Specialized ribosomes and the control of translation

2018 ◽  
Vol 46 (4) ◽  
pp. 855-869 ◽  
Author(s):  
Huili Guo
Keyword(s):  
Protein Synthesis ◽  
Translational Control ◽  
Mrna Translation ◽  
Current Evidence ◽  
Protein Levels ◽  
End Point ◽  
Recent Developments ◽  
Different Tissues

The control of translation is increasingly recognized as a major factor in determining protein levels in the cell. The ribosome — the cellular machine that mediates protein synthesis — is typically seen as a key, but invariant, player in this process. This is because translational control is thought to be mediated by other auxiliary factors while ribosome recruitment is seen as the end-point of regulation. However, recent developments have made it clear that heterogeneous ribosome types can exist in different tissues, and more importantly, that these ribosomes can preferentially translate different subsets of mRNAs. In so doing, heterogeneous ribosomes could be key regulatory players in differentiation and development. Here, we examine current evidence for the existence of different ribosome types and how they might arise. In particular, we will take a close look at the mechanisms through which these ribosomes might mediate selective mRNA translation. We also summarize recently developed techniques/approaches that will aid in our understanding of the functions of such specialized ribosomes.

scholarly journals eIF-Three to Tango: Emerging Functions of Translation Initiation Factor eIF3 in Protein Synthesis and Disease

2019 ◽  
Author(s):  
Dieter A. Wolf ◽  
Yingying Lin ◽  
Haoran Duan ◽  
Yabin Cheng
Keyword(s):  
Protein Synthesis ◽  
Posttranslational Modifications ◽  
Protein Production ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Homeostasis ◽  
Subcellular Targeting ◽  
The Past ◽  
Different Tissues

Studies over the past three years have substantially expanded the involvements of eIF3 in mRNA translation. It now appears that this multi-subunit complex is involved in every possible form of mRNA translation, controlling every step of protein synthesis from initiation to elongation, termination and quality control in positive as well as negative fashion. Through the study of eIF3, we are beginning to appreciate protein synthesis as a highly integrated process coordinating protein production with protein folding, subcellular targeting, and degradation. At the same time, eIF3 subunits appear to have specific functions that probably vary between different tissues and individual cells. Considering the broad functions of eIF3 in protein homeostasis, it comes as little surprise that eIF3 is increasingly implicated in major human diseases and first attempts at therapeutically targeting eIF3 have been undertaken. Much remains to be learned, however, about subunit- and tissue-specific functions of eIF3 in protein synthesis and disease and their regulation by environmental conditions and posttranslational modifications.

scholarly journals Processing Body Formation Limits Proinflammatory Cytokine Synthesis in Endotoxin-Tolerant Monocytes and Murine Septic Macrophages

2015 ◽  
Vol 7 (6) ◽  
pp. 572-583 ◽  
Author(s):  
Clara McClure ◽  
Laura Brudecki ◽  
Zhi Q. Yao ◽  
Charles E. McCall ◽  
Mohamed El Gazzar
Keyword(s):  
Protein Synthesis ◽  
Rna Binding ◽  
Mrna Translation ◽  
Endotoxin Tolerance ◽  
Translational Repression ◽  
Binding Motif ◽  
Body Formation ◽  
Translational Repressor ◽  
Protein Levels ◽  
Repressor Complex

