scholarly journals Essential role of translation factor eIF5a in cytokine production and cell cycle regulation in primary CD8 T lymphocytes

2021 ◽  
Author(s):  
Thomas Ching-Jen Tan ◽  
Van Kelly ◽  
Xiaoyan Zou ◽  
Tony Ly ◽  
Rose Zamoyska
Keyword(s):  
Translational Control ◽  
Immune Cell ◽  
Control Point ◽  
Elongation Factor ◽  
Mrna Translation ◽  
Post Translational Modification ◽  
Translation Factors ◽  
Cycle Regulation ◽  
Multiple Immune Cell

Translational control adjusts protein production rapidly and facilitates local cellular responses to environmental conditions. Translation can be regulated through sequestration of mRNAs by regulatory proteins or RNAs, but also by the availability of ribosomes and translation factors which enable initiation and elongation of nascent polypeptides. Traditionally initiation of mRNA translation has been considered to be a major translational control point, however, control of peptide elongation can also play a role. Here we show that post-translational modification of the elongation factor, eIF5a, controls translation of subsets of proteins in naive T-cells upon activation. Sequencing of nascent polypeptides indicated that functional eIF5a was required for the production of proteins which regulate T-cell proliferation and effector function. Control of translation in multiple immune cell lineages is required to co-ordinate immune responses and these data illustrate that translational elongation can contribute to post-transcriptional regulons important for the control of inflammation.

scholarly journals The Role of Translation Initiation Regulation in Haematopoiesis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Control ◽  
Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

scholarly journals Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease

2020 ◽  
pp. jbc.RA120.014956
Author(s):  
Karl Norris ◽  
Rachel E Hodgson ◽  
Tawni Dornelles ◽  
K Elizabeth Allen ◽  
Ben M Abell ◽  
...  
Keyword(s):  
Translational Control ◽  
Translational Regulation ◽  
Mutational Analysis ◽  
Control Point ◽  
The Body ◽  
Initiation Factor ◽  
Regulatory Subunit ◽  
Missense Mutations ◽  
Eif2α Phosphorylation

Eukaryotic initiation factor 2B (eIF2B) serves as a vital control point within protein synthesis and regulates translation initiation in response to cellular stress. Mutations within eIF2B result in the fatal disease, leukoencephalopathy with vanishing white matter (VWM). Previous biochemical studies on VWM mutations have illustrated that changes in the activity of eIF2B poorly correlates with disease severity. This suggests that there may be additional characteristics of eIF2B contributing to VWM pathogenesis. Here, we investigated whether the localisation of eIF2B to eIF2B bodies was integral for function and whether this localisation could provide insight into the pathogenesis of VWM. We demonstrate that the regulatory subunit, eIF2Bα, is required for the assembly of eIF2B bodies in yeast and that loss of eIF2B bodies correlates with an inability of cells to regulate eIF2B activity.  Mutational analysis of eIF2Bα showed that missense mutations which disrupt the regulation of eIF2B similarly disrupt the assembly of eIF2B bodies. In contrast, when eIF2Bα mutations which impact the catalytic activity of eIF2B were analysed, eIF2B bodies were absent and instead eIF2B localised to small foci, termed microfoci. FRAP analysis highlighted that within these microfoci, eIF2 shuttles more slowly indicating that formation of eIF2B bodies correlates with full eIF2B activity. When eIF2Bα VWM mutations were analysed a diverse impact on localisation was observed, which did not seem to correlate with eIF2B activity.  These findings provide key insights into how the eIF2B body assembles and suggest that the body is a fundamental part of the translational regulation via eIF2α phosphorylation.

scholarly journals N1-acetylspermidine is a determinant of hair follicle stem cell fate

2021 ◽  
Vol 134 (9) ◽  
Author(s):  
Kira Allmeroth ◽  
Christine S. Kim ◽  
Andrea Annibal ◽  
Andromachi Pouikli ◽  
Janis Koester ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hair Follicle ◽  
Cell Fate ◽  
Translational Control ◽  
Mrna Translation ◽  
Stem Cell Differentiation ◽  
Stem Cell Fate ◽  
Cell Fate Decisions ◽  
Hair Follicle Stem Cell

