-Complex Proteins Show RNA-Dependent Binding Events at the Cell Membrane and Distinct Single-Molecule Dynamics
by Rebecca Hinrichs, Nadiia Pozhydaieva, Katharina Höfer and Peter L. Graumann
Cells 2022, 11(6), 933; https://doi.org/10.3390/cells11060933 - 09 Mar 2022
Cited by 1 | Viewed by 2739
Abstract
Bacteria are dependent on rapid alterations in gene expression. A prerequisite for rapid adaptations is efficient RNA turnover, with endonuclease RNase Y playing a crucial role in mRNA stability as well as in maturation. In Bacillus subtilis, RNase Y in turn interacts [...] Read more.
Bacteria are dependent on rapid alterations in gene expression. A prerequisite for rapid adaptations is efficient RNA turnover, with endonuclease RNase Y playing a crucial role in mRNA stability as well as in maturation. In Bacillus subtilis, RNase Y in turn interacts with the so-called “Y-complex” consisting of three proteins, which play important functions in sporulation, natural transformation and biofilm formation. It is thought that the Y-complex acts as an accessory factor in RNase Y regulation but might also have independent functions. Using single-molecule tracking, we show that all three Y-complex proteins exhibit three distinct mobilities, including movement through the cytosol and confined motion, predominantly at membrane-proximal sites but also within the cell center. A transcriptional arrest leads to a strong change in localization and dynamics of YmcA, YlbF and YaaT, supporting their involvement in global RNA degradation. However, Y-complex proteins show distinguishable protein dynamics, and the deletion of yaaT or ylbF shows a minor effect on the dynamics of YmcA. Cell fractionation reveals that YaaT displays a mixture of membrane association and presence in the cytosol, while YlbF and YmcA do not show direct membrane attachment. Taken together, our experiments reveal membrane-associated and membrane-independent activities of Y-complex proteins and a dynamic interplay between them with indirect membrane association of YmcA and YlbF via YaaT. Full article
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15 pages, 2834 KiB  
Article
EGCG Promotes FUS Condensate Formation in a Methylation-Dependent Manner
by Aneta J. Lenard, Qishun Zhou, Corina Madreiter-Sokolowski, Benjamin Bourgeois, Hermann Habacher, Yukti Khanna and Tobias Madl
Cells 2022, 11(4), 592; https://doi.org/10.3390/cells11040592 - 09 Feb 2022
Cited by 4 | Viewed by 3017
Abstract
Millions of people worldwide are affected by neurodegenerative diseases (NDs), and to date, no effective treatment has been reported. The hallmark of these diseases is the formation of pathological aggregates and fibrils in neural cells. Many studies have reported that catechins, polyphenolic compounds [...] Read more.
Millions of people worldwide are affected by neurodegenerative diseases (NDs), and to date, no effective treatment has been reported. The hallmark of these diseases is the formation of pathological aggregates and fibrils in neural cells. Many studies have reported that catechins, polyphenolic compounds found in a variety of plants, can directly interact with amyloidogenic proteins, prevent the formation of toxic aggregates, and in turn play neuroprotective roles. Besides harboring amyloidogenic domains, several proteins involved in NDs possess arginine-glycine/arginine-glycine-glycine (RG/RGG) regions that contribute to the formation of protein condensates. Here, we aimed to assess whether epigallocatechin gallate (EGCG) can play a role in neuroprotection via direct interaction with such RG/RGG regions. We show that EGCG directly binds to the RG/RGG region of fused in sarcoma (FUS) and that arginine methylation enhances this interaction. Unexpectedly, we found that low micromolar amounts of EGCG were sufficient to restore RNA-dependent condensate formation of methylated FUS, whereas, in the absence of EGCG, no phase separation could be observed. Our data provide new mechanistic roles of EGCG in the regulation of phase separation of RG/RGG-containing proteins, which will promote understanding of the intricate function of EGCG in cells. Full article
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2021

Jump to: 2022

23 pages, 6258 KiB  
Article
hnRNP Q and hnRNP A1 Regulate the Translation of Cofilin in Response to Transient Oxygen–Glucose Deprivation in Hippocampal Neurons
by Sung Wook Kim, In Kyung Hong, Mingee Kim, Yun Seon Song and Kyong-Tai Kim
Cells 2021, 10(12), 3567; https://doi.org/10.3390/cells10123567 - 17 Dec 2021
Cited by 1 | Viewed by 2543
Abstract
Protein aggregates of cofilin and actin have been found in neurons under oxygen–glucose deprivation. However, the regulatory mechanism behind the expression of Cfl1 during oxygen–glucose deprivation remains unclear. Here, we found that heterogeneous nuclear ribonucleoproteins (hnRNP) Q and hnRNP A1 regulate the translation [...] Read more.
