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19 pages, 2368 KiB

Open AccessArticle

Inhibition of Eukaryotic Translation Initiation Factor 5A (eIF5A) Hypusination Suppress p53 Translation and Alters the Association of eIF5A to the Ribosomes

by Marianna Martella, Caterina Catalanotto, Claudio Talora, Anna La Teana, Paola Londei and Dario Benelli

Int. J. Mol. Sci. 2020, 21(13), 4583; https://doi.org/10.3390/ijms21134583 - 27 Jun 2020

Cited by 16 | Viewed by 3762

Abstract

The eukaryotic translation initiation factor 5A (eIF5A) is an essential protein for the viability of the cells whose proposed function is to prevent the stalling of the ribosomes during translation elongation. eIF5A activity requires a unique and functionally essential post-translational modification, the change [...] Read more.

The eukaryotic translation initiation factor 5A (eIF5A) is an essential protein for the viability of the cells whose proposed function is to prevent the stalling of the ribosomes during translation elongation. eIF5A activity requires a unique and functionally essential post-translational modification, the change of a lysine to hypusine. eIF5A is recognized as a promoter of cell proliferation, but it has also been suggested to induce apoptosis. To date, the precise molecular mechanism through which eIF5A affects these processes remains elusive. In the present study, we explored whether eIF5A is involved in controlling the stress-induced expression of the key cellular regulator p53. Our results show that treatment of HCT-116 colon cancer cells with the deoxyhypusine (DHS) inhibitor N1-guanyl-1,7-diamineheptane (GC7) caused both inhibition of eIF5A hypusination and a significant reduction of p53 expression in UV-treated cells, and that eIF5A controls p53 expression at the level of protein synthesis. Furthermore, we show that treatment with GC7 followed by UV-induced stress counteracts the pro-apoptotic process triggered by p53 up-regulation. More in general, the importance of eIF5A in the cellular stress response is illustrated by the finding that exposure to UV light promotes the binding of eIF5A to the ribosomes, whereas UV treatment complemented by the presence of GC7 inhibits such binding, allowing a decrease of de novo synthesis of p53 protein. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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16 pages, 2388 KiB

Open AccessArticle

Post-Transcriptional Regulation of Alpha One Antitrypsin by a Proteasome Inhibitor

by Lang Rao, Yi Xu, Lucas Charles Reineke, Abhisek Bhattacharya, Alexey Tyryshkin, Jin Na Shin and N. Tony Eissa

Int. J. Mol. Sci. 2020, 21(12), 4318; https://doi.org/10.3390/ijms21124318 - 17 Jun 2020

Cited by 2 | Viewed by 3164

Abstract

Alpha one antitrypsin (α1AT), a serine proteinase inhibitor primarily produced by the liver, protects pulmonary tissue from neutrophil elastase digestion. Mutations of the SERPINA1 gene results in a misfolded α1AT protein which aggregates inside hepatocytes causing cellular damage. Therefore, inhibition of mutant α1AT [...] Read more.

Alpha one antitrypsin (α1AT), a serine proteinase inhibitor primarily produced by the liver, protects pulmonary tissue from neutrophil elastase digestion. Mutations of the SERPINA1 gene results in a misfolded α1AT protein which aggregates inside hepatocytes causing cellular damage. Therefore, inhibition of mutant α1AT production is one practical strategy to alleviate liver damage. Here we show that proteasome inhibitors can selectively downregulate α1AT expression in human hepatocytes by suppressing the translation of α1AT. Translational suppression of α1AT is mediated by phosphorylation of eukaryotic translation initiation factor 2α and increased association of RNA binding proteins, especially stress granule protein Ras GAP SH3 binding protein (G3BP1), with α1AT mRNA. Treatment of human-induced pluripotent stem cell-derived hepatocytes with a proteasome inhibitor also results in translational inhibition of mutant α1AT in a similar manner. Together we revealed a previously undocumented role of proteasome inhibitors in the regulation of α1AT translation. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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18 pages, 2224 KiB

