scholarly journals Ribosome specialization and its potential role in the control of protein translation and skeletal muscle size

2019 ◽  
Vol 127 (2) ◽  
pp. 599-607 ◽  
Author(s):  
Thomas Chaillou
Keyword(s):  
Skeletal Muscle ◽  
Posttranslational Modifications ◽  
Translational Control ◽  
Ribosome Biogenesis ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Subcellular Location ◽  
Protein Translation ◽  
Muscle Size ◽  
Associated Proteins

The ribosome is typically viewed as a supramolecular complex with constitutive and invariant capacity in mediating translation of mRNA into protein. This view has been challenged by recent research revealing that ribosome composition could be heterogeneous, and this heterogeneity leads to functional ribosome specialization. This review presents the idea that ribosome heterogeneity results from changes in its various components, including variations in ribosomal protein (RP) composition, posttranslational modifications of RPs, changes in ribosomal-associated proteins, alternative forms of rRNA, and posttranscriptional modifications of rRNAs. Ribosome heterogeneity could be orchestrated at several levels and may depend on numerous factors, such as the subcellular location, cell type, tissue specificity, the development state, cell state, ribosome biogenesis, RP turnover, physiological stimuli, and circadian rhythm. Ribosome specialization represents a completely new concept for the regulation of gene expression. Specialized ribosomes could modulate several aspects of translational control, such as mRNA translation selectivity, translation initiation, translational fidelity, and translation elongation. Recent research indicates that the expression of Rpl3 is markedly increased, while that of Rpl3l is highly reduced during mouse skeletal muscle hypertrophy. Moreover, Rpl3l overexpression impairs the growth and myogenic fusion of myotubes. Although the function of Rpl3 and Rpl3l in the ribosome remains to be clarified, these findings suggest that ribosome specialization may be potentially involved in the control of protein translation and skeletal muscle size. Limited data concerning ribosome specialization are currently available in skeletal muscle. Future investigations have the potential to delineate the function of specialized ribosomes in skeletal muscle.

scholarly journals Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in protein translation

2020 ◽  
Author(s):  
M. Regina Scarpin ◽  
Samuel Leiboff ◽  
Jacob O. Brunkard
Keyword(s):  
Ribosomal Protein ◽  
Translational Control ◽  
Ribosome Biogenesis ◽  
Rna Binding ◽  
Mrna Translation ◽  
Protein Translation ◽  
Auxin Signaling ◽  
In Planta ◽  
Signaling Axis ◽  
Evolutionary Context

ABSTRACTTARGET OF RAPAMYCIN (TOR) is a deeply conserved protein kinase that coordinates eukaryotic metabolism with nutrient availability. In mammals, TOR specifically promotes translation of ribosomal protein mRNAs when amino acids are available to support protein synthesis. The mechanisms controlling translation downstream from TOR remain contested, however, and are largely unexplored in plants. Here, we took parallel global profiling approaches to define the in planta TOR-regulated transcriptome, translatome, proteome, and phosphoproteome. We found that TOR regulates ribosome biogenesis in plants at multiple levels, but through mechanisms that do not directly depend on the canonical 5′ oligopyrimidine tract motif (5′TOP) found in mammalian ribosomal protein mRNAs. To investigate this further, we focused on a putative TOR substrate identified in our phosphoproteome: LARP1, a eukaryotic RNA-binding protein that is proposed to mediate TOR translational control of 5′TOP mRNAs in humans and that has gained increased interest because it associates with SARS-CoV-2. By conducting parallel global profiling experiments with larp1 mutants, we discovered that the TOR-LARP1 signaling axis controls 5′TOP mRNA translation in plants and defined a set of conserved eukaryotic 5′TOP mRNAs that encode cyclins, importins/karyopherins, translation elongation factors, and TCTP1, among others. We then identified novel, plant-specific 5′TOP mRNAs involved in critical biological processes, including ribosome biogenesis, chromatin remodeling, and auxin signaling. Our study illuminates the ancestral roles of the TOR-LARP1-5′TOP metabolic regulatory network and provides evolutionary context for ongoing debates about the molecular function of LARP1 in eukaryotic cells.

scholarly journals PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1425
Author(s):  
Alena Shmakova ◽  
Mark Frost ◽  
Michael Batie ◽  
Niall S. Kenneth ◽  
Sonia Rocha
Keyword(s):  
Protein Expression ◽  
Cellular Response ◽  
Transcriptional Activity ◽  
Mrna Translation ◽  
Protein Translation ◽  
Signalling Pathways ◽  
Independent Function ◽  
Protein Levels ◽  
Associated Proteins ◽  
Core Components

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.