Protein aggregates of cofilin and actin have been found in neurons under oxygen–glucose deprivation. However, the regulatory mechanism behind the expression of Cfl1 during oxygen–glucose deprivation remains unclear. Here, we found that heterogeneous nuclear ribonucleoproteins (hnRNP) Q and hnRNP A1 regulate the translation of Cfl1 mRNA, and formation of cofilin–actin aggregates. The interaction between hnRNP A1 and Cfl1 mRNA was interrupted by hnRNP Q under normal conditions, while the changes in the expression and localization of hnRNP Q and hnRNP A1 increased such interaction, as did the translation of Cfl1 mRNA under oxygen–glucose deprived conditions. These findings reveal a new translational regulatory mechanism of Cfl1 mRNA in hippocampal neurons under oxygen–glucose deprivation. Full article
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20 pages, 3070 KiB  
Article
Double-Stranded RNA Structural Elements Holding the Key to Translational Regulation in Cancer: The Case of Editing in RNA-Binding Motif Protein 8A
by Asra Abukar, Martin Wipplinger, Ananya Hariharan, Suna Sun, Manuel Ronner, Marika Sculco, Agata Okonska, Jelena Kresoja-Rakic, Hubert Rehrauer, Weihong Qi, Victor W. van Beusechem and Emanuela Felley-Bosco
Cells 2021, 10(12), 3543; https://doi.org/10.3390/cells10123543 - 15 Dec 2021
Cited by 5 | Viewed by 2785
Abstract
Mesothelioma is an aggressive cancer associated with asbestos exposure. RNA-binding motif protein 8a (RBM8A) mRNA editing increases in mouse tissues upon asbestos exposure. The aim of this study was to further characterize the role of RBM8A in mesothelioma and the consequences of its [...] Read more.
Mesothelioma is an aggressive cancer associated with asbestos exposure. RNA-binding motif protein 8a (RBM8A) mRNA editing increases in mouse tissues upon asbestos exposure. The aim of this study was to further characterize the role of RBM8A in mesothelioma and the consequences of its mRNA editing. RBM8A protein expression was higher in mesothelioma compared to mesothelial cells. Silencing RBM8A changed splicing patterns in mesothelial and mesothelioma cells but drastically reduced viability only in mesothelioma cells. In the tissues of asbestos-exposed mice, editing of Rbm8a mRNA was associated with increased protein immunoreactivity, with no change in mRNA levels. Increased adenosine deaminase acting on dsRNA (ADAR)-dependent editing of Alu elements in the RBM8A 3′UTR was observed in mesothelioma cells compared to mesothelial cells. Editing stabilized protein expression. The unedited RBM8A 3′UTR had a stronger interaction with Musashi (MSI) compared to the edited form. The silencing of MSI2 in mesothelioma or overexpression of Adar2 in mesothelial cells resulted in increased RBM8A protein levels. Therefore, ADAR-dependent editing contributes to maintaining elevated RBM8A protein levels in mesothelioma by counteracting MSI2-driven downregulation. A wider implication of this mechanism for the translational control of protein expression is suggested by the editing of similarly structured Alu elements in several other transcripts. Full article
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12 pages, 1232 KiB  
Review
MUT-7 Provides Molecular Insight into the Werner Syndrome Exonuclease
by Tsung-Yuan Hsu, Ling-Nung Hsu, Shih-Yu Chen and Bi-Tzen Juang
Cells 2021, 10(12), 3457; https://doi.org/10.3390/cells10123457 - 08 Dec 2021
Viewed by 3113
Abstract
Werner syndrome (WS) is a rare recessive genetic disease characterized by premature aging. Individuals with this disorder develop normally during childhood, but their physiological conditions exacerbate the aging process in late adolescence. WS is caused by mutation of the human WS gene ( [...] Read more.
Werner syndrome (WS) is a rare recessive genetic disease characterized by premature aging. Individuals with this disorder develop normally during childhood, but their physiological conditions exacerbate the aging process in late adolescence. WS is caused by mutation of the human WS gene (WRN), which encodes two main domains, a 3′-5′ exonuclease and a 3′-5′ helicase. Caenorhabditis elegans expresses human WRN orthologs as two different proteins: MUT-7, which has a 3′-5′ exonuclease domain, and C. elegans WRN-1 (CeWRN-1), which has only helicase domains. These unique proteins dynamically regulate olfactory memory in C. elegans, providing insight into the molecular roles of WRN domains in humans. In this review, we specifically focus on characterizing the function of MUT-7 in small interfering RNA (siRNA) synthesis in the cytoplasm and the roles of siRNA in directing nuclear CeWRN-1 loading onto a heterochromatin complex to induce negative feedback regulation. Further studies on the different contributions of the 3′-5′ exonuclease and helicase domains in the molecular mechanism will provide clues to the accelerated aging processes in WS. Full article
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26 pages, 5768 KiB  
Article
Hundreds of LncRNAs Display Circadian Rhythmicity in Zebrafish Larvae
by Shital Kumar Mishra, Zhaomin Zhong and Han Wang
Cells 2021, 10(11), 3173; https://doi.org/10.3390/cells10113173 - 15 Nov 2021
Cited by 1 | Viewed by 2534
Abstract
Long noncoding RNAs (lncRNAs) have been shown to play crucial roles in various life processes, including circadian rhythms. Although next generation sequencing technologies have facilitated faster profiling of lncRNAs, the resulting datasets require sophisticated computational analyses. In particular, the regulatory roles of lncRNAs [...] Read more.