An anti-inflammatory phenotype with pronounced immunosuppression develops during sepsis, during which time neutrophils and monocytes/macrophages limit their Toll-like receptor 4 responses to bacterial lipopolysaccharide (LPS/endotoxin). We previously reported that during this endotoxin-tolerant state, distinct signaling pathways differentially repress transcription and translation of proinflammatory cytokines such as TNFα and IL-6. Sustained endotoxin tolerance contributes to sepsis mortality. While transcription repression requires chromatin modifications, a translational repressor complex of Argonaute 2 (Ago2) and RNA-binding motif protein 4 (RBM4), which bind the 3′-UTR of TNFα and IL-6 mRNA, limits protein synthesis. Here, we show that Dcp1 supports the assembly of the Ago2 and RBM4 repressor complex into cytoplasmic processing bodies (p-bodies) in endotoxin-tolerant THP-1 human monocytes following stimulation with LPS, resulting in translational repression and limiting protein synthesis. Importantly, this translocation process is reversed by Dcp1 knockdown, which restores TNFα and IL-6 protein levels. We also find this translational repression mechanism in primary macrophages of septic mice. Because p-body formation is a critical step in mRNA translation repression, we conclude that Dcp1 is a major component of the translational repression machinery of endotoxin tolerance and may contribute to sepsis outcome.

β-Oxidation of free fatty acids is required to maintain translational control of protein synthesis in heart

2002 ◽  
Vol 283 (6) ◽  
pp. E1144-E1150 ◽  
Author(s):  
Stephen J. Crozier ◽  
Douglas R. Bolster ◽  
Ali K. Reiter ◽  
Scot R. Kimball ◽  
Leonard S. Jefferson
Keyword(s):  
Fatty Acids ◽  
Protein Synthesis ◽  
Free Fatty Acids ◽  
Translation Initiation ◽  
Translational Control ◽  
Mrna Translation ◽  
Nucleotide Exchange ◽  
Energy Status ◽  
Α Subunit

The study described herein investigated the role of free fatty acids (FFAs) in the maintenance of protein synthesis in vivo in rat cardiac and skeletal muscle. Suppression of FFA β-oxidation by methyl palmoxirate caused a marked reduction in protein synthesis in the heart. The effect on protein synthesis was mediated in part by changes in the function of eukaryotic initiation factors (eIFs) involved in the initiation of mRNA translation. The guanine nucleotide exchange activity of eIF2B was repressed, phosphorylation of the α-subunit of eIF2 was enhanced, and phosphorylation of eIF4E-binding protein-1 and ribosomal protein S6 kinase was reduced. Similar changes in protein synthesis and translation initiation were not observed in the gastrocnemius following treatment with methyl palmoxirate. In heart, repressed β-oxidation of FFA correlated, as demarcated by changes in the ATP/AMP ratio and phosphorylation of AMP-activated kinase, with alterations in the energy status of the tissue. Therefore, the activation state of signal transduction pathways that are responsive to cellular energy stress represents one mechanism whereby translation initiation may be regulated in cardiac muscle.

scholarly journals TOP mRNPs: Molecular Mechanisms and Principles of Regulation

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 969 ◽  
Author(s):  
Eric Cockman ◽  
Paul Anderson ◽  
Pavel Ivanov
Keyword(s):  
Protein Synthesis ◽  
Translational Control ◽  
Gene Networks ◽  
Cellular Response ◽  
Ribosome Biogenesis ◽  
Molecular Mechanisms ◽  
Mrna Translation ◽  
Ribonucleoprotein Complexes ◽  
Global Protein Synthesis ◽  
Protein Components

The cellular response to changes in the surrounding environment and to stress requires the coregulation of gene networks aiming to conserve energy and resources. This is often achieved by downregulating protein synthesis. The 5’ Terminal OligoPyrimidine (5’ TOP) motif-containing mRNAs, which encode proteins that are essential for protein synthesis, are the primary targets of translational control under stress. The TOP motif is a cis-regulatory RNA element that begins directly after the m7G cap structure and contains the hallmark invariant 5’-cytidine followed by an uninterrupted tract of 4–15 pyrimidines. Regulation of translation via the TOP motif coordinates global protein synthesis with simultaneous co-expression of the protein components required for ribosome biogenesis. In this review, we discuss architecture of TOP mRNA-containing ribonucleoprotein complexes, the principles of their assembly, and the modes of regulation of TOP mRNA translation.

