International Journal of Molecular Sciences

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14 pages, 3573 KiB

Open AccessArticle

Polysome Profiling of a Human Glioblastoma Reveals Intratumoral Heterogeneity

by Fernanda Cristina Sulla Lupinacci, Hellen Kuasne, Martin Roffé, Julia Avian Vassalakis, Fernanda Ferreira da Silva, Tiago Góss Santos, Victor Piana Andrade, Paulo Sanematsu, Vilma Regina Martins, Silvia Regina Rogatto and Glaucia Noeli Maroso Hajj

Int. J. Mol. Sci. 2019, 20(9), 2177; https://doi.org/10.3390/ijms20092177 - 2 May 2019

Cited by 8 | Viewed by 4277

Abstract

Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the [...] Read more.

Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs. Full article

(This article belongs to the Special Issue Translational Control)

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19 pages, 2761 KiB

Open AccessArticle

Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling

by Gesche K. Gerresheim, Jochen Bathke, Audrey M. Michel, Dmitri E. Andreev, Lyudmila A. Shalamova, Oliver Rossbach, Pan Hu, Dieter Glebe, Markus Fricke, Manja Marz, Alexander Goesmann, Stephen J. Kiniry, Pavel V. Baranov, Ivan N. Shatsky and Michael Niepmann

Int. J. Mol. Sci. 2019, 20(6), 1321; https://doi.org/10.3390/ijms20061321 - 15 Mar 2019

Cited by 16 | Viewed by 6117

Abstract

Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces [...] Read more.

Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known. Methods: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days. Results: Established viral replication does not cause global changes in host gene expression—only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes. Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here. Full article

(This article belongs to the Special Issue Translational Control)

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14 pages, 3273 KiB

Open AccessArticle

Translational Control of Canonical and Non-Canonical Translation Initiation Factors at the Sea Urchin Egg to Embryo Transition

by Héloïse Chassé, Sandrine Boulben, Patrick Cormier and Julia Morales

Int. J. Mol. Sci. 2019, 20(3), 626; https://doi.org/10.3390/ijms20030626 - 1 Feb 2019

Cited by 5 | Viewed by 3697

Abstract

Sea urchin early development is a powerful model to study translational regulation under physiological conditions. Fertilization triggers an activation of the translation machinery responsible for the increase of protein synthesis necessary for the completion of the first embryonic cell cycles. The cap-binding protein [...] Read more.

Sea urchin early development is a powerful model to study translational regulation under physiological conditions. Fertilization triggers an activation of the translation machinery responsible for the increase of protein synthesis necessary for the completion of the first embryonic cell cycles. The cap-binding protein eIF4E, the helicase eIF4A and the large scaffolding protein eIF4G are assembled upon fertilization to form an initiation complex on mRNAs involved in cap-dependent translation initiation. The presence of these proteins in unfertilized and fertilized eggs has already been demonstrated, however data concerning the translational status of translation factors are still scarce. Using polysome fractionation, we analyzed the impact of fertilization on the recruitment of mRNAs encoding initiation factors. Strikingly, whereas the mRNAs coding eIF4E, eIF4A, and eIF4G were not recruited into polysomes at 1 h post-fertilization, mRNAs for eIF4B and for non-canonical initiation factors such as DAP5, eIF4E2, eIF4E3, or hnRNP Q, are recruited and are differentially sensitive to the activation state of the mechanistic target of rapamycin (mTOR) pathway. We discuss our results suggesting alternative translation initiation in the context of the early development of sea urchins. Full article

(This article belongs to the Special Issue Translational Control)

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16 pages, 2708 KiB

Open AccessArticle

Characterizing Cellular Responses During Oncolytic Maraba Virus Infection

by Golnoush Hassanzadeh, Thet Naing, Tyson Graber, Seyed Mehdi Jafarnejad, David F. Stojdl, Tommy Alain and Martin Holcik

Int. J. Mol. Sci. 2019, 20(3), 580; https://doi.org/10.3390/ijms20030580 - 29 Jan 2019

Cited by 10 | Viewed by 5317

Abstract

The rising demand for powerful oncolytic virotherapy agents has led to the identification of Maraba virus, one of the most potent oncolytic viruses from Rhabdoviridae family which displays high selectivity for killing malignant cells and low cytotoxicity in normal cells. Although the virus [...] Read more.