Open AccessArticle

Functional Cyclization of Eukaryotic mRNAs

by Olga M. Alekhina, Ilya M. Terenin, Sergey E. Dmitriev and Konstantin S. Vassilenko

Int. J. Mol. Sci. 2020, 21(5), 1677; https://doi.org/10.3390/ijms21051677 - 29 Feb 2020

Cited by 29 | Viewed by 6391

Abstract

The closed-loop model of eukaryotic translation states that mRNA is circularized by a chain of the cap-eIF4E-eIF4G-poly(A)-binding protein (PABP)-poly(A) interactions that brings 5′ and 3′ ends together. This circularization is thought to promote the engagement of terminating ribosomes to a new round of [...] Read more.

The closed-loop model of eukaryotic translation states that mRNA is circularized by a chain of the cap-eIF4E-eIF4G-poly(A)-binding protein (PABP)-poly(A) interactions that brings 5′ and 3′ ends together. This circularization is thought to promote the engagement of terminating ribosomes to a new round of translation at the same mRNA molecule, thus enhancing protein synthesis. Despite the general acceptance and the elegance of the hypothesis, it has never been proved experimentally. Using continuous in situ monitoring of luciferase synthesis in a mammalian in vitro system, we show here that the rate of translation initiation at capped and polyadenylated reporter mRNAs increases after the time required for the first ribosomes to complete mRNA translation. Such acceleration strictly requires the presence of a poly(A)-tail and is abrogated by the addition of poly(A) RNA fragments or m⁷GpppG cap analog to the translation reaction. The optimal functional interaction of mRNA termini requires 5′ untranslated region (UTR) and 3′ UTR of moderate lengths and provides stronger acceleration, thus a longer poly(A)-tail. Besides, we revealed that the inhibitory effect of the dominant negative R362Q mutant of initiation factor eIF4A diminishes in the course of translation reaction, suggesting a relaxed requirement for ATP. Taken together, our results imply that, upon the functional looping of an mRNA, the recycled ribosomes can be recruited to the start codon of the same mRNA molecule in an eIF4A-independent fashion. This non-canonical closed-loop assisted reinitiation (CLAR) mode provides efficient translation of the functionally circularized mRNAs. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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23 pages, 3375 KiB

Open AccessArticle

Identifying the Translatome of Mouse NEBD-Stage Oocytes via SSP-Profiling; A Novel Polysome Fractionation Method

by Tomas Masek, Edgar del Llano, Lenka Gahurova, Michal Kubelka, Andrej Susor, Kristina Roucova, Chih-Jen Lin, Alexander W. Bruce and Martin Pospisek

Int. J. Mol. Sci. 2020, 21(4), 1254; https://doi.org/10.3390/ijms21041254 - 13 Feb 2020

Cited by 19 | Viewed by 10037

Abstract

Meiotic maturation of oocyte relies on pre-synthesised maternal mRNA, the translation of which is highly coordinated in space and time. Here, we provide a detailed polysome profiling protocol that demonstrates a combination of the sucrose gradient ultracentrifugation in small SW55Ti tubes with the [...] Read more.

Meiotic maturation of oocyte relies on pre-synthesised maternal mRNA, the translation of which is highly coordinated in space and time. Here, we provide a detailed polysome profiling protocol that demonstrates a combination of the sucrose gradient ultracentrifugation in small SW55Ti tubes with the qRT-PCR-based quantification of 18S and 28S rRNAs in fractionated polysome profile. This newly optimised method, named Scarce Sample Polysome Profiling (SSP-profiling), is suitable for both scarce and conventional sample sizes and is compatible with downstream RNA-seq to identify polysome associated transcripts. Utilising SSP-profiling we have assayed the translatome of mouse oocytes at the onset of nuclear envelope breakdown (NEBD)—a developmental point, the study of which is important for furthering our understanding of the molecular mechanisms leading to oocyte aneuploidy. Our analyses identified 1847 transcripts with moderate to strong polysome occupancy, including abundantly represented mRNAs encoding mitochondrial and ribosomal proteins, proteasomal components, glycolytic and amino acids synthetic enzymes, proteins involved in cytoskeleton organization plus RNA-binding and translation initiation factors. In addition to transcripts encoding known players of meiotic progression, we also identified several mRNAs encoding proteins of unknown function. Polysome profiles generated using SSP-profiling were more than comparable to those developed using existing conventional approaches, being demonstrably superior in their resolution, reproducibility, versatility, speed of derivation and downstream protocol applicability. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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15 pages, 2215 KiB

