scholarly journals c-Myc steers translation in lymphoma

2019 ◽  
Vol 216 (7) ◽  
pp. 1471-1473 ◽  
Author(s):  
Marie Cargnello ◽  
Ivan Topisirovic
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Lymphoma Cells ◽  
Master Regulators ◽  
Selection Of

Members of the MYC family of oncogenes are master regulators of mRNA translation. In this issue of JEM, Singh et al. (https://doi.org/10.1084/jem.20181726) demonstrate that c-Myc governs protein synthesis in lymphoma cells by interfering with SRSF1- and RBM42-mediated suppression of mRNA translation and by altering selection of translation initiation sites.

scholarly journals Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

2021 ◽  
Vol 14 (668) ◽  
pp. eabc5429
Author(s):  
Mauricio M. Oliveira ◽  
Mychael V. Lourenco ◽  
Francesco Longo ◽  
Nicole P. Kasica ◽  
Wenzhong Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Postmortem Brain Tissue ◽  
Phosphorylated Eif2α

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

scholarly journals A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines

2021 ◽  
Vol 12 ◽  
Author(s):  
Victor Barrenechea ◽  
Maryhory Vargas-Reyes ◽  
Miguel Quiliano ◽  
Pohl Milón
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Ribosomal Subunit ◽  
Mrna Translation ◽  
Resistance Mechanisms ◽  
Dissociation Rate ◽  
Initiation Factor ◽  
Translation Elongation ◽  
Initiation Phase ◽  
Complementary Mechanism

Tetracycline has positively impacted human health as well as the farming and animal industries. Its extensive usage and versatility led to the spread of resistance mechanisms followed by the development of new variants of the antibiotic. Tetracyclines inhibit bacterial growth by impeding the binding of elongator tRNAs to the ribosome. However, a small number of reports indicated that Tetracyclines could also inhibit translation initiation, yet the molecular mechanism remained unknown. Here, we use biochemical and computational methods to study how Oxytetracycline (Otc), Demeclocycline (Dem), and Tigecycline (Tig) affect the translation initiation phase of protein synthesis. Our results show that all three Tetracyclines induce Initiation Factor IF3 to adopt a compact conformation on the 30S ribosomal subunit, similar to that induced by Initiation Factor IF1. This compaction was faster for Tig than Dem or Otc. Furthermore, all three tested tetracyclines affected IF1-bound 30S complexes. The dissociation rate constant of IF1 in early 30S complexes was 14-fold slower for Tig than Dem or Otc. Late 30S initiation complexes (30S pre-IC or IC) exhibited greater IF1 stabilization by Tig than for Dem and Otc. Tig and Otc delayed 50S joining to 30S initiation complexes (30S ICs). Remarkably, the presence of Tig considerably slowed the progression to translation elongation and retained IF1 in the resulting 70S initiation complex (70S IC). Molecular modeling of Tetracyclines bound to the 30S pre-IC and 30S IC indicated that the antibiotics binding site topography fluctuates along the initiation pathway. Mainly, 30S complexes show potential contacts between Dem or Tig with IF1, providing a structural rationale for the enhanced affinity of the antibiotics in the presence of the factor. Altogether, our data indicate that Tetracyclines inhibit translation initiation by allosterically perturbing the IF3 layout on the 30S, retaining IF1 during 70S IC formation, and slowing the transition toward translation elongation. Thus, this study describes a new complementary mechanism by which Tetracyclines may inhibit bacterial protein synthesis.

scholarly journals Inferring efficiency of translation initiation and elongation from ribosome profiling

2020 ◽  
Vol 48 (17) ◽  
pp. 9478-9490
Author(s):  
Juraj Szavits-Nossan ◽  
Luca Ciandrini
Keyword(s):  
Protein Synthesis ◽  
Mathematical Modelling ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Elongation Rate ◽  
Ribosome Profiling ◽  
Translation Elongation ◽  
Recent Advances ◽  
Two Stages

