scholarly journals The RNA-binding protein, Rasputin/G3BP, enhances the stability and translation of its target mRNAs

2020 ◽  
Author(s):  
John D. Laver ◽  
Jimmy Ly ◽  
Allison K. Winn ◽  
Angelo Karaiskakis ◽  
Sichun Lin ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Binding Protein ◽  
Stress Granules ◽  
Direct Role ◽  
Target Mrnas ◽  
Core Components ◽  
The Stability

SUMMARYG3BP RNA-binding proteins are important components of stress granules (SGs). Here we analyze the role of Drosophila G3BP, Rasputin (RIN), in unstressed cells, where RIN is not SG associated. Immunoprecipitation followed by microarray analysis identified over 550 mRNAs that copurify with RIN. The mRNAs found in SGs are long and translationally silent. In contrast, we find that RIN-bound mRNAs, which encode core components of the transcription, splicing and translation machinery, are short, stable and highly translated. We show that RIN is associated with polysomes and provide evidence for a direct role for RIN and its human homologs in stabilizing and upregulating the translation of their target mRNAs. We propose that when cells are stressed the resulting incorporation of RIN/G3BPs into SGs sequesters them away from their short target mRNAs. This would downregulate the expression of these transcripts, even though they are not incorporated into stress granules.

scholarly journals ALBA proteins are stage regulated during trypanosome development in the tsetse fly and participate in differentiation

2011 ◽  
Vol 22 (22) ◽  
pp. 4205-4219 ◽  
Author(s):  
Ines Subota ◽  
Brice Rotureau ◽  
Thierry Blisnick ◽  
Sandra Ngwabyt ◽  
Mickaël Durand-Dubief ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fluorescent Proteins ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Protozoan Parasite ◽  
Tsetse Fly ◽  
First Time

The protozoan parasite Trypanosoma brucei is responsible for sleeping sickness and alternates between mammal and tsetse fly hosts, where it has to adapt to different environments. We investigated the role of two members of the ALBA family, which encodes hypothetical RNA-binding proteins conserved in most eukaryotes. We show that ALBA3/4 proteins colocalize with the DHH1 RNA-binding protein and with a subset of poly(A+) RNA in stress granules upon starvation. Depletion of ALBA3/4 proteins by RNA interference in the cultured procyclic stage produces cell modifications mimicking several morphogenetic aspects of trypanosome differentiation that usually take place in the fly midgut. A combination of immunofluorescence data and videomicroscopy analysis of live trypanosomes expressing endogenously ALBA fused with fluorescent proteins revealed that ALBA3/4 are present throughout the development of the parasite in the tsetse fly, with the striking exception of the transition stages found in the proventriculus region. This involves migration of the nucleus toward the posterior end of the cell, a phenomenon that is perturbed upon forced expression of ALBA3 during the differentiation process, showing for the first time the involvement of an RNA-binding protein in trypanosome development in vivo.

scholarly journals RNA-Binding Proteins Tia-1 and Tiar Link the Phosphorylation of Eif-2α to the Assembly of Mammalian Stress Granules

1999 ◽  
Vol 147 (7) ◽  
pp. 1431-1442 ◽  
Author(s):  
Nancy L. Kedersha ◽  
Mita Gupta ◽  
Wei Li ◽  
Ira Miller ◽  
Paul Anderson
Keyword(s):  
Environmental Stress ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Binding Protein ◽  
Plant Cells ◽  
Stress Granules ◽  
Binding Domains ◽  
Translational Arrest ◽  
In Cells

In response to environmental stress, the related RNA-binding proteins TIA-1 and TIAR colocalize with poly(A)+ RNA at cytoplasmic foci that resemble the stress granules (SGs) that harbor untranslated mRNAs in heat shocked plant cells (Nover et al. 1989; Nover et al. 1983; Scharf et al. 1998). The accumulation of untranslated mRNA at SGs is reversible in cells that recover from a sublethal stress, but irreversible in cells subjected to a lethal stress. We have found that the assembly of TIA-1/R+ SGs is initiated by the phosphorylation of eIF-2α. A phosphomimetic eIF-2α mutant (S51D) induces the assembly of SGs, whereas a nonphosphorylatable eIF-2α mutant (S51A) prevents the assembly of SGs. The ability of a TIA-1 mutant lacking its RNA-binding domains to function as a transdominant inhibitor of SG formation suggests that this RNA-binding protein acts downstream of the phosphorylation of eIF-2α to promote the sequestration of untranslated mRNAs at SGs. The assembly and disassembly of SGs could regulate the duration of stress- induced translational arrest in cells recovering from environmental stress.