The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3374-3383 ◽  
Author(s):  
Philipp B. Staber ◽  
Paul Vesely ◽  
Naznin Haq ◽  
Rene G. Ott ◽  
Kotaro Funato ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Translational Control ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Mrna Translation ◽  
Large Cell ◽  
Protein Levels ◽  
M Phase ◽  
Alk Positive ◽  
Interfering Rna

Abstract Anaplastic large cell lymphomas (ALCLs) are highly proliferating tumors that commonly express the AP-1 transcription factor JunB. ALK fusions occur in approximately 50% of ALCLs, and among these, 80% have the t(2;5) translocation with NPM-ALK expression. We report greater activity of JunB in NPM-ALK–positive than in NPM-ALK–negative ALCLs. Specific knockdown of JUNB mRNA using small interfering RNA and small hairpin RNA in NPM-ALK–expressing cells decreases cellular proliferation as evidenced by a reduced cell count in the G2/M phase of the cell cycle. Expression of NPM-ALK results in ERK1/2 activation and transcriptional up-regulation of JUNB. Both NPM-ALK–positive and –negative ALCL tumors demonstrate active ERK1/2 signaling. In contrast to NPM-ALK–negative ALCL, the mTOR pathway is active in NPM-ALK–positive lymphomas. Pharmacological inhibition of mTOR in NPM-ALK–positive cells down-regulates JunB protein levels by shifting JUNB mRNA translation from large polysomes to monosomes and ribonucleic particles (RNPs), and decreases cellular proliferation. Thus, JunB is a critical target of mTOR and is translationally regulated in NPM-ALK–positive lymphomas. This is the first study demonstrating translational control of AP-1 transcription factors in human neoplasia. In conjunction with NPM-ALK, JunB enhances cell cycle progression and may therefore represent a therapeutic target.

scholarly journals Role of mTORC1 in mechanically induced increases in translation and skeletal muscle mass

2019 ◽  
Vol 127 (2) ◽  
pp. 581-590 ◽  
Author(s):  
Craig A. Goodman
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Mrna Translation ◽  
Current Evidence ◽  
Mechanical Stimuli ◽  
Serine Threonine Kinase ◽  
Mtor Complex 1

Skeletal muscle mass is, in part, regulated by the rate of mRNA translation (i.e., protein synthesis). The conserved serine/threonine kinase, mTOR (the mammalian/mechanistic target of rapamycin), found in the multiprotein complex, mTOR complex 1 (mTORC1), is a major positive regulator of protein synthesis. The purpose of this review is to describe some of the critical steps in translation initiation, mTORC1 and its potential direct and indirect roles in regulating translation, and evidence that mTORC1 regulates protein synthesis and muscle mass, with a particular focus on basal conditions and the response to mechanical stimuli. Current evidence suggests that for acute contraction models of mechanical stimuli, there is an emerging pattern suggesting that there is an early increase in protein synthesis governed by a rapamycin-sensitive mTORC1-dependent mechanism, while at later poststimulation time points, the mechanism may change to a rapamycin-insensitive mTORC1-dependent or even an mTORC1-independent mechanism. Furthermore, evidence suggests that mTORC1 appears to be absolutely necessary for muscle fiber hypertrophy induced by chronic mechanical loading but may only play a partial role in the hypertrophy induced by more intermittent types of acute resistance exercise, with the possibility of mTORC1-independent mechanisms also playing a role. Despite the progress that has been made, many questions about the activation of mTORC1, and its downstream targets, remain to be answered. Further research will hopefully provide novel insights into the regulation of skeletal muscle mTORC1 that may eventually be translated into novel exercise programing and/or targeted pharmacological therapies aimed at preventing muscle wasting and/or increasing muscle mass.

scholarly journals Generally applicable transcriptome-wide analysis of translation using anota2seq

2019 ◽  
Vol 47 (12) ◽  
pp. e70-e70 ◽  
Author(s):  
Christian Oertlin ◽  
Julie Lorent ◽  
Carl Murie ◽  
Luc Furic ◽  
Ivan Topisirovic ◽  
...  
Keyword(s):  
Translational Control ◽  
Gene Expression Regulation ◽  
Neurological Diseases ◽  
Mrna Translation ◽  
Protein Levels ◽  
Pathological Conditions ◽  
Evolutionarily Conserved ◽  
Statistical Identification ◽  
Advance Knowledge