Open AccessArticle

In Steatotic Cells, ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism, Contributing to the Stimulation of De Novo Lipogenesis

by Luisa Siculella, Laura Giannotti, Mariangela Testini, Gabriele V. Gnoni and Fabrizio Damiano

Int. J. Mol. Sci. 2020, 21(4), 1206; https://doi.org/10.3390/ijms21041206 - 11 Feb 2020

Cited by 15 | Viewed by 3464

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease in which excessive amount of lipids is accumulated as droplets in hepatocytes. Recently, cumulative evidences suggested that a sustained de novo lipogenesis can play an important role in NAFLD. Dysregulated expression of lipogenic genes, including ATP-citrate lyase (ACLY), has been found in liver diseases associated with lipid accumulation. ACLY is a ubiquitous cytosolic enzyme positioned at the intersection of nutrients catabolism and cholesterol and fatty acid biosyntheses. In the present study, the molecular mechanism of ACLY expression in a cell model of steatosis has been reported. We identified an internal ribosome entry site (IRES) in the 5′ untranslated region of the ACLY mRNA, that can support an efficient mRNA translation through a Cap-independent mechanism. In steatotic HepG2 cells, ACLY expression was up-regulated through IRES-mediated translation. Since it has been demonstrated that lipid accumulation in cells induces endoplasmic reticulum (ER) stress, the involvement of this cellular pathway in the translational regulation of ACLY has been also evaluated. Our results showed that ACLY expression was increased in ER-stressed cells, through IRES-mediated translation of ACLY mRNA. A potential role of the Cap-independent translation of ACLY in NAFLD has been discussed. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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Review

Jump to: Research

18 pages, 726 KiB

Open AccessReview

Circular RNA, the Key for Translation

by Anne-Catherine Prats, Florian David, Leila H. Diallo, Emilie Roussel, Florence Tatin, Barbara Garmy-Susini and Eric Lacazette

Int. J. Mol. Sci. 2020, 21(22), 8591; https://doi.org/10.3390/ijms21228591 - 14 Nov 2020

Cited by 102 | Viewed by 9067

Abstract

It was thought until the 1990s that the eukaryotic translation machinery was unable to translate a circular RNA. However internal ribosome entry sites (IRESs) and m⁶A-induced ribosome engagement sites (MIRESs) were discovered, promoting 5′ end-independent translation initiation. Today a new family [...] Read more.

It was thought until the 1990s that the eukaryotic translation machinery was unable to translate a circular RNA. However internal ribosome entry sites (IRESs) and m⁶A-induced ribosome engagement sites (MIRESs) were discovered, promoting 5′ end-independent translation initiation. Today a new family of so-called “noncoding” circular RNAs (circRNAs) has emerged, revealing the pivotal role of 5′ end-independent translation. CircRNAs have a strong impact on translational control via their sponge function, and form a new mRNA family as they are translated into proteins with pathophysiological roles. While there is no more doubt about translation of covalently closed circRNA, the linearity of canonical mRNA is only theoretical: it has been shown for more than thirty years that polysomes exhibit a circular form and mRNA functional circularization has been demonstrated in the 1990s by the interaction of initiation factor eIF4G with poly(A) binding protein. More recently, additional mechanisms of 3′–5′ interaction have been reported, including m⁶A modification. Functional circularization enhances translation via ribosome recycling and acceleration of the translation initiation rate. This update of covalently and noncovalently closed circular mRNA translation landscape shows that RNA with circular shape might be the rule for translation with an important impact on disease development and biotechnological applications. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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15 pages, 1175 KiB