ABSTRACT Stem cell differentiation is accompanied by increased mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine and spermine, which are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through translational control remains obscure. Here, we investigate the function of polyamines in stem cell fate decisions using hair follicle stem cell (HFSC) organoids. Compared to progenitor cells, HFSCs showed lower translation rates, correlating with reduced polyamine levels. Surprisingly, overall polyamine depletion decreased translation but did not affect cell fate. In contrast, specific depletion of natural polyamines mediated by spermidine/spermine N1-acetyltransferase (SSAT; also known as SAT1) activation did not reduce translation but enhanced stemness. These results suggest a translation-independent role of polyamines in cell fate regulation. Indeed, we identified N1-acetylspermidine as a determinant of cell fate that acted through increasing self-renewal, and observed elevated N1-acetylspermidine levels upon depilation-mediated HFSC proliferation and differentiation in vivo. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions. This article has an associated First Person interview with the first author of the paper.

scholarly journals The Role of O-GlcNAcylation in Immune Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Amy Qiang ◽  
Chad Slawson ◽  
Patrick E. Fields
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Nutrient Sensing ◽  
Post Translational Modification ◽  
Immune Cell Activation ◽  
Glcnac Transferase ◽  
Diabetes And Obesity ◽  
Normal Cellular Function

O-GlcNAcylation is a dynamic post-translational modification where the sugar, O-linked β-N-acetylglucosamine (O-GlcNAc) is added to or removed from various cytoplasmic, nuclear, and mitochondrial proteins. This modification is regulated by only two enzymes: O-GlcNAc transferase (OGT), which adds O-GlcNAc, and O-GlcNAcase (OGA), which removes the sugar from proteins. O-GlcNAcylation is integral to maintaining normal cellular function, especially in processes such as nutrient sensing, metabolism, transcription, and growth and development of the cell. Aberrant O-GlcNAcylation has been associated with a number of pathological conditions, including, neurodegenerative diseases, cancer, diabetes, and obesity. However, the role of O-GlcNAcylation in immune cell growth/proliferation, or other immune responses, is currently incompletely understood. In this review, we highlight the effects of O-GlcNAcylation on certain cells of the immune system, especially those involved in pro-inflammatory responses associated with diabetes and obesity.

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.

scholarly journals Molecular evolution of protein-RNA mimicry as a mechanism for translational control

2013 ◽  
Vol 42 (5) ◽  
pp. 3261-3271 ◽  
Author(s):  
Assaf Katz ◽  
Lindsey Solden ◽  
S. Betty Zou ◽  
William Wiley Navarre ◽  
Michael Ibba
Keyword(s):  
Translational Control ◽  
Elongation Factor ◽  
Trna Synthetase ◽  
Post Translational Modification ◽  
Translation Control ◽  
Trna Synthetases ◽  
Ribosome Binding ◽  
Trna Recognition ◽  
Aminoacyl Trna Synthetases ◽  
Secondary Mechanism

Abstract Elongation factor P (EF-P) is a conserved ribosome-binding protein that structurally mimics tRNA to enable the synthesis of peptides containing motifs that otherwise would induce translational stalling, including polyproline. In many bacteria, EF-P function requires post-translational modification with (R)-β-lysine by the lysyl-tRNA synthetase paralog PoxA. To investigate how recognition of EF-P by PoxA evolved from tRNA recognition by aminoacyl-tRNA synthetases, we compared the roles of EF-P/PoxA polar contacts with analogous interactions in a closely related tRNA/synthetase complex. PoxA was found to recognize EF-P solely via identity elements in the acceptor loop, the domain of the protein that interacts with the ribosome peptidyl transferase center and mimics the 3'-acceptor stem of tRNA. Although the EF-P acceptor loop residues required for PoxA recognition are highly conserved, their conservation was found to be independent of the phylogenetic distribution of PoxA. This suggests EF-P first evolved tRNA mimicry to optimize interactions with the ribosome, with PoxA-catalyzed aminoacylation evolving later as a secondary mechanism to further improve ribosome binding and translation control.

scholarly journals Translational control of gurken mRNA in Drosophila development

2016 ◽  
Author(s):  
Christopher J. Derrick ◽  
Timothy T. Weil
Keyword(s):  
Cell Fate ◽  
Translational Control ◽  
Mrna Translation ◽  
Nurse Cells ◽  
Processing Bodies ◽  
Over Expression ◽  
Egg Chambers ◽  
Key Aspects ◽  
Spatiotemporal Control