Abstract mRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated contributes to various disorders including metabolic and neurological diseases and cancer. Notwithstanding that optimal and universally applicable methods are critical for understanding the complex role of translational control under physiological and pathological conditions, approaches to analyze translatomes are largely underdeveloped. To address this, we developed the anota2seq algorithm which outperforms current methods for statistical identification of changes in translation. Notably, in contrast to available analytical methods, anota2seq also allows specific identification of an underappreciated mode of gene expression regulation whereby translation acts as a buffering mechanism which maintains protein levels despite fluctuations in corresponding mRNA abundance (‘translational buffering’). Thus, the universal anota2seq algorithm allows efficient and hitherto unprecedented interrogation of translatomes which is anticipated to advance knowledge regarding the role of translation in homeostasis and disease.

The cytoplasmic fate of mRNA

2001 ◽  
Vol 114 (10) ◽  
pp. 1797-1798
Author(s):  
L.C. Kuhn
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Translational Control ◽  
Rna World ◽  
Mrna Translation ◽  
Fine Tuning ◽  
Control Mechanisms ◽  
Control Of Gene Expression ◽  
Interaction Sites ◽  
Translation Apparatus

Translational Control of Gene Expression edited by N. Sonenberg, J. W. B. Hershey and M. B. Matthews Cold Spring Harbor Laboratory Press (2000) 1020 pages. ISBN 0–87969-568-4 US$115 At the beginning of the 90s most molecular biologists were focusing on transcription and RNA splicing. mRNA translation and its temporal and spatial regulation seemed research topics for insiders at that time. However, all aspects of mRNA fate in the cytoplasm will certainly attract much more attention during the next decade. The field is now flourishing with connections to all disciplines of biology. This book will help you to realize the tremendous variation of translational regulatory mechanisms existing in nature. The evidence for their importance has become so overwhelming that nobody seriously interested in gene expression can ignore it any longer. It is the great merit of the editors of this book that they have brought together an impressive series of first-class reviews written by the most prominent scientists in the field. The new monograph takes a fresh look at the field and is greatly expanded compared with the earlier 1996 version. The book is judiciously divided into two parts. The first part comprises eight broad chapters, giving an overview of the main principles of protein synthesis and its regulation. They serve as a thorough basis for the second part, which comprises twenty-eight chapters, each about 20 pages in length, that present in depth additional exciting areas in which there is strong research activity. Your appetite for this book will be stimulated right at the beginning by the wonderful introductory chapter, which is written jointly by the editors and defines the field in its entire complexity. Given that translation is of course a unifying principle of all living organisms, why are there such a large number of different control mechanisms modulating the use of mRNA templates and making actual protein level not predictable from RNA quantity alone? Are these just remnants of an RNA world or, as the authors seem to believe, effective adaptations for fine-tuning gene expression that have been opportunistically added during evolution? Five broad chapters are devoted to our knowledge of initiation, elongation and termination of translation both in eukaryotes and in prokaryotes. It is amazing how much detail has been added, in just the past five years, to our picture of the biochemistry, structure and function of ribosomes, initiation sites, and translation factors. However, translational control of gene expression is not just a matter of the translation machinery alone. It seems rather that the tremendously versatile mRNA sequences and structures impose the way they are seen by the translation apparatus and its factors. Particularly in eukaryotes, the untranslated parts of mRNAs play a decisive role by providing additional interaction sites for cytoplasmic proteins that modulate mRNA stability, mRNA localization or accessibility of mRNAs to translation. In turn, many of the proteins interacting with mRNA are themselves regulated by metabolites or post-translational modifications. This is beautifully documented in an exciting chapter on the role of translational control in developmental decisions. For example, in Drosophila, a specific cascade of factors acting on RNA localization and translation controls the anterior-posterior body axis. In C. elegans, the fate of germ-line cells is determined by translational repression. And you will find many more such examples. Another important section of the book is devoted to changes in translation that occur during virus infection. Again one is amazed by the variety of ways by which viruses divert the host translation apparatus for their own sake. The shorter chapters give insight into additional exciting areas in the field. For example, research into how heat shock or signal transduction pathways feed into translation, what we know about mRNA degradation of normal and nonsense-containing transcripts, and the evidence that local synaptic protein synthesis represents a molecular hallmark of learning and memory. This book is the most complete and up-to-date review of translational control mechanisms. It is a must for students entering the field, and it will constitute for many years a major reference guide for any investigator who is seriously interested in the full picture of gene expression.