The rising demand for powerful oncolytic virotherapy agents has led to the identification of Maraba virus, one of the most potent oncolytic viruses from Rhabdoviridae family which displays high selectivity for killing malignant cells and low cytotoxicity in normal cells. Although the virus is readied to be used for clinical trials, the interactions between the virus and the host cells is still unclear. Using a newly developed interferon-sensitive mutant Maraba virus (MG1), we have identified two key regulators of global translation (4E-BP1 and eIF2α) as being involved in the regulation of protein synthesis in the infected cells. Despite the translational arrest upon viral stress, we showed an up-regulation of anti-apoptotic Bcl-xL protein that provides a survival benefit for the host cell, yet facilitates effective viral propagation. Given the fact that eIF5B canonically regulates 60S ribosome subunit end joining and is able to replace the role of eIF2 in delivering initiator tRNA to the 40S ribosome subunit upon the phosphorylation of eIF2α we have tested whether eIF5B mediates the translation of target mRNAs during MG1 infection. Our results show that the inhibition of eIF5B significantly down-regulates the level of Bcl-xL steady-state mRNA, thus indirectly attenuates viral propagation. Full article

(This article belongs to the Special Issue Translational Control)

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16 pages, 1786 KiB

Open AccessArticle

Cold-Responsive Regions of Paradigm Cold-Shock and Non-Cold-Shock mRNAs Responsible for Cold Shock Translational Bias

by Anna Maria Giuliodori, Attilio Fabbretti and Claudio Gualerzi

Int. J. Mol. Sci. 2019, 20(3), 457; https://doi.org/10.3390/ijms20030457 - 22 Jan 2019

Cited by 14 | Viewed by 3928

Abstract

In Escherichia coli, the mRNA transcribed from the main cold-shock gene cspA is a thermosensor, which at low temperature adopts a conformation particularly suitable for translation in the cold. Unlike cspA, its paralogue cspD is expressed only at 37 °C, is [...] Read more.

In Escherichia coli, the mRNA transcribed from the main cold-shock gene cspA is a thermosensor, which at low temperature adopts a conformation particularly suitable for translation in the cold. Unlike cspA, its paralogue cspD is expressed only at 37 °C, is toxic so cannot be hyper-expressed in E. coli and is poorly translated in vitro, especially at low temperature. In this work, chimeric mRNAs consisting of different segments of cspA and cspD were constructed to determine if parts of cspA could confer cold-responsive properties to cspD to improve its expression. The activities of these chimeric mRNAs in translation and in partial steps of translation initiation such as formation of 30S initiation complexes and 50S subunits docking to 30S complexes to yield 70S initiation complexes were analyzed. We show that the 5′ untranslated region (5′UTR) of cspA mRNA is sufficient to improve the translation of cspD mRNA at 37 °C whereas both the 5′UTR and the region immediately downstream the cspA mRNA initiation triplet are essential for translation at low temperature. Furthermore, the translational apparatus of cold-stressed cells contains trans-active elements targeting both 5′UTR and downstream regions of cspA mRNA, thereby improving translation of specific chimeric constructs at both 15 and 37 °C. Full article

(This article belongs to the Special Issue Translational Control)

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10 pages, 806 KiB

Open AccessArticle

miRNAmotif—A Tool for the Prediction of Pre-miRNA–Protein Interactions

by Martyna O. Urbanek-Trzeciak, Edyta Jaworska and Wlodzimierz J. Krzyzosiak

Int. J. Mol. Sci. 2018, 19(12), 4075; https://doi.org/10.3390/ijms19124075 - 17 Dec 2018

Cited by 9 | Viewed by 5146

Abstract

MicroRNAs (miRNAs) are short, non-coding post-transcriptional gene regulators. In mammalian cells, mature miRNAs are produced from primary precursors (pri-miRNAs) using canonical protein machinery, which includes Drosha/DGCR8 and Dicer, or the non-canonical mirtron pathway. In plant cells, mature miRNAs are excised from pri-miRNAs by [...] Read more.