Long noncoding RNAs (lncRNAs) have been shown to play crucial roles in various life processes, including circadian rhythms. Although next generation sequencing technologies have facilitated faster profiling of lncRNAs, the resulting datasets require sophisticated computational analyses. In particular, the regulatory roles of lncRNAs in circadian clocks are far from being completely understood. In this study, we conducted RNA-seq-based transcriptome analysis of zebrafish larvae under both constant darkness (DD) and constant light (LL) conditions in a circadian manner, employing state-of-the-art computational approaches to identify approximately 3220 lncRNAs from zebrafish larvae, and then uncovered 269 and 309 lncRNAs displaying circadian rhythmicity under DD and LL conditions, respectively, with 30 of them are coexpressed under both DD and LL conditions. Subsequently, GO, COG, and KEGG pathway enrichment analyses of all these circadianly expressed lncRNAs suggested their potential involvement in numerous biological processes. Comparison of these circadianly expressed zebrafish larval lncRNAs, with rhythmically expressed lncRNAs in the zebrafish pineal gland and zebrafish testis, revealed that nine (DD) and twelve (LL) larval lncRNAs are coexpressed in the zebrafish pineal gland and testis, respectively. Intriguingly, among peptides encoded by these coexpressing circadianly expressed lncRNAs, three peptides (DD) and one peptide (LL) were found to have the known domains from the Protein Data Bank. Further, the conservation analysis of these circadianly expressed zebrafish larval lncRNAs with human and mouse genomes uncovered one lncRNA and four lncRNAs shared by all three species under DD and LL conditions, respectively. We also investigated the conserved lncRNA-encoded peptides and found one peptide under DD condition conserved in these three species and computationally predicted its 3D structure and functions. Our study reveals that hundreds of lncRNAs from zebrafish larvae exhibit circadian rhythmicity and should help set the stage for their further functional studies. Full article
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12 pages, 509 KiB  
Review
Protein Binding to Cis-Motifs in mRNAs Coding Sequence Is Common and Regulates Transcript Stability and the Rate of Translation
by Ewa A. Grzybowska and Maciej Wakula
Cells 2021, 10(11), 2910; https://doi.org/10.3390/cells10112910 - 27 Oct 2021
Cited by 6 | Viewed by 2362
Abstract
Protein binding to the non-coding regions of mRNAs is relatively well characterized and its functionality has been described in many examples. New results obtained by high-throughput methods indicate that binding to the coding sequence (CDS) by RNA-binding proteins is also quite common, but [...] Read more.
Protein binding to the non-coding regions of mRNAs is relatively well characterized and its functionality has been described in many examples. New results obtained by high-throughput methods indicate that binding to the coding sequence (CDS) by RNA-binding proteins is also quite common, but the functions thereof are more obscure. As described in this review, CDS binding has a role in the regulation of mRNA stability, but it has also a more intriguing role in the regulation of translational efficiency. Global approaches, which suggest the significance of CDS binding along with specific examples of CDS-binding RBPs and their modes of action, are outlined here, pointing to the existence of a relatively less-known regulatory network controlling mRNA stability and translation on yet another level. Full article
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20 pages, 2456 KiB  
Article
Influence of Subcellular Localization and Functional State on Protein Turnover
by Roya Yousefi, Kristina Jevdokimenko, Verena Kluever, David Pacheu-Grau and Eugenio F. Fornasiero
Cells 2021, 10(7), 1747; https://doi.org/10.3390/cells10071747 - 10 Jul 2021
Cited by 9 | Viewed by 3470
Abstract
Protein homeostasis is an equilibrium of paramount importance that maintains cellular performance by preserving an efficient proteome. This equilibrium avoids the accumulation of potentially toxic proteins, which could lead to cellular stress and death. While the regulators of proteostasis are the machineries controlling [...] Read more.
Protein homeostasis is an equilibrium of paramount importance that maintains cellular performance by preserving an efficient proteome. This equilibrium avoids the accumulation of potentially toxic proteins, which could lead to cellular stress and death. While the regulators of proteostasis are the machineries controlling protein production, folding and degradation, several other factors can influence this process. Here, we have considered two factors influencing protein turnover: the subcellular localization of a protein and its functional state. For this purpose, we used an imaging approach based on the pulse-labeling of 17 representative SNAP-tag constructs for measuring protein lifetimes. With this approach, we obtained precise measurements of protein turnover rates in several subcellular compartments. We also tested a selection of mutants modulating the function of three extensively studied proteins, the Ca2+ sensor calmodulin, the small GTPase Rab5a and the brain creatine kinase (CKB). Finally, we followed up on the increased lifetime observed for the constitutively active Rab5a (Q79L), and we found that its stabilization correlates with enlarged endosomes and increased interaction with membranes. Overall, our data reveal that both changes in protein localization and functional state are key modulators of protein turnover, and protein lifetime fluctuations can be considered to infer changes in cellular behavior. Full article
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