scholarly journals Investigation of protein synthesis in Drosophila larvae using puromycin labelling

2017 ◽  
Author(s):  
Lisa Deliu ◽  
Abhishek Ghosh ◽  
Savraj S. Grewal
Keyword(s):  
Protein Synthesis ◽  
Translational Control ◽  
Ex Vivo ◽  
Mrna Translation ◽  
Cost Effective ◽  
Whole Body ◽  
Control Of Gene Expression ◽  
Cost Effective Approach ◽  
Drosophila Larvae ◽  
Important Regulator

ABSTRACTTranslational control of gene expression is an important regulator of growth, homeostasis and aging in Drosophila. The ability to measure changes in protein synthesis in response to genetic and environmental cues is therefore important in studying these processes. Here we describe a simple and cost effective approach to assay protein synthesis in Drosophila larval cells and tissues. The method is based on the incorporation of puromycin into nascent peptide chains. Using an ex vivo approach, we label newly synthesized peptides in larvae with puromycin and then measure levels of new protein synthesis using an anti-puromycin antibody. We show that this method can detect changes in protein synthesis in specific cells and tissues in the larvae, either by immunostaining or western blotting. We find that the assay reliably detects changes in protein synthesis induced by two known stimulators of mRNA translation - the nutrient/TORC1 kinase pathway and the transcription factor dMyc. We also use the assay to describe how protein synthesis changes through larval development and in response to two environmental stressors – hypoxia and heat-shock. We propose that this puromycin-labelling assay is a simple but robust method to detect protein synthesis changes at the levels of cells, tissues or whole body in Drosophila.

scholarly journals Timed global reorganization of protein synthesis during neocortex neurogenesis at codon resolution

2021 ◽  
Author(s):  
Dermot Harnett ◽  
Mateusz C. Ambrozkiewicz ◽  
Ulrike Zinnall ◽  
Ekaterina Borisova ◽  
Alexandra Rusanova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Rna Binding ◽  
Mrna Translation ◽  
Cortical Plate ◽  
Protein Levels ◽  
Neuronal Subtype ◽  
Targeted Gene Expression ◽  
The Relationship ◽  
Kinetics Of

Translation modulates the timing and amplification of gene expression after transcription. Development of the brain's neocortex requires precisely timed and spatially targeted gene expression, but the relationship between mRNA vs. protein synthesis throughout the genome is unknown. We perform a comprehensive analysis of the reactants, synthesis, and products of mRNA translation spanning mouse neocortex neurogenesis. Ribosome number in the cortical plate decreases sharply at mid-neurogenesis during a transition in neuronal subtype specification, shifting the fundamental kinetics of protein synthesis, with mRNA and protein levels frequently divergent. Satb2, which drives an essential neuronal subtype-specific program, is a highly dynamically translated mRNA with surprisingly broad transcription across diverse neuronal lineages. Satb2 protein achieves its neuronal subtype expression through timed regulation by the RNA-binding protein Pumilio2. Thus, the refinement of transcriptional programs by protein synthesis is a widespread feature of neuronal specification. Developmental neocortex translatome data are provided in an open-source resource: https://shiny.mdc-berlin.de/cortexomics/.

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