MicroRNAs (miRNAs) are short, non-coding post-transcriptional gene regulators. In mammalian cells, mature miRNAs are produced from primary precursors (pri-miRNAs) using canonical protein machinery, which includes Drosha/DGCR8 and Dicer, or the non-canonical mirtron pathway. In plant cells, mature miRNAs are excised from pri-miRNAs by the DICER-LIKE1 (DCL1) protein complex. The involvement of multiple regulatory proteins that bind directly to distinct miRNA precursors in a sequence- or structure-dependent manner adds to the complexity of the miRNA maturation process. Here, we present a web server that enables searches for miRNA precursors that can be recognized by diverse RNA-binding proteins based on known sequence motifs to facilitate the identification of other proteins involved in miRNA biogenesis. The database used by the web server contains known human, murine, and Arabidopsis thaliana pre-miRNAs. The web server can also be used to predict new RNA-binding protein motifs based on a list of user-provided sequences. We show examples of miRNAmotif applications, presenting precursors that contain motifs recognized by Lin28, MCPIP1, and DGCR8 and predicting motifs within pre-miRNA precursors that are recognized by two DEAD-box helicases—DDX1 and DDX17. miRNAmotif is released as an open-source software under the MIT License. The code is available at GitHub (www.github.com/martynaut/mirnamotif). The webserver is freely available at http://mirnamotif.ibch.poznan.pl. Full article

(This article belongs to the Special Issue Translational Control)

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15 pages, 1569 KiB

Open AccessArticle

Eukaryotic Initiation Factor 5B (eIF5B) Cooperates with eIF1A and eIF5 to Facilitate uORF2-Mediated Repression of ATF4 Translation

by Joseph A. Ross, Kamiko R. Bressler and Nehal Thakor

Int. J. Mol. Sci. 2018, 19(12), 4032; https://doi.org/10.3390/ijms19124032 - 13 Dec 2018

Cited by 14 | Viewed by 6600

Abstract

A variety of cellular stresses lead to global translation attenuation due to phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2), which decreases the availability of the eIF2-GTP-Met-tRNA_i ternary complex. However, a subset of mRNAs continues to be translated by [...] Read more.

A variety of cellular stresses lead to global translation attenuation due to phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2), which decreases the availability of the eIF2-GTP-Met-tRNA_i ternary complex. However, a subset of mRNAs continues to be translated by non-canonical mechanisms under these conditions. In fact, although translation initiation of activating transcription factor 4 (ATF4) is normally repressed by an upstream open reading frame (uORF), a decreased availability of ternary complex leads to increased translation of the main ATF4-coding ORF. We show here that siRNA-mediated depletion of eIF5B—which can substitute for eIF2 in delivering Met-tRNA_i—leads to increased levels of ATF4 protein in mammalian cells. This de-repression is not due to phosphorylation of eIF2α under conditions of eIF5B depletion. Although eIF5B depletion leads to a modest increase in the steady-state levels of ATF4 mRNA, we show by polysome profiling that the depletion of eIF5B enhances ATF4 expression primarily at the level of translation. Moreover, eIF5B silencing increases the expression of an ATF4-luciferase translational reporter by a mechanism requiring the repressive uORF2. Further experiments suggest that eIF5B cooperates with eIF1A and eIF5, but not eIF2A, to facilitate the uORF2-mediated repression of ATF4 translation. Full article

(This article belongs to the Special Issue Translational Control)

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19 pages, 3574 KiB

Open AccessArticle

mRNA-Mediated Duplexes Play Dual Roles in the Regulation of Bidirectional Ribosomal Frameshifting

by Wan-Ping Huang, Che-Pei Cho and Kung-Yao Chang

Int. J. Mol. Sci. 2018, 19(12), 3867; https://doi.org/10.3390/ijms19123867 - 4 Dec 2018

Cited by 4 | Viewed by 3943

Abstract

In contrast to −1 programmed ribosomal frameshifting (PRF) stimulation by an RNA pseudoknot downstream of frameshifting sites, a refolding upstream RNA hairpin juxtaposing the frameshifting sites attenuates −1 PRF in human cells and stimulates +1 frameshifting in yeast. This eukaryotic functional mimicry of [...] Read more.

In contrast to −1 programmed ribosomal frameshifting (PRF) stimulation by an RNA pseudoknot downstream of frameshifting sites, a refolding upstream RNA hairpin juxtaposing the frameshifting sites attenuates −1 PRF in human cells and stimulates +1 frameshifting in yeast. This eukaryotic functional mimicry of the internal Shine-Dalgarno (SD) sequence-mediated duplex was confirmed directly in the 70S translation system, indicating that both frameshifting regulation activities of upstream hairpin are conserved between 70S and 80S ribosomes. Unexpectedly, a downstream pseudoknot also possessed two opposing hungry codon-mediated frameshifting regulation activities: attenuation of +1 frameshifting and stimulation of a non-canonical −1 frameshifting within the +1 frameshift-prone CUUUGA frameshifting site in the absence of release factor 2 (RF2) in vitro. However, the −1 frameshifting activity of the downstream pseudoknot is not coupled with its +1 frameshifting attenuation ability. Similarly, the +1 frameshifting activity of the upstream hairpin is not required for its −1 frameshifting attenuation function Thus, each of the mRNA duplexes flanking the two ends of a ribosomal mRNA-binding channel possesses two functions in bi-directional ribosomal frameshifting regulation: frameshifting stimulation and counteracting the frameshifting activity of each other. Full article