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 Satellite cell expansion is mediated by P-eIF2α dependent Tacc3 translation

Development ◽  
2020 ◽  
pp. dev.194480
Author(s):  
Ryo Fujita ◽  
Solène Jamet ◽  
Graham Lean ◽  
Harry Chun Man Cheng ◽  
Steven Hébert ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Translational Control ◽  
Ex Vivo ◽  
Adult Stem Cell ◽  
Mrna Translation ◽  
Spindle Pole ◽  
Mrna Levels ◽  
Self Renewal ◽  
Control Of Gene Expression

Translational control of gene expression is an important regulator of adult stem cell quiescence, activation and self-renewal. In skeletal muscle, quiescent satellite cells maintain low levels of protein synthesis, mediated in part through the phosphorylation of eIF2α (P-eIF2α). Pharmacological inhibition of the eIF2α phosphatase with the small molecule sal003 maintains P-eIF2α and permits the expansion of satellite cells ex vivo. Paradoxically, P-eIF2α also increases the translation of specific mRNAs, which is mediated by P-eIF2α dependent readthrough of inhibitory upstream open reading frames (uORFs). Here, we ask whether P-eIF2α dependent mRNA translation enables expansion of satellite cells. Using transcriptomic and proteomic analyses, we show a number of genes associated with the assembly of the spindle pole to be upregulated at the level of protein, without corresponding change in mRNA levels, in satellite cells expanded in the presence of sal003. We show that uORFs in the 5'UTR of mRNA for the mitotic spindle stability gene Tacc3 direct P-eIF2α dependent translation. Satellite cells deficient for TACC3 exhibit defects in expansion, self-renewal and regeneration of skeletal muscle.

scholarly journals Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

2017 ◽  
Vol 114 (30) ◽  
pp. E6117-E6126 ◽  
Author(s):  
Thomas C. J. Tan ◽  
John Knight ◽  
Thomas Sbarrato ◽  
Kate Dudek ◽  
Anne E. Willis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Ribosome Biogenesis ◽  
Cell Activation ◽  
Mrna Translation ◽  
Protein Translation ◽  
Cell Receptor ◽  
Tcr Signaling

Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes. A major pathway that was compromised, when TCR signaling was suboptimal, was linked to ribosome biogenesis, a rate-limiting factor in both cell growth and proliferation. Defective TCR signaling affected transcription and processing of ribosomal RNA precursors, as well as the translation of specific ribosomal proteins and translation factors. Mechanistically, IL-2 production was compromised in weakly stimulated T cells, affecting the abundance of Myc protein, a known regulator of ribosome biogenesis. Consequently, weakly activated T cells showed impaired production of ribosomes and a failure to maintain proliferative capacity after stimulation. We demonstrate that primary T cells respond to various environmental cues by regulating ribosome biogenesis and mRNA translation at multiple levels to sustain proliferation and differentiation.

scholarly journals RNA helicase, DDX27 regulates skeletal muscle growth and regeneration by modulation of translational processes

2017 ◽  
Author(s):  
Alexis H Bennett ◽  
Marie-Francoise O’Donohue ◽  
Stacey R. Gundry ◽  
Aye T. Chan ◽  
Jeffery Widrick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Translational Control ◽  
Regulation Of Gene Expression ◽  
Muscle Growth ◽  
Rna Helicase ◽  
Genetic Screen ◽  
Control Of Gene Expression ◽  
Muscle Diseases ◽  
Skeletal Muscle Growth

ABSTRACTGene expression in a tissue-specific context depends on the combined efforts of epigenetic, transcriptional and post-transcriptional processes that lead to the production of specific proteins that are important determinants of cellular identity. Ribosomes are a central component of the protein biosynthesis machinery in cells; however, their regulatory roles in the translational control of gene expression in skeletal muscle remain to be defined. In a genetic screen to identify critical regulators of myogenesis, we identified a DEAD-Box RNA helicase, DDX27, that is required for skeletal muscle growth and regeneration. We demonstrate that DDX27 regulates ribosomal RNA (rRNA) maturation, and thereby the ribosome biogenesis and the translation of specific transcripts during myogenesis. These findings provide insight into the translational regulation of gene expression in myogenesis and suggest novel functions for ribosomes in regulating gene expression in skeletal muscles.AUTHOR SUMMARYInherited skeletal muscle diseases are the most common form of genetic disorders with primary abnormalities in the structure and function of skeletal muscle resulting in the impaired locomotion in affected patients. A major hindrance to the development of effective therapies is a lack of understanding of biological processes that promote skeletal muscle growth. By performing a forward genetic screen in zebrafish we have identified mutation in a RNA helicase that leads to perturbations of ribosomal biogenesis pathway and impairs skeletal muscle growth and regeneration. Therefore, our studies have identified novel ribosome-based disease processes that may be therapeutic modulated to restore muscle function in skeletal muscle diseases.

scholarly journals mTORC1 signaling is not essential for the maintenance of muscle mass and function in adult sedentary mice

2019 ◽  
Author(s):  
Alexander S. Ham ◽  
Kathrin Chojnowska ◽  
Lionel A. Tintignac ◽  
Shuo Lin ◽  
Alexander Schmidt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Ex Vivo ◽  
Morphological Changes ◽  
Muscle Fibers ◽  
Protein Translation ◽  
Muscle Size ◽  
Mtorc1 Signaling ◽  
And Function