Abstract One of the main goals of ribosome profiling is to quantify the rate of protein synthesis at the level of translation. Here, we develop a method for inferring translation elongation kinetics from ribosome profiling data using recent advances in mathematical modelling of mRNA translation. Our method distinguishes between the elongation rate intrinsic to the ribosome’s stepping cycle and the actual elongation rate that takes into account ribosome interference. This distinction allows us to quantify the extent of ribosomal collisions along the transcript and identify individual codons where ribosomal collisions are likely. When examining ribosome profiling in yeast, we observe that translation initiation and elongation are close to their optima and traffic is minimized at the beginning of the transcript to favour ribosome recruitment. However, we find many individual sites of congestion along the mRNAs where the probability of ribosome interference can reach $50\%$. Our work provides new measures of translation initiation and elongation efficiencies, emphasizing the importance of rating these two stages of translation separately.

scholarly journals Protein synthesis rates and ribosome occupancies reveal determinants of translation elongation rates

2018 ◽  
Author(s):  
Andrea Riba ◽  
Noemi Di Nanni ◽  
Nitish Mittal ◽  
Erik Arhné ◽  
Alexander Schmidt ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Amino Acid Composition ◽  
Acid Composition ◽  
Translation Initiation ◽  
Mrna Translation ◽  
Elongation Rate ◽  
Translation Elongation ◽  
Lower Protein ◽  
Protein Output

AbstractAlthough protein synthesis dynamics has been studied both with theoretical models and by profiling ribosome footprints, the determinants of ribosome flux along open reading frames (ORFs) are not fully understood. Combining measurements of protein synthesis rate with ribosome footprinting data, we here inferred translation initiation and elongation rates for over a thousand ORFs in exponentially-growing wildtype yeast cells. We found that the amino acid composition of synthesized proteins is as important a determinant of translation elongation rate as parameters related to codon and tRNA adaptation. We did not find evidence of ribosome collisions curbing the protein output of yeast transcripts, either in high translation conditions associated with exponential growth, or in strains in which deletion of individual ribosomal protein genes leads to globally increased or decreased translation. Slow translation elongation is characteristic of RP-encoding transcripts, which have markedly lower protein output than other transcripts with equally high ribosome densities.Significance StatementAlthough sequencing of ribosome footprints has uncovered new aspects of mRNA translation, the determinants of ribosome flux remain incompletely understood. Combining ribosome footprint data with measurements of protein synthesis rates, we here inferred translation initiation and elongation rates for over a thousand ORFs in yeast strains with varying translation capacity. We found that the translation elongation rate varies up to ~20-fold among yeast transcripts, and is significantly correlated with the rate of translation initiation. Furthermore, the amino acid composition of synthesized proteins impacts the rate of translation elongation to the same extent as measures of codon and tRNA adaptation. Transcripts encoding ribosomal proteins are translated especially slow, having markedly lower protein output than other transcripts with equally high ribosome densities.

scholarly journals Regulation of translation by one-carbon metabolism in bacteria and the eukaryotic organelles

2020 ◽  
pp. jbc.REV120.011985
Author(s):  
Sunil Shetty ◽  
Umesh Varshney
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Carbon Metabolism ◽  
Mrna Translation ◽  
Energy Reserves ◽  
Cellular Activity ◽  
Translation Factors ◽  
Translation Apparatus ◽  
Alternative Translation ◽  
One Carbon Metabolism

Protein synthesis is an energetically costly cellular activity. It is therefore important that the process of mRNA translation remains in excellent synchrony with cellular metabolism and its energy reserves. Unregulated translation could lead to the production of incomplete, mistranslated, or misfolded proteins, squandering the energy needed for cellular sustenance, and causing cytotoxicity. One-carbon metabolism (OCM), an integral part of cellular intermediary metabolism, produces a number of one-carbon unit intermediates (formyl, methylene, methenyl, methyl). These OCM intermediates are required for the production of amino acids like methionine, and biomolecules such as purines, thymidylate, and redox regulators. In this review, we discuss how OCM impacts the translation apparatus (composed of ribosome, tRNA, mRNA, and translation factors) and regulates crucial steps in protein synthesis. More specifically, we address how the OCM metabolites regulate the fidelity and rate of translation initiation in bacteria and eukaryotic organelles such as mitochondria. Modulation of the fidelity of translation initiation by OCM opens new avenues to understand alternative translation mechanisms involved in stress tolerance and drug resistance.