(This article belongs to the Special Issue Translational Control)

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15 pages, 1350 KiB

Open AccessArticle

Biological and Evolutionary Significance of Terminal Extensions of Mitochondrial Translation Initiation Factor 3

by Ksenia Derbikova, Anton Kuzmenko, Sergey Levitskii, Maria Klimontova, Ivan Chicherin, Maria V. Baleva, Igor A. Krasheninnikov and Piotr Kamenski

Int. J. Mol. Sci. 2018, 19(12), 3861; https://doi.org/10.3390/ijms19123861 - 4 Dec 2018

Cited by 11 | Viewed by 3542

Abstract

Protein biosynthesis in mitochondria is organized in a bacterial manner. However, during evolution, mitochondrial translation mechanisms underwent many organelle-specific changes. In particular, almost all mitochondrial translation factors, being orthologous to bacterial proteins, are characterized by some unique elements of primary or secondary structure. [...] Read more.

Protein biosynthesis in mitochondria is organized in a bacterial manner. However, during evolution, mitochondrial translation mechanisms underwent many organelle-specific changes. In particular, almost all mitochondrial translation factors, being orthologous to bacterial proteins, are characterized by some unique elements of primary or secondary structure. In the case of the organellar initiation factor 3 (IF3), these elements are several dozen amino acids long N- and C-terminal extensions. This study focused on the terminal extensions of baker’s yeast mitochondrial IF3, Aim23p. By in vivo deletion and complementation analysis, we show that at least one extension is necessary for Aim23p function. At the same time, human mitochondrial IF3 is fully functional in yeast mitochondria even without both terminal extensions. While Escherichia coli IF3 itself is poorly active in yeast mitochondria, adding Aim23p terminal extensions makes the resulting chimeric protein as functional as the cognate factor. Our results show that the terminal extensions of IF3 have evolved as the “adaptors” that accommodate the translation factor of bacterial origin to the evolutionary changed protein biosynthesis system in mitochondria. Full article

(This article belongs to the Special Issue Translational Control)

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19 pages, 4359 KiB

Open AccessArticle

CPEB2 Is Necessary for Proper Porcine Meiotic Maturation and Embryonic Development

by Barbora Prochazkova, Pavla Komrskova and Michal Kubelka

Int. J. Mol. Sci. 2018, 19(10), 3138; https://doi.org/10.3390/ijms19103138 - 12 Oct 2018

Cited by 13 | Viewed by 3292

Abstract

Oocyte meiotic maturation and embryogenesis are some of the most important physiological processes that occur in organisms, playing crucial roles in the preservation of life in all species. The post-transcriptional regulation of maternal messenger ribonucleic acids (mRNAs) and the post-translational regulation of proteins [...] Read more.

Oocyte meiotic maturation and embryogenesis are some of the most important physiological processes that occur in organisms, playing crucial roles in the preservation of life in all species. The post-transcriptional regulation of maternal messenger ribonucleic acids (mRNAs) and the post-translational regulation of proteins are critical in the control of oocyte maturation and early embryogenesis. Translational control affects the basic mechanism of protein synthesis, thus, knowledge of the key components included in this machinery is required in order to understand its regulation. Cytoplasmic polyadenylation element binding proteins (CPEBs) bind to the 3′-end of mRNAs to regulate their localization and translation and are necessary for proper development. In this study we examined the expression pattern of cytoplasmic polyadenylation element binding protein 2 (CPEB2) both on the mRNA (by real-time quantitative reverse transcription polymerase chain reaction, qRT-PCR) and protein (by Western blotting, WB) level, as well as its localization during the meiotic maturation of porcine oocytes and early embryonic development by immunocytochemistry (ICC). For the elucidation of its functions, CPEB2 knockdown by double-strand RNA (dsRNA) was used. We discovered that CPEB2 is expressed during all stages of porcine meiotic maturation and embryonic development. Moreover, we found that it is necessary to enable a high percentage of oocytes to reach the metaphase II (MII) stage, as well as for the production of good-quality parthenogenetic blastocysts. Full article