scholarly journals LINE-1 ORF1 Protein Localizes in Stress Granules with Other RNA-Binding Proteins, Including Components of RNA Interference RNA-Induced Silencing Complex

2007 ◽  
Vol 27 (18) ◽  
pp. 6469-6483 ◽  
Author(s):  
John L. Goodier ◽  
Lili Zhang ◽  
Melissa R. Vetter ◽  
Haig H. Kazazian
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Binding Protein ◽  
Protein A ◽  
Rna Binding Protein ◽  
Stress Granules ◽  
Plasminogen Activator Inhibitor ◽  
Cellular Damage ◽  
Activator Inhibitor

ABSTRACT LINE-1 retrotransposons constitute one-fifth of human DNA and have helped shape our genome. A full-length L1 encodes a 40-kDa RNA-binding protein (ORF1p) and a 150-kDa protein (ORF2p) with endonuclease and reverse transcriptase activities. ORF1p is distinctive in forming large cytoplasmic foci, which we identified as cytoplasmic stress granules. A phylogenetically conserved central region of the protein is critical for wild-type localization and retrotransposition. Yeast two-hybrid screens revealed several RNA-binding proteins that coimmunoprecipitate with ORF1p and colocalize with ORF1p in foci. Two of these proteins, YB-1 and hnRNPA1, were previously reported in stress granules. We identified additional proteins associated with stress granules, including DNA-binding protein A, 9G8, and plasminogen activator inhibitor RNA-binding protein 1 (PAI-RBP1). PAI-RBP1 is a homolog of VIG, a part of the Drosophila melanogaster RNA-induced silencing complex (RISC). Other RISC components, including Ago2 and FMRP, also colocalize with PAI-RBP1 and ORF1p. We suggest that targeting ORF1p, and possibly the L1 RNP, to stress granules is a mechanism for controlling retrotransposition and its associated genetic and cellular damage.

scholarly journals The Emerging Role of Stress Granules in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (17) ◽  
pp. 9428
Author(s):  
Dobrochna Dolicka ◽  
Michelangelo Foti ◽  
Cyril Sobolewski
Keyword(s):  
Hepatocellular Carcinoma ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Stress Granules ◽  
Molecular Tools ◽  
Anti Cancer ◽  
Expression Activity

Stress granules (SGs) are small membrane-free cytosolic liquid-phase ordered entities in which mRNAs are protected and translationally silenced during cellular adaptation to harmful conditions (e.g., hypoxia, oxidative stress). This function is achieved by structural and functional SG components such as scaffold proteins and RNA-binding proteins controlling the fate of mRNAs. Increasing evidence indicates that the capacity of cells to assemble/disassemble functional SGs may significantly impact the onset and the development of metabolic and inflammatory diseases, as well as cancers. In the liver, the abnormal expression of SG components and formation of SG occur with chronic liver diseases, hepatocellular carcinoma (HCC), and selective hepatic resistance to anti-cancer drugs. Although, the role of SG in these diseases is still debated, the modulation of SG assembly/disassembly or targeting the expression/activity of specific SG components may represent appealing strategies to treat hepatic disorders and potentially cancer. In this review, we discuss our current knowledge about pathophysiological functions of SGs in HCC as well as available molecular tools and drugs capable of modulating SG formation and functions for therapeutic purposes.

scholarly journals RNA-binding protein HuR promotes growth of small intestinal mucosa by activating the Wnt signaling pathway

2014 ◽  
Vol 25 (21) ◽  
pp. 3308-3318 ◽  
Author(s):  
Lan Liu ◽  
Eleni Christodoulou-Vafeiadou ◽  
Jaladanki N. Rao ◽  
Tongtong Zou ◽  
Lan Xiao ◽  
...  
Keyword(s):  
Small Intestine ◽  
Intestinal Epithelium ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Wnt Signaling Pathway ◽  
Small Intestinal Mucosa ◽  
Mucosal Atrophy ◽  
Target Mrnas