Open AccessReview

Regulation of Translation in the Protozoan Parasite Leishmania

by Zemfira N. Karamysheva, Sneider Alexander Gutierrez Guarnizo and Andrey L. Karamyshev

Int. J. Mol. Sci. 2020, 21(8), 2981; https://doi.org/10.3390/ijms21082981 - 23 Apr 2020

Cited by 25 | Viewed by 5109

Abstract

Leishmaniasis represents a serious health problem worldwide and drug resistance is a growing concern. Leishmania parasites use unusual mechanisms to control their gene expression. In contrast to many other species, they do not have transcriptional regulation. The lack of transcriptional control is mainly [...] Read more.

Leishmaniasis represents a serious health problem worldwide and drug resistance is a growing concern. Leishmania parasites use unusual mechanisms to control their gene expression. In contrast to many other species, they do not have transcriptional regulation. The lack of transcriptional control is mainly compensated by post-transcriptional mechanisms, including tight translational control and regulation of mRNA stability/translatability by RNA-binding proteins. Modulation of translation plays a major role in parasite survival and adaptation to dramatically different environments during change of host; however, our knowledge of fine molecular mechanisms of translation in Leishmania remains limited. Here, we review the current progress in our understanding of how changes in the translational machinery promote parasite differentiation during transmission from a sand fly to a mammalian host, and discuss how translational reprogramming can contribute to the development of drug resistance. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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15 pages, 1889 KiB

Open AccessReview

Translational Control of Secretory Proteins in Health and Disease

by Andrey L. Karamyshev, Elena B. Tikhonova and Zemfira N. Karamysheva

Int. J. Mol. Sci. 2020, 21(7), 2538; https://doi.org/10.3390/ijms21072538 - 6 Apr 2020

Cited by 24 | Viewed by 7188

Abstract

Secretory proteins are synthesized in a form of precursors with additional sequences at their N-terminal ends called signal peptides. The signal peptides are recognized co-translationally by signal recognition particle (SRP). This interaction leads to targeting to the endoplasmic reticulum (ER) membrane and translocation [...] Read more.

Secretory proteins are synthesized in a form of precursors with additional sequences at their N-terminal ends called signal peptides. The signal peptides are recognized co-translationally by signal recognition particle (SRP). This interaction leads to targeting to the endoplasmic reticulum (ER) membrane and translocation of the nascent chains into the ER lumen. It was demonstrated recently that in addition to a targeting function, SRP has a novel role in protection of secretory protein mRNAs from degradation. It was also found that the quality of secretory proteins is controlled by the recently discovered Regulation of Aberrant Protein Production (RAPP) pathway. RAPP monitors interactions of polypeptide nascent chains during their synthesis on the ribosomes and specifically degrades their mRNAs if these interactions are abolished due to mutations in the nascent chains or defects in the targeting factor. It was demonstrated that pathological RAPP activation is one of the molecular mechanisms of human diseases associated with defects in the secretory proteins. In this review, we discuss recent progress in understanding of translational control of secretory protein biogenesis on the ribosome and pathological consequences of its dysregulation in human diseases. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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19 pages, 2319 KiB

Open AccessReview

eIF4E and Interactors from Unicellular Eukaryotes

by Daniela Ross-Kaschitza and Michael Altmann

Int. J. Mol. Sci. 2020, 21(6), 2170; https://doi.org/10.3390/ijms21062170 - 21 Mar 2020

Cited by 8 | Viewed by 4049

Abstract

eIF4E, the mRNA cap-binding protein, is well known as a general initiation factor allowing for mRNA-ribosome interaction and cap-dependent translation in eukaryotic cells. In this review we focus on eIF4E and its interactors in unicellular organisms such as yeasts and protozoan eukaryotes. In [...] Read more.