(This article belongs to the Special Issue Translational Control)

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17 pages, 2059 KiB

Open AccessArticle

Increased Expression of Maturation Promoting Factor Components Speeds Up Meiosis in Oocytes from Aged Females

by Marketa Koncicka, Anna Tetkova, Denisa Jansova, Edgar Del Llano, Lenka Gahurova, Jana Kracmarova, Sarka Prokesova, Tomas Masek, Martin Pospisek, Alexander W. Bruce, Michal Kubelka and Andrej Susor

Int. J. Mol. Sci. 2018, 19(9), 2841; https://doi.org/10.3390/ijms19092841 - 19 Sep 2018

Cited by 15 | Viewed by 5538

Abstract

The rate of chromosome segregation errors that emerge during meiosis I in the mammalian female germ line are known to increase with maternal age; however, little is known about the underlying molecular mechanism. The objective of this study was to analyze meiotic progression [...] Read more.

The rate of chromosome segregation errors that emerge during meiosis I in the mammalian female germ line are known to increase with maternal age; however, little is known about the underlying molecular mechanism. The objective of this study was to analyze meiotic progression of mouse oocytes in relation to maternal age. Using the mouse as a model system, we analyzed the timing of nuclear envelope breakdown and the morphology of the nuclear lamina of oocytes obtained from young (2 months old) and aged females (12 months old). Oocytes obtained from older females display a significantly faster progression through meiosis I compared to the ones obtained from younger females. Furthermore, in oocytes from aged females, lamin A/C structures exhibit rapid phosphorylation and dissociation. Additionally, we also found an increased abundance of MPF components and increased translation of factors controlling translational activity in the oocytes of aged females. In conclusion, the elevated MPF activity observed in aged female oocytes affects precocious meiotic processes that can multifactorially contribute to chromosomal errors in meiosis I. Full article

(This article belongs to the Special Issue Translational Control)

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Review

Jump to: Research

18 pages, 801 KiB

Open AccessReview

Translation Control of HAC1 by Regulation of Splicing in Saccharomyces cerevisiae

by Xuhua Xia

Int. J. Mol. Sci. 2019, 20(12), 2860; https://doi.org/10.3390/ijms20122860 - 12 Jun 2019

Cited by 19 | Viewed by 5712

Abstract

Hac1p is a key transcription factor regulating the unfolded protein response (UPR) induced by abnormal accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) in Saccharomyces cerevisiae. The accumulation of unfolded/misfolded proteins is sensed by protein Ire1p, which then undergoes trans-autophosphorylation and [...] Read more.

Hac1p is a key transcription factor regulating the unfolded protein response (UPR) induced by abnormal accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) in Saccharomyces cerevisiae. The accumulation of unfolded/misfolded proteins is sensed by protein Ire1p, which then undergoes trans-autophosphorylation and oligomerization into discrete foci on the ER membrane. HAC1 pre-mRNA, which is exported to the cytoplasm but is blocked from translation by its intron sequence looping back to its 5’UTR to form base-pair interaction, is transported to the Ire1p foci to be spliced, guided by a cis-acting bipartite element at its 3’UTR (3’BE). Spliced HAC1 mRNA can be efficiently translated. The resulting Hac1p enters the nucleus and activates, together with coactivators, a large number of genes encoding proteins such as protein chaperones to restore and maintain ER homeostasis and secretary protein quality control. This review details the translation regulation of Hac1p production, mediated by the nonconventional splicing, in the broad context of translation control and summarizes the evolution and diversification of the UPR signaling pathway among fungal, metazoan and plant lineages. Full article

(This article belongs to the Special Issue Translational Control)

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20 pages, 1253 KiB

Open AccessReview

Emerging Role of Eukaryote Ribosomes in Translational Control

by Nicole Dalla Venezia, Anne Vincent, Virginie Marcel, Frédéric Catez and Jean-Jacques Diaz

Int. J. Mol. Sci. 2019, 20(5), 1226; https://doi.org/10.3390/ijms20051226 - 11 Mar 2019

Cited by 49 | Viewed by 9847

Abstract

Translation is one of the final steps that regulate gene expression. The ribosome is the effector of translation through to its role in mRNA decoding and protein synthesis. Many mechanisms have been extensively described accounting for translational regulation. However it emerged only recently [...] Read more.