ABSTRACTLocalised mRNA translation is a widespread mechanism for targeting protein synthesis, important for cell fate, motility and pathogenesis. In Drosophila, the spatiotemporal control of gurken/TGF-α mRNA translation is required for establishing the embryonic body axes. A number of recent studies have highlighted key aspects of the mechanism of gurken mRNA translational control at the dorsoanterior corner of the mid-stage oocyte. Orb/CPEB and Wispy/GLD-2 are required for polyadenylation of gurken mRNA, but mis-localised gurken mRNA in the oocyte is not fully polyadenylated1. At the dorsoanterior corner, Orb and gurken mRNA have been shown to be enriched at the edge of Processing bodies, where translation occurs2. Over-expression of Orb in the adjacent nurse cells, where gurken mRNA is transcribed, is sufficient to cause mis-expression of Gurken protein3. In orb mutant egg chambers, reducing the activity of CK2, a Serine/Threonine protein kinase, enhances polarity defects, consistent with a phenotype relating to a mutation of a factor involved in gurken translation4. Here we show that sites phosphorylated by CK2 overlap with active Orb and with Gurken protein expression. We also consolidate the current literature into a working model for gurken mRNA translational control and review the role of kinases, cell cycle factors and polyadenylation machinery highlighting a multitude of conserved factors and mechanisms in the Drosophila egg chamber.

scholarly journals IRES-dependent regulation of FGF-2 mRNA translation in pathophysiological conditions in the mouse

2006 ◽  
Vol 34 (1) ◽  
pp. 17-21 ◽  
Author(s):  
I.G. Gonzalez-Herrera ◽  
L. Prado-Lourenco ◽  
S. Teshima-Kondo ◽  
K. Kondo ◽  
F. Cabon ◽  
...  
Keyword(s):  
Translational Control ◽  
Vascular Complications ◽  
Mrna Translation ◽  
Adult Brain ◽  
Angiogenic Factor ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Nuclear Ribonucleoprotein

The mRNA coding for FGF-2 (fibroblast growth factor 2), a major angiogenic factor, is translated by an IRES (internal ribosome entry site)-dependent mechanism. We have studied the role of the IRES in the regulation of FGF-2 expression in vivo, under pathophysiological conditions, by creating transgenic mice lines expressing bioluminescent bicistronic transgenes. Analysis of FGF-2 IRES activity indicates strong tissue specificity in adult brain and testis, suggesting a role of the IRES in the activation of FGF-2 expression in testis maturation and brain function. We have explored translational control of FGF-2 mRNA under diabetic hyperglycaemic conditions, as FGF-2 is implied in diabetes-related vascular complications. FGF-2 IRES is specifically activated in the aorta wall in streptozotocin-induced diabetic mice, in correlation with increased expression of endogenous FGF-2. Thus, under hyperglycaemic conditions, where cap-dependent translation is blocked, IRES activation participates in FGF-2 overexpression, which is one of the keys of diabetes-linked atherosclerosis aggravation. IRES activation under such pathophysiological conditions may involve ITAFs (IRES trans-acting factors), such as p53 or hnRNP AI (heterogeneous nuclear ribonucleoprotein AI), recently identified as inhibitory or activatory ITAFs respectively for FGF-2 IRES.

Translational control mechanisms in metabolic regulation: critical role of RNA binding proteins, microRNAs, and cytoplasmic RNA granules

2011 ◽  
Vol 301 (6) ◽  
pp. E1051-E1064 ◽  
Author(s):  
Khosrow Adeli
Keyword(s):  
Protein Synthesis ◽  
Translational Control ◽  
Metabolic Regulation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Mrna Translation ◽  
Rna Granules

Regulated cell metabolism involves acute and chronic regulation of gene expression by various nutritional and endocrine stimuli. To respond effectively to endogenous and exogenous signals, cells require rapid response mechanisms to modulate transcript expression and protein synthesis and cannot, in most cases, rely on control of transcriptional initiation that requires hours to take effect. Thus, co- and posttranslational mechanisms have been increasingly recognized as key modulators of metabolic function. This review highlights the critical role of mRNA translational control in modulation of global protein synthesis as well as specific protein factors that regulate metabolic function. First, the complex lifecycle of eukaryotic mRNAs will be reviewed, including our current understanding of translational control mechanisms, regulation by RNA binding proteins and microRNAs, and the role of RNA granules, including processing bodies and stress granules. Second, the current evidence linking regulation of mRNA translation with normal physiological and metabolic pathways and the associated disease states are reviewed. A growing body of evidence supports a key role of translational control in metabolic regulation and implicates translational mechanisms in the pathogenesis of metabolic disorders such as type 2 diabetes. The review also highlights translational control of apolipoprotein B (apoB) mRNA by insulin as a clear example of endocrine modulation of mRNA translation to bring about changes in specific metabolic pathways. Recent findings made on the role of 5′-untranslated regions (5′-UTR), 3′-UTR, RNA binding proteins, and RNA granules in mediating insulin regulation of apoB mRNA translation, apoB protein synthesis, and hepatic lipoprotein production are discussed.

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