Inhibition of growth of the intestinal epithelium, a rapidly self-renewing tissue, is commonly found in various critical disorders. The RNA-binding protein HuR is highly expressed in the gut mucosa and modulates the stability and translation of target mRNAs, but its exact biological function in the intestinal epithelium remains unclear. Here, we investigated the role of HuR in intestinal homeostasis using a genetic model and further defined its target mRNAs. Targeted deletion of HuR in intestinal epithelial cells caused significant mucosal atrophy in the small intestine, as indicated by decreased cell proliferation within the crypts and subsequent shrinkages of crypts and villi. In addition, the HuR-deficient intestinal epithelium also displayed decreased regenerative potential of crypt progenitors after exposure to irradiation. HuR deficiency decreased expression of the Wnt coreceptor LDL receptor–related protein 6 (LRP6) in the mucosal tissues. At the molecular level, HuR was found to bind the Lrp6 mRNA via its 3′-untranslated region and enhanced LRP6 expression by stabilizing Lrp6 mRNA and stimulating its translation. These results indicate that HuR is essential for normal mucosal growth in the small intestine by altering Wnt signals through up-regulation of LRP6 expression and highlight a novel role of HuR deficiency in the pathogenesis of intestinal mucosal atrophy under pathological conditions.

scholarly journals Role of PUM RNA-Binding Proteins in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 129
Author(s):  
Maciej J. Smialek ◽  
Erkut Ilaslan ◽  
Marcin P. Sajek ◽  
Jadwiga Jaruzelska
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Alternative Polyadenylation ◽  
Cancer Therapies ◽  
Target Mrnas ◽  
Non Coding Rna ◽  
Specific Localization ◽  
Transcriptional Gene Regulation ◽  
Cancer Tissues

Until recently, post-transcriptional gene regulation (PTGR), in contrast to transcriptional regulation, was not extensively explored in cancer, even though it seems to be highly important. PUM proteins are well described in the PTGR of several organisms and contain the PUF RNA-binding domain that recognizes the UGUANAUA motif, located mostly in the 3′ untranslated region (3′UTR) of target mRNAs. Depending on the protein cofactors recruited by PUM proteins, target mRNAs are directed towards translation, repression, activation, degradation, or specific localization. Abnormal profiles of PUM expression have been shown in several types of cancer, in some of them being different for PUM1 and PUM2. This review summarizes the dysregulation of PUM1 and PUM2 expression in several cancer tissues. It also describes the regulatory mechanisms behind the activity of PUMs, including cooperation with microRNA and non-coding RNA machineries, as well as the alternative polyadenylation pathway. It also emphasizes the importance of future studies to gain a more complete picture of the role of PUM proteins in different types of cancer. Such studies may result in identification of novel targets for future cancer therapies.

scholarly journals Whi3, an S. cerevisiae RNA-Binding Protein, Is a Component of Stress Granules That Regulates Levels of Its Target mRNAs

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e84060 ◽  
Author(s):  
Kristen J. Holmes ◽  
Daniel M. Klass ◽  
Evan L. Guiney ◽  
Martha S. Cyert
Keyword(s):  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Stress Granules ◽  
Target Mrnas

scholarly journals Single-molecule imaging reveals translation of mRNAs localized to stress granules

2020 ◽  
Author(s):  
Daniel Mateju ◽  
Bastian Eichenberger ◽  
Jan Eglinger ◽  
Gregory Roth ◽  
Jeffrey A. Chao
Keyword(s):  
Single Molecule ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cellular Stress ◽  
Mrna Translation ◽  
Stress Granules ◽  
Living Cells ◽  
Single Molecule Imaging ◽  
Direct Role

SUMMARYCellular stress leads to reprogramming of mRNA translation and formation of stress granules (SGs), membraneless organelles consisting of mRNA and RNA-binding proteins. Although the function of SGs remains largely unknown, it is widely assumed they contain exclusively nontranslating mRNA. Here we re-examine this hypothesis using single-molecule imaging of mRNA translation in living cells. While our data confirms that non-translating mRNAs are preferentially recruited to SGs, we find unequivocal evidence for translation of mRNA localized to SGs. Our data indicate that SG-associated translation is not rare and that the entire translation cycle (initiation, elongation and termination) can occur for these transcripts. Furthermore, translating mRNAs can be observed transitioning between the cytosol and SGs without changing their translational status. Together, these results argue against a direct role for SGs in inhibition of mRNA translation.