Translation is one of the final steps that regulate gene expression. The ribosome is the effector of translation through to its role in mRNA decoding and protein synthesis. Many mechanisms have been extensively described accounting for translational regulation. However it emerged only recently that ribosomes themselves could contribute to this regulation. Indeed, though it is well-known that the translational efficiency of the cell is linked to ribosome abundance, studies recently demonstrated that the composition of the ribosome could alter translation of specific mRNAs. Evidences suggest that according to the status, environment, development, or pathological conditions, cells produce different populations of ribosomes which differ in their ribosomal protein and/or RNA composition. Those observations gave rise to the concept of “specialized ribosomes”, which proposes that a unique ribosome composition determines the translational activity of this ribosome. The current review will present how technological advances have participated in the emergence of this concept, and to which extent the literature sustains this concept today. Full article

(This article belongs to the Special Issue Translational Control)

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16 pages, 1261 KiB

Open AccessReview

Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity

by Jack T. Rogers, Ning Xia, Angela Wong, Rachit Bakshi and Catherine M. Cahill

Int. J. Mol. Sci. 2019, 20(4), 994; https://doi.org/10.3390/ijms20040994 - 25 Feb 2019

Cited by 23 | Viewed by 6319

Abstract

The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer’s disease (AD) caused by APP gene duplications (Dup–APP) and in aging Down syndrome individuals. APP mRNA translation [...] Read more.

The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer’s disease (AD) caused by APP gene duplications (Dup–APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5’untranslated region (5’UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. We have reported that the environmental metallotoxins Lead (Pb) and manganese (Mn) cause neuronal death by interfering with IRE dependent translation of APP and ferritin. The loss of these iron homeostatic neuroprotectants thereby caused an embargo of iron (Fe) export from neurons as associated with excess unstored intracellular iron and the formation of toxic reactive oxidative species (ROS). We propose that APP 5’UTR directed translation activators can be employed therapeutically to protect neurons exposed to high acute Pb and/or Mn exposure. Certainly, high potency APP translation activators, exemplified by the Food and Drug Administration (FDA) pre-approved M1 muscarinic agonist AF102B and high throughput-screened APP 5’UTR translation activators, are available for drug development to treat acute toxicity caused by Pb/Mn exposure to neurons. We conclude that APP translation activators can be predicted to prevent acute metal toxicity to neurons by a mechanism related to the 5’UTR specific yohimbine which binds and targets the canonical IRE RNA stem loop as an H-ferritin translation activator. Full article

(This article belongs to the Special Issue Translational Control)

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21 pages, 2696 KiB

Open AccessReview

Start Codon Recognition in Eukaryotic and Archaeal Translation Initiation: A Common Structural Core

by Emmanuelle Schmitt, Pierre-Damien Coureux, Auriane Monestier, Etienne Dubiez and Yves Mechulam

Int. J. Mol. Sci. 2019, 20(4), 939; https://doi.org/10.3390/ijms20040939 - 21 Feb 2019

Cited by 11 | Viewed by 6376

Abstract

Understanding molecular mechanisms of ribosomal translation sheds light on the emergence and evolution of protein synthesis in the three domains of life. Universally, ribosomal translation is described in three steps: initiation, elongation and termination. During initiation, a macromolecular complex assembled around the small [...] Read more.

Understanding molecular mechanisms of ribosomal translation sheds light on the emergence and evolution of protein synthesis in the three domains of life. Universally, ribosomal translation is described in three steps: initiation, elongation and termination. During initiation, a macromolecular complex assembled around the small ribosomal subunit selects the start codon on the mRNA and defines the open reading frame. In this review, we focus on the comparison of start codon selection mechanisms in eukaryotes and archaea. Eukaryotic translation initiation is a very complicated process, involving many initiation factors. The most widespread mechanism for the discovery of the start codon is the scanning of the mRNA by a pre-initiation complex until the first AUG codon in a correct context is found. In archaea, long-range scanning does not occur because of the presence of Shine-Dalgarno (SD) sequences or of short 5′ untranslated regions. However, archaeal and eukaryotic translation initiations have three initiation factors in common: e/aIF1, e/aIF1A and e/aIF2 are directly involved in the selection of the start codon. Therefore, the idea that these archaeal and eukaryotic factors fulfill similar functions within a common structural ribosomal core complex has emerged. A divergence between eukaryotic and archaeal factors allowed for the adaptation to the long-range scanning process versus the SD mediated prepositioning of the ribosome. Full article

(This article belongs to the Special Issue Translational Control)