AbstractBackgroundThe balance between protein synthesis and degradation (proteostasis) is a determining factor for muscle size and function. Signaling via the mammalian target of rapamycin complex 1 (mTORC1) regulates proteostasis in skeletal muscle by affecting protein synthesis and autophagosomal protein degradation. Indeed, genetic inactivation of mTORC1 in developing and growing muscle causes atrophy resulting in a lethal myopathy. However, systemic dampening of mTORC1 signaling by its allosteric inhibitor rapamycin is beneficial at the organismal level and increases lifespan. Whether the beneficial effect of rapamycin comes at the expense of muscle mass and function is yet to be established.MethodsWe conditionally ablated the gene coding for the mTORC1-essential component raptor in muscle fibers of adult mice (iRAmKO). We performed detailed phenotypic and biochemical analyses of iRAmKO mice and compared them with RAmKO mice, which lack raptor in developing muscle fibers. We also used polysome profiling and proteomics to assess protein translation and associated signaling in skeletal muscle of iRAmKO mice.ResultsAnalysis at different time points reveal that, as in RAmKO mice, the proportion of oxidative fibers decreases, but slow-type fibers increase in iRAmKO mice. Nevertheless, no significant decrease in body and muscle mass, or muscle fiber area was detected up to 5 months post-raptor depletion. Similarly, ex vivo muscle force was not significantly reduced in iRAmKO mice. Despite stable muscle size and function, inducible raptor depletion significantly reduced the expression of key components of the translation machinery and overall translation rates.ConclusionsRaptor depletion and hence complete inhibition of mTORC1 signaling in fully-grown muscle leads to metabolic and morphological changes without inducing muscle atrophy even after 5 months. Together, our data indicate that maintenance of muscle size does not require mTORC1 signaling, suggesting that rapamycin treatment is unlikely to negatively affect muscle mass and function.

Glucocorticoids oppose translational control by leucine in skeletal muscle

2000 ◽  
Vol 279 (5) ◽  
pp. E1185-E1190 ◽  
Author(s):  
O. Jameel Shah ◽  
Joshua C. Anthony ◽  
Scot R. Kimball ◽  
Leonard S. Jefferson
Keyword(s):  
Skeletal Muscle ◽  
Translational Control ◽  
Regulatory Element ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Protein Homeostasis ◽  
S6 Kinase ◽  
Translational Machinery ◽  
Ribosomal Protein S6 ◽  
Translational Apparatus

Glucocorticoids comprise an important class of hormonal mediators of fuel and protein homeostasis in normal and pathological scenarios. In skeletal muscle, exposure to glucocorticoids is characterized by a reduction in protein synthetic rate coincident with hampered translation initiation. However, it is unclear whether this involves attenuation of anabolic stimuli or is simply due to inhibition of the basally activated translational apparatus. Therefore, this inquiry was designed to determine whether leucine, administered orally, could rescue the translational inhibition induced by glucocorticoids. Dexamethasone, injected intraperitoneally, acutely diminished protein synthetic rates to 80% of control values in skeletal muscle from rat hindlimb. The eukaryotic initiation factor (eIF)4 regulatory element was simultaneously and negatively impacted via sequestration of eIF4E by the hypophosphorylated form of the translational suppressor, eIF4E binding protein 1 (4E-BP1). The 70-kDa ribosomal protein S6 kinase (S6K1) was also dephosphorylated, notably at T389, in response to glucocorticoids. Leucine, administered orally, effectively restored each aforementioned translational parameter to control levels. Inasmuch as leucine's potency in modulation of the translational machinery, and indeed of protein turnover in general, is widely appreciated, this amino acid may prove useful in normalizing the impairment of mRNA translation associated with various muscle-wasting pathologies, such as glucocorticoid excess.

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.

New Perspectives on the Storage and Organization of Muscle Glycogen

2002 ◽  
Vol 27 (2) ◽  
pp. 179-203 ◽  
Author(s):  
Jane Shearer ◽  
Terry E. Graham
Keyword(s):  
Skeletal Muscle ◽  
Muscle Glycogen ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Subcellular Location ◽  
Glycogen Metabolism ◽  
Large Mass ◽  
The Body ◽  
Associated Proteins ◽  
Related Proteins

Due to its large mass, skeletal muscle contains the largest depot of stored carbohydrate in the body in the form of muscle glycogen. Readily visualized by the electron microscope, glycogen granules appear as bead-like structures localized to specific subcellular locales. Each glycogen granule is a functional unit, not only containing carbohydrate, but also enzymes and other proteins needed for its metabolism. These proteins are not static, but rather associate and dissociate depending on the carbohydrate balance in the muscle. This review examines glycogen-associated proteins, their interactions, and roles in regulating glycogen metabolism. While certain enzymes such as glycogen synthase and glycogen phosphorylase have been extensively studied, other proteins such as the glycogen initiating and targeting proteins are just beginning to be understood. Two metabolically distinct forms of glycogen, pro- and marcoglycogen have been identified that vary in their carbohydrate complement per molecule and have different sensitivities to glycogen synthesis and degradation. Glycogen regulation takes place not only by allosteric regulation of enzymes, but also due to other factors such as subcellular location, granule size, and association with various glycogen-related proteins. Keywords: glycogen-associated proteins, skeletal muscle, carbohydrate metabolism, proglycogen, macroglycogen.

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