eIF4E, the mRNA cap-binding protein, is well known as a general initiation factor allowing for mRNA-ribosome interaction and cap-dependent translation in eukaryotic cells. In this review we focus on eIF4E and its interactors in unicellular organisms such as yeasts and protozoan eukaryotes. In a first part, we describe eIF4Es from yeast species such as Saccharomyces cerevisiae, Candida albicans, and Schizosaccharomyces pombe. In the second part, we will address eIF4E and interactors from parasite unicellular species—trypanosomatids and marine microorganisms—dinoflagellates. We propose that different strategies have evolved during evolution to accommodate cap-dependent translation to differing requirements. These evolutive “adjustments” involve various forms of eIF4E that are not encountered in all microorganismic species. In yeasts, eIF4E interactors, particularly p20 and Eap1 are found exclusively in Saccharomycotina species such as S. cerevisiae and C. albicans. For protozoan parasites of the Trypanosomatidae family beside a unique cap4-structure located at the 5′UTR of all mRNAs, different eIF4Es and eIF4Gs are active depending on the life cycle stage of the parasite. Additionally, an eIF4E-interacting protein has been identified in Leishmania major which is important for switching from promastigote to amastigote stages. For dinoflagellates, little is known about the structure and function of the multiple and diverse eIF4Es that have been identified thanks to widespread sequencing in recent years. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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24 pages, 1852 KiB

Open AccessReview

A Retrospective on eIF2A—and Not the Alpha Subunit of eIF2

by Anton A. Komar and William C. Merrick

Int. J. Mol. Sci. 2020, 21(6), 2054; https://doi.org/10.3390/ijms21062054 - 17 Mar 2020

Cited by 42 | Viewed by 11327

Abstract

Initiation of protein synthesis in eukaryotes is a complex process requiring more than 12 different initiation factors, comprising over 30 polypeptide chains. The functions of many of these factors have been established in great detail; however, the precise role of some of them [...] Read more.

Initiation of protein synthesis in eukaryotes is a complex process requiring more than 12 different initiation factors, comprising over 30 polypeptide chains. The functions of many of these factors have been established in great detail; however, the precise role of some of them and their mechanism of action is still not well understood. Eukaryotic initiation factor 2A (eIF2A) is a single chain 65 kDa protein that was initially believed to serve as the functional homologue of prokaryotic IF2, since eIF2A and IF2 catalyze biochemically similar reactions, i.e., they stimulate initiator Met-tRNA_i binding to the small ribosomal subunit. However, subsequent identification of a heterotrimeric 126 kDa factor, eIF2 (α,β,γ) showed that this factor, and not eIF2A, was primarily responsible for the binding of Met-tRNA_i to 40S subunit in eukaryotes. It was found however, that eIF2A can promote recruitment of Met-tRNA_i to 40S/mRNA complexes under conditions of inhibition of eIF2 activity (eIF2α-phosphorylation), or its absence. eIF2A does not function in major steps in the initiation process, but is suggested to act at some minor/alternative initiation events such as re-initiation, internal initiation, or non-AUG initiation, important for translational control of specific mRNAs. This review summarizes our current understanding of the eIF2A structure and function. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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22 pages, 1483 KiB

Open AccessReview

Comprehensive Genome-Wide Approaches to Activity-Dependent Translational Control in Neurons

by Han Kyoung Choe and Jun Cho

Int. J. Mol. Sci. 2020, 21(5), 1592; https://doi.org/10.3390/ijms21051592 - 26 Feb 2020

Cited by 6 | Viewed by 4370

Abstract

Activity-dependent regulation of gene expression is critical in experience-mediated changes in the brain. Although less appreciated than transcriptional control, translational control is a crucial regulatory step of activity-mediated gene expression in physiological and pathological conditions. In the first part of this review, we [...] Read more.