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29 pages, 915 KiB

Open AccessReview

IRES Trans-Acting Factors, Key Actors of the Stress Response

by Anne-Claire Godet, Florian David, Fransky Hantelys, Florence Tatin, Eric Lacazette, Barbara Garmy-Susini and Anne-Catherine Prats

Int. J. Mol. Sci. 2019, 20(4), 924; https://doi.org/10.3390/ijms20040924 - 20 Feb 2019

Cited by 130 | Viewed by 11756

Abstract

The cellular stress response corresponds to the molecular changes that a cell undergoes in response to various environmental stimuli. It induces drastic changes in the regulation of gene expression at transcriptional and posttranscriptional levels. Actually, translation is strongly affected with a blockade of [...] Read more.

The cellular stress response corresponds to the molecular changes that a cell undergoes in response to various environmental stimuli. It induces drastic changes in the regulation of gene expression at transcriptional and posttranscriptional levels. Actually, translation is strongly affected with a blockade of the classical cap-dependent mechanism, whereas alternative mechanisms are activated to support the translation of specific mRNAs. A major mechanism involved in stress-activated translation is the internal ribosome entry site (IRES)-driven initiation. IRESs, first discovered in viral mRNAs, are present in cellular mRNAs coding for master regulators of cell responses, whose expression must be tightly controlled. IRESs allow the translation of these mRNAs in response to different stresses, including DNA damage, amino-acid starvation, hypoxia or endoplasmic reticulum stress, as well as to physiological stimuli such as cell differentiation or synapse network formation. Most IRESs are regulated by IRES trans-acting factor (ITAFs), exerting their action by at least nine different mechanisms. This review presents the history of viral and cellular IRES discovery as well as an update of the reported ITAFs regulating cellular mRNA translation and of their different mechanisms of action. The impact of ITAFs on the coordinated expression of mRNA families and consequences in cell physiology and diseases are also highlighted. Full article

(This article belongs to the Special Issue Translational Control)

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23 pages, 2253 KiB

Open AccessReview

Translatomics: The Global View of Translation

by Jing Zhao, Bo Qin, Rainer Nikolay, Christian M. T. Spahn and Gong Zhang

Int. J. Mol. Sci. 2019, 20(1), 212; https://doi.org/10.3390/ijms20010212 - 8 Jan 2019

Cited by 71 | Viewed by 12888

Abstract

In all kingdoms of life, proteins are synthesized by ribosomes in a process referred to as translation. The amplitude of translational regulation exceeds the sum of transcription, mRNA degradation and protein degradation. Therefore, it is essential to investigate translation in a global scale. [...] Read more.

In all kingdoms of life, proteins are synthesized by ribosomes in a process referred to as translation. The amplitude of translational regulation exceeds the sum of transcription, mRNA degradation and protein degradation. Therefore, it is essential to investigate translation in a global scale. Like the other “omics”-methods, translatomics investigates the totality of the components in the translation process, including but not limited to translating mRNAs, ribosomes, tRNAs, regulatory RNAs and nascent polypeptide chains. Technical advances in recent years have brought breakthroughs in the investigation of these components at global scale, both for their composition and dynamics. These methods have been applied in a rapidly increasing number of studies to reveal multifaceted aspects of translation control. The process of translation is not restricted to the conversion of mRNA coding sequences into polypeptide chains, it also controls the composition of the proteome in a delicate and responsive way. Therefore, translatomics has extended its unique and innovative power to many fields including proteomics, cancer research, bacterial stress response, biological rhythmicity and plant biology. Rational design in translation can enhance recombinant protein production for thousands of times. This brief review summarizes the main state-of-the-art methods of translatomics, highlights recent discoveries made in this field and introduces applications of translatomics on basic biological and biomedical research. Full article

(This article belongs to the Special Issue Translational Control)

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18 pages, 1838 KiB

Open AccessReview

Cap-Independent mRNA Translation in Germ Cells

by Brett D. Keiper

Int. J. Mol. Sci. 2019, 20(1), 173; https://doi.org/10.3390/ijms20010173 - 5 Jan 2019

Cited by 10 | Viewed by 6984

Abstract

Cellular mRNAs in plants and animals have a 5′-cap structure that is accepted as the recognition point to initiate translation by ribosomes. Consequently, it was long assumed that the translation initiation apparatus was built solely for a cap-dependent (CD) mechanism. Exceptions that emerged [...] Read more.