Thermal injury impairs cardiac protein synthesis and is associated with alterations in translation initiation

2004 ◽  
Vol 286 (4) ◽  
pp. R740-R750 ◽  
Author(s):  
Charles H. Lang ◽  
Robert A. Frost ◽  
Thomas C. Vary
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Thermal Injury ◽  
Burn Injury ◽  
Total Body Surface Area ◽  
Mrna Translation ◽  
Translation Efficiency ◽  
High Mobility Group Protein ◽  
Translational Repressor ◽  
Significant Difference

The purpose of the present study was to determine whether burn injury decreases myocardial protein synthesis and potential contributing mechanisms for this impairment. To address this aim, thermal injury was produced by a 40% total body surface area full-thickness scald burn in anesthetized rats, and the animals were studied 24 h later. Burn decreased the in vivo-determined rate of myocardial protein synthesis and translation efficiency by 25% but did not alter the protein synthetic rate in skeletal muscle. To identify potential mechanisms responsible for regulating mRNA translation in cardiac muscle, we examined several eukaryotic initiation factors (eIFs) and elongation factors (eEFs). Burn failed to alter eIF2B activity or the total amount or phosphorylation status of either eIF2α or eIF2Bϵ in heart. In contrast, hearts from burned rats demonstrated 1) an increased binding of the translational repressor 4E-BP1 with eIF4E, 2) a decreased amount of eIF4E associated with eIF4G, and 3) a decreased amount of the hyperphosphorylated γ-form of 4E-BP1. These changes in eIF4E availability were not seen in gastrocnemius muscle where burn injury did not decrease protein synthesis. Furthermore, constitutive phosphorylation of mTOR, S6K1, the ribosomal protein S6, and eIF4G were also decreased in hearts from burned rats. Burn did not appear to adversely affect elongation because there was no significant difference in the myocardial content of eEF1α or eEF2 or the phosphorylation state of eEF2. The above-mentioned burn-induced changes in mRNA translation were associated with an impairment of in vitro myocardial performance. Finally, 24 h postburn, the cardiac mRNA content of IL-1β, IL-6, and high-mobility group protein B1 (but not TNF-α) was increased. In summary, these data suggest that thermal injury specifically decreases cardiac protein synthesis in part by decreasing mRNA translation efficiency resulting from an impairment in translation initiation associated with alterations in eIF4E availability and S6K1 activity.

Role of Amino Acids and Peptides in the Molecular Signaling in Skeletal Muscle after Resistance Exercise

2007 ◽  
Vol 17 (s1) ◽  
pp. S47-S57 ◽  
Author(s):  
René Koopman
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Resistance Exercise ◽  
Translation Initiation ◽  
Intracellular Signaling ◽  
Muscle Protein ◽  
Mrna Translation ◽  
Molecular Signaling ◽  
Stimulation Of

Resistance exercise can effectively result in an increase in muscle mass, or hypertrophy, which generally becomes apparent after several weeks of training. Muscle hypertrophy requires muscle protein synthesis to exceed protein breakdown during an extended time period. It has been firmly established that the interaction between exercise and nutrition (i.e., protein intake) is necessary to attain net protein accretion in skeletal muscle. The stimulation of protein synthesis is caused in part by stimulation of mRNA translation initiation. There is relatively little information on the response of intracellular signaling controlling mRNA translation to exercise and nutrition, especially in humans, but the available data in humans seem to suggest that a single bout of resistance exercise does not substantially enhance PI-3 kinase/mTOR signaling during the first 2 h after exercise. Moreover, it is demonstrated that the ingestion of protein or amino acids after exercise is crucial to further stimulate molecular signaling that controls translation initiation. The aim of this review is to provide an overview of the intracellular signaling related to translational control and to provide a summary of the current knowledge about the response of the signaling pathways controlling the anabolic response to exercise and nutrient intake in vivo in humans.