Activity-dependent regulation of gene expression is critical in experience-mediated changes in the brain. Although less appreciated than transcriptional control, translational control is a crucial regulatory step of activity-mediated gene expression in physiological and pathological conditions. In the first part of this review, we overview evidence demonstrating the importance of translational controls under the context of synaptic plasticity as well as learning and memory. Then, molecular mechanisms underlying the translational control, including post-translational modifications of translation factors, mTOR signaling pathway, and local translation, are explored. We also summarize how activity-dependent translational regulation is associated with neurodevelopmental and psychiatric disorders, such as autism spectrum disorder and depression. In the second part, we highlight how recent application of high-throughput sequencing techniques has added insight into genome-wide studies on translational regulation of neuronal genes. Sequencing-based strategies to identify molecular signatures of the active neuronal population responding to a specific stimulus are discussed. Overall, this review aims to highlight the implication of translational control for neuronal gene regulation and functions of the brain and to suggest prospects provided by the leading-edge techniques to study yet-unappreciated translational regulation in the nervous system. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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24 pages, 1930 KiB

Open AccessReview

Expanding Role of Ubiquitin in Translational Control

by Shannon E. Dougherty, Austin O. Maduka, Toshifumi Inada and Gustavo M. Silva

Int. J. Mol. Sci. 2020, 21(3), 1151; https://doi.org/10.3390/ijms21031151 - 9 Feb 2020

Cited by 43 | Viewed by 7813

Abstract

The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding [...] Read more.

The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding proteins, translation and associated factors, numerous enzymes, and by post-translational modifications (PTM). Ubiquitination, a prominent PTM discovered as the signal for protein degradation, has newly emerged as a modulator of protein synthesis by controlling several processes in translation. Advances in proteomics and cryo-electron microscopy have identified ubiquitin modifications of several ribosomal proteins and provided numerous insights on how this modification affects ribosome structure and function. The variety of pathways and functions of translation controlled by ubiquitin are determined by the various enzymes involved in ubiquitin conjugation and removal, by the ubiquitin chain type used, by the target sites of ubiquitination, and by the physiologic signals triggering its accumulation. Current research is now elucidating multiple ubiquitin-mediated mechanisms of translational control, including ribosome biogenesis, ribosome degradation, ribosome-associated protein quality control (RQC), and redox control of translation by ubiquitin (RTU). This review discusses the central role of ubiquitin in modulating the dynamism of the cellular proteome and explores the molecular aspects responsible for the expanding puzzle of ubiquitin signals and functions in translation. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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13 pages, 1905 KiB

Open AccessReview

Dbp5/DDX19 between Translational Readthrough and Nonsense Mediated Decay

by Christian Beißel, Sebastian Grosse and Heike Krebber

Int. J. Mol. Sci. 2020, 21(3), 1085; https://doi.org/10.3390/ijms21031085 - 6 Feb 2020

Cited by 12 | Viewed by 6032

Abstract

The DEAD-box protein Dbp5 (human DDX19) remodels RNA-protein complexes. Dbp5 functions in ribonucleoprotein export and translation termination. Termination occurs, when the ribosome has reached a stop codon through the Dbp5 mediated delivery of the eukaryotic termination factor eRF1. eRF1 contacts eRF3 upon dissociation [...] Read more.

The DEAD-box protein Dbp5 (human DDX19) remodels RNA-protein complexes. Dbp5 functions in ribonucleoprotein export and translation termination. Termination occurs, when the ribosome has reached a stop codon through the Dbp5 mediated delivery of the eukaryotic termination factor eRF1. eRF1 contacts eRF3 upon dissociation of Dbp5, resulting in polypeptide chain release and subsequent ribosomal subunit splitting. Mutations in DBP5 lead to stop codon readthrough, because the eRF1 and eRF3 interaction is not controlled and occurs prematurely. This identifies Dbp5/DDX19 as a possible potent drug target for nonsense suppression therapy. Neurodegenerative diseases and cancer are caused in many cases by the loss of a gene product, because its mRNA contained a premature termination codon (PTC) and is thus eliminated through the nonsense mediated decay (NMD) pathway, which is described in the second half of this review. We discuss translation termination and NMD in the light of Dbp5/DDX19 and subsequently speculate on reducing Dbp5/DDX19 activity to allow readthrough of the PTC and production of a full-length protein to detract the RNA from NMD as a possible treatment for diseases. Full article

(This article belongs to the Special Issue Translational Control 2.0)

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