Cellular mRNAs in plants and animals have a 5′-cap structure that is accepted as the recognition point to initiate translation by ribosomes. Consequently, it was long assumed that the translation initiation apparatus was built solely for a cap-dependent (CD) mechanism. Exceptions that emerged invoke structural damage (proteolytic cleavage) to eukaryotic initiation factor 4 (eIF4) factors that disable cap recognition. The residual eIF4 complex is thought to be crippled, but capable of cap-independent (CI) translation to recruit viral or death-associated mRNAs begrudgingly when cells are in great distress. However, situations where CI translation coexists with CD translation are now known. In such cases, CI translation is still a minor mechanism in the major background of CD synthesis. In this review, I propose that germ cells do not fit this mold. Using observations from various animal models of oogenesis and spermatogenesis, I suggest that CI translation is a robust partner to CD translation to carry out the translational control that is so prevalent in germ cell development. Evidence suggests that CI translation provides surveillance of germ cell homeostasis, while CD translation governs the regulated protein synthesis that ushers these meiotic cells through the remarkable steps in sperm/oocyte differentiation. Full article

(This article belongs to the Special Issue Translational Control)

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29 pages, 1555 KiB

Open AccessReview

Focus on Translation Initiation of the HIV-1 mRNAs

by Sylvain De Breyne and Théophile Ohlmann

Int. J. Mol. Sci. 2019, 20(1), 101; https://doi.org/10.3390/ijms20010101 - 28 Dec 2018

Cited by 25 | Viewed by 8160

Abstract

To replicate and disseminate, viruses need to manipulate and modify the cellular machinery for their own benefit. We are interested in translation, which is one of the key steps of gene expression and viruses that have developed several strategies to hijack the ribosomal [...] Read more.

To replicate and disseminate, viruses need to manipulate and modify the cellular machinery for their own benefit. We are interested in translation, which is one of the key steps of gene expression and viruses that have developed several strategies to hijack the ribosomal complex. The type 1 human immunodeficiency virus is a good paradigm to understand the great diversity of translational control. Indeed, scanning, leaky scanning, internal ribosome entry sites, and adenosine methylation are used by ribosomes to translate spliced and unspliced HIV-1 mRNAs, and some require specific cellular factors, such as the DDX3 helicase, that mediate mRNA export and translation. In addition, some viral and cellular proteins, including the HIV-1 Tat protein, also regulate protein synthesis through targeting the protein kinase PKR, which once activated, is able to phosphorylate the eukaryotic translation initiation factor eIF2α, which results in the inhibition of cellular mRNAs translation. Finally, the infection alters the integrity of several cellular proteins, including initiation factors, that directly or indirectly regulates translation events. In this review, we will provide a global overview of the current situation of how the HIV-1 mRNAs interact with the host cellular environment to produce viral proteins. Full article

(This article belongs to the Special Issue Translational Control)

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12 pages, 972 KiB

Open AccessReview

Translation Stress Regulates Ribosome Synthesis and Cell Proliferation

by Sivakumar Vadivel Gnanasundram and Robin Fåhraeus

Int. J. Mol. Sci. 2018, 19(12), 3757; https://doi.org/10.3390/ijms19123757 - 27 Nov 2018

Cited by 20 | Viewed by 7191

Abstract

Ribosome and protein synthesis are major metabolic events that control cellular growth and proliferation. Impairment in ribosome biogenesis pathways and mRNA translation is associated with pathologies such as cancer and developmental disorders. Processes that control global protein synthesis are tightly regulated at different [...] Read more.

Ribosome and protein synthesis are major metabolic events that control cellular growth and proliferation. Impairment in ribosome biogenesis pathways and mRNA translation is associated with pathologies such as cancer and developmental disorders. Processes that control global protein synthesis are tightly regulated at different levels by numerous factors and linked with multiple cellular signaling pathways. Several of these merge on the growth promoting factor c-Myc, which induces ribosome biogenesis by stimulating Pol I, Pol II, and Pol III transcription. However, how cells sense and respond to mRNA translation stress is not well understood. It was more recently shown that mRNA translation stress activates c-Myc, through a specific induction of E2F1 synthesis via a PI3Kδ-dependent pathway. This review focuses on how this novel feedback pathway stimulates cellular growth and proliferation pathways to synchronize protein synthesis with ribosome biogenesis. It also describes for the first time the oncogenic activity of the mRNA, and not the encoded protein. Full article

(This article belongs to the Special Issue Translational Control)

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