TNF-α impairs heart and skeletal muscle protein synthesis by altering translation initiation

2002 ◽  
Vol 282 (2) ◽  
pp. E336-E347 ◽  
Author(s):  
Charles H. Lang ◽  
Robert A. Frost ◽  
Angus C. Nairn ◽  
David A. MacLean ◽  
Thomas C. Vary
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Translation Initiation ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mrna Translation ◽  
Translational Efficiency ◽  
Skeletal Muscle Protein ◽  
Phosphorylation State ◽  
Tnf Α

This study examined potential mechanisms contributing to the inhibition of protein synthesis in skeletal muscle and heart after administration of tumor necrosis factor (TNF)-α. Rats had vascular catheters implanted, and TNF-α was infused continuously for 24 h. TNF-α decreased in vivo-determined rates of global protein synthesis in gastrocnemius (39%) and heart (25%). The TNF-α-induced decrease in protein synthesis in the gastrocnemius involved a reduction in the synthesis of both myofibrillar and sarcoplasmic proteins. To identify potential mechanisms responsible for regulating mRNA translation, we examined several eukaryotic initiation factors (eIFs) and elongation factors (eEFs). TNF-α decreased the activity of eIF-2B in muscle (39%) but not in heart. This diminished activity was not caused by a reduction in the content of eIF-2Bε or the content and phosphorylation state of eIF-2α. Skeletal muscle and heart from TNF-α-treated rats demonstrated 1) an increased binding of the translation repressor 4E-binding protein-1 (4E-BP1) with eIF-4E, 2) a decreased amount of eIF-4E associated with eIF-4G, and 3) a decreased content of the hyperphosphorylated γ-form of 4E-BP1. In contrast, the infusion of TNF-α did not alter the content of eEF-1α or eEF-2, or the phosphorylation state of eEF-2. In summary, these data suggest that TNF-α impairs skeletal muscle and heart protein synthesis, at least in part, by decreasing mRNA translational efficiency resulting from an impairment in translation initiation associated with alterations in eIF-4E availability.

scholarly journals Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

2016 ◽  
Vol 2016 ◽  
pp. 1-19 ◽  
Author(s):  
Divya Khandige Sharma ◽  
Kamiko Bressler ◽  
Harshil Patel ◽  
Nirujah Balasingam ◽  
Nehal Thakor
Keyword(s):  
Protein Synthesis ◽  
Cancer Progression ◽  
Translation Initiation ◽  
Tumor Development ◽  
Mrna Translation ◽  
Translation Control ◽  
Initiation Factors ◽  
Eukaryotic Initiation Factors ◽  
Rate Limiting Step ◽  
Precise Understanding

Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.

scholarly journals mTORC1 signalling and eIF4E/4E-BP1 translation initiation factor stoichiometry influence recombinant protein productivity from GS-CHOK1 cells

2016 ◽  
Vol 473 (24) ◽  
pp. 4651-4664 ◽  
Author(s):  
Lyne Jossé ◽  
Jianling Xie ◽  
Christopher G. Proud ◽  
C. Mark Smales
Keyword(s):  
Protein Synthesis ◽  
Cell Growth ◽  
Recombinant Protein ◽  
Cell Lines ◽  
Translation Initiation ◽  
Mammalian Cells ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Cho Cell

Many protein-based biotherapeutics are produced in cultured Chinese hamster ovary (CHO) cell lines. Recent reports have demonstrated that translation of recombinant mRNAs and global control of the translation machinery via mammalian target of rapamycin (mTOR) signalling are important determinants of the amount and quality of recombinant protein such cells can produce. mTOR complex 1 (mTORC1) is a master regulator of cell growth/division, ribosome biogenesis and protein synthesis, but the relationship between mTORC1 signalling, cell growth and proliferation and recombinant protein yields from mammalian cells, and whether this master regulating signalling pathway can be manipulated to enhance cell biomass and recombinant protein production (rPP) are not well explored. We have investigated mTORC1 signalling and activity throughout batch culture of a panel of sister recombinant glutamine synthetase-CHO cell lines expressing different amounts of a model monoclonal IgG4, to evaluate the links between mTORC1 signalling and cell proliferation, autophagy, recombinant protein expression, global protein synthesis and mRNA translation initiation. We find that the expression of the mTORC1 substrate 4E-binding protein 1 (4E-BP1) fluctuates throughout the course of cell culture and, as expected, that the 4E-BP1 phosphorylation profiles change across the culture. Importantly, we find that the eIF4E/4E-BP1 stoichiometry positively correlates with cell productivity. Furthermore, eIF4E amounts appear to be co-regulated with 4E-BP1 amounts. This may reflect a sensing of either change at the mRNA level as opposed to the protein level or the fact that the phosphorylation status, as well as the amount of 4E-BP1 present, is important in the co-regulation of eIF4E and 4E-BP1.

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