scholarly journals A comprehensive analysis of 3′ end sequencing data sets reveals novel polyadenylation signals and the repressive role of heterogenous ribonucleoprotein C on cleavage and polyadenylation

2015 ◽  
Author(s):  
Andreas J Gruber ◽  
Ralf Schmidt ◽  
Andreas R Gruber ◽  
Georges Martin ◽  
Souvik Ghosh ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Protein Localization ◽  
Alternative Polyadenylation ◽  
General Mechanism ◽  
Data Sets ◽  
Sequencing Data ◽  
A Genome ◽  
The Stability

Alternative polyadenylation (APA) is a general mechanism of transcript diversification in mammals, which has been recently linked to proliferative states and cancer. Different 3′ untranslated region (3′ UTR) isoforms interact with different RNA binding proteins (RBPs), which modify the stability, translation, and subcellular localization of the corresponding transcripts. Although the heterogeneity of pre-mRNA 3′ end processing has been established with high-throughput approaches, the mechanisms that underlie systematic changes in 3′ UTR lengths remain to be characterized. Through a uniform analysis of a large number of 3′ end sequencing data sets we have uncovered 18 signals, 6 of which novel, whose positioning with respect to pre-mRNA cleavage sites indicates a role in pre-mRNA 3′ end processing in both mouse and human. With 3′ end sequencing we have demonstrated that the heterogeneous ribonucleoprotein C (HNRNPC), which binds the poly(U) motif whose frequency also peaks in the vicinity of polyadenylation (poly(A)) sites, has a genome-wide effect on poly(A) site usage. HNRNPC-regulated 3′ UTRs are enriched in ELAV-like RNA binding protein 1 (ELAVL1) binding sites and include those of the CD47 molecule (CD47) gene, which participate in the recently discovered mechanism of 3′ UTR-dependent protein localization (UDPL). Our study thus establishes an up-to-date, high-confidence catalog of 3′ end processing sites and poly(A) signals and it uncovers an important role of HNRNPC in regulating 3′ end processing. It further suggests that U-rich elements mediate interactions with multiple RBPs that regulate different stages in a transcript’s life cycle.

scholarly journals Protein Ligands to Hur Modulate Its Interaction with Target Mrnas in Vivo

2000 ◽  
Vol 151 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Christopher M. Brennan ◽  
Imed-Eddine Gallouzi ◽  
Joan A. Steitz
Keyword(s):  
Nuclear Export ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Nuclear Retention ◽  
Target Mrnas ◽  
Cellular Mrnas ◽  
Phosphatase 2A ◽  
The Stability ◽  
Leucine Rich Repeats

AU-rich elements (AREs) present in the 3′ untranslated regions of many protooncogene, cytokine, and lymphokine messages target them for rapid degradation. HuR, a ubiquitously expressed member of the ELAV (embryonic lethal abnormal vision) family of RNA binding proteins, selectively binds AREs and stabilizes ARE-containing mRNAs in transiently transfected cells. Here, we identify four mammalian proteins that bind regions of HuR known to be essential for its ability to shuttle between the nucleus and the cytoplasm and to stabilize mRNA: SETα, SETβ, pp32, and acidic protein rich in leucine (APRIL). Three have been reported to be protein phosphatase 2A inhibitors. All four ligands contain long, acidic COOH-terminal tails, while pp32 and APRIL share a second motif: rev-like leucine-rich repeats in their NH2-terminal regions. We show that pp32 and APRIL are nucleocytoplasmic shuttling proteins that interact with the nuclear export factor CRM1 (chromosomal region maintenance protein 1). The inhibition of CRM1 by leptomycin B leads to the nuclear retention of pp32 and APRIL, their increased association with HuR, and an increase in HuR's association with nuclear poly(A)+ RNA. Furthermore, transcripts from the ARE-containing c-fos gene are selectively retained in the nucleus, while the cytoplasmic distribution of total poly(A)+ RNA is not altered. These data provide evidence that interaction of its ligands with HuR modulate HuR's ability to bind its target mRNAs in vivo and suggest that CRM1 is instrumental in the export of at least some cellular mRNAs under certain conditions. We discuss the possible role of these ligands upstream of HuR in pathways that govern the stability of ARE-containing mRNAs.

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