scholarly journals Community control in cellular protein production: consequences for amino acid starvation

2015 ◽  
Vol 373 (2056) ◽  
pp. 20150107 ◽  
Author(s):  
Frank S. Heldt ◽  
Chris A. Brackley ◽  
Celso Grebogi ◽  
Marco Thiel
Keyword(s):  
Amino Acid ◽  
Protein Production ◽  
Control Mechanism ◽  
Supply And Demand ◽  
Mrna Translation ◽  
Cellular Protein ◽  
Amino Acid Starvation ◽  
Community Control ◽  
Trna Species ◽  
A Cell

Deprivation of essential nutrients can have stark consequences for many processes in a cell. We consider amino acid starvation, which can result in bottlenecks in mRNA translation when ribosomes stall due to lack of resources, i.e. tRNAs charged with the missing amino acid. Recent experiments also show less obvious effects such as increased charging of other (non-starved) tRNA species and selective charging of isoaccepting tRNAs. We present a mechanism which accounts for these observations and shows that production of some proteins can actually increase under starvation. One might assume that such responses could only be a result of sophisticated control pathways, but here we show that these effects can occur naturally due to changes in the supply and demand for different resources, and that control can be accomplished through selective use of rare codons. We develop a model for translation which includes the dynamics of the charging and use of aminoacylated tRNAs, explicitly taking into account the effect of specific codon sequences. This constitutes a new control mechanism in gene regulation which emerges at the community level, i.e. via resources used by all ribosomes.

scholarly journals The hnRNA-Binding Proteins hnRNP L and PTB Are Required for Efficient Translation of the Cat-1 Arginine/Lysine Transporter mRNA during Amino Acid Starvation

2009 ◽  
Vol 29 (10) ◽  
pp. 2899-2912 ◽  
Author(s):  
Mithu Majumder ◽  
Ibrahim Yaman ◽  
Francesca Gaccioli ◽  
Vladimir V. Zeenko ◽  
Chuanping Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Amino Acid ◽  
Binding Protein ◽  
Mrna Translation ◽  
Amino Acid Starvation ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Polypyrimidine Tract Binding Protein ◽  
Global Protein Synthesis

ABSTRACT The response to amino acid starvation involves the global decrease of protein synthesis and an increase in the translation of some mRNAs that contain an internal ribosome entry site (IRES). It was previously shown that translation of the mRNA for the arginine/lysine amino acid transporter Cat-1 increases during amino acid starvation via a mechanism that utilizes an IRES in the 5′ untranslated region of the Cat-1 mRNA. It is shown here that polypyrimidine tract binding protein (PTB) and an hnRNA binding protein, heterogeneous nuclear ribonucleoprotein L (hnRNP L), promote the efficient translation of Cat-1 mRNA during amino acid starvation. Association of both proteins with Cat-1 mRNA increased during starvation with kinetics that paralleled that of IRES activation, although the levels and subcellular distribution of the proteins were unchanged. The sequence CUUUCU within the Cat-1 IRES was important for PTB binding and for the induction of translation during amino acid starvation. Binding of hnRNP L to the IRES or the Cat-1 mRNA in vivo was independent of PTB binding but was not sufficient to increase IRES activity or Cat-1 mRNA translation during amino acid starvation. In contrast, binding of PTB to the Cat-1 mRNA in vivo required hnRNP L. A wider role of hnRNP L in mRNA translation was suggested by the decrease of global protein synthesis in cells with reduced hnRNP L levels. It is proposed that PTB and hnRNP L are positive regulators of Cat-1 mRNA translation via the IRES under stress conditions that cause a global decrease of protein synthesis.

scholarly journals Human Retrovirus Codon Usage from tRNA Point of View: Therapeutic Insights

2013 ◽  
Vol 7 ◽  
pp. BBI.S12093 ◽  
Author(s):  
Diego Frias ◽  
Joana P. Monteiro-Cunha ◽  
Aline C. Mota-Miranda ◽  
Vagner S. Fonseca ◽  
Tulio De Oliveira ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Codon Usage ◽  
Supply And Demand ◽  
Mrna Translation ◽  
Protein Translation ◽  
Point Of View ◽  
T Score ◽  
Synonymous Codons ◽  
Trna Species ◽  
Gene Data

The purpose of this study was to investigate the balance between transfer ribonucleic acid (tRNA) supply and demand in retrovirus-infected cells, seeking the best targets for antiretroviral therapy based on the hypothetical tRNA Inhibition Therapy (TRIT). Codon usage and tRNA gene data were retrieved from public databases. Based on logistic principles, a therapeutic score (T-score) was calculated for all sense codons, in each retrovirus-host system. Codons that are critical for viral protein translation, but not as critical for the host, have the highest T-score values. Theoretically, inactivating the cognate tRNA species should imply a severe reduction of the elongation rate during viral mRNA translation. We developed a method to predict tRNA species critical for retroviral protein synthesis. Four of the best TRIT targets in HIV-1 and HIV-2 encode Large Hydrophobic Residues (LHR), which have a central role in protein folding. One of them, codon CUA, is also a TRIT target in both HTLV-1 and HTLV-2. Therefore, a drug designed for inactivating or reducing the cytoplasmatic concentration of tRNA species with anticodon TAG could attenuate significantly both HIV and HTLV protein synthesis rates. Inversely, replacing codons ending in UA by synonymous codons should increase the expression, which is relevant for DNA vaccine design.

scholarly journals Regulation of the Transcription Factor Gcn4 by Pho85 Cyclin Pcl5

2002 ◽  
Vol 22 (15) ◽  
pp. 5395-5404 ◽  
Author(s):  
Revital Shemer ◽  
Ariella Meimoun ◽  
Tsvi Holtzman ◽  
Daniel Kornitzer
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Cellular Protein ◽  
Amino Acid Starvation ◽  
Cyclin Dependent Kinase ◽  
Homeostatic Mechanism ◽  
Metabolic Instability

ABSTRACT The yeast transcription factor Gcn4 is regulated by amino acid starvation at the levels of both protein synthesis and stability. Gcn4 degradation depends on the ubiquitination complex SCFCDC4 and requires phosphorylation by the cyclin-dependent kinase Pho85. Here, we show that Pcl5 is the Pho85 cyclin specifically required for Gcn4 degradation. PCL5 is itself induced by Gcn4 at the level of transcription. However, even when PCL5 is constitutively overexpressed, Pho85-associated Gcn4 phosphorylation activity is reduced in starved cells and Gcn4 degradation is decreased. Under these conditions, the Pcl5 protein disappears because of rapid constitutive turnover. We suggest that, by virtue of its constitutive metabolic instability, Pcl5 may be a sensor of cellular protein biosynthetic capacity. The fact that PCL5 is transcriptionally induced in the presence of Gcn4 suggests that it is part of a homeostatic mechanism that reduces Gcn4 levels upon recovery from starvation.

scholarly journals Aichi Virus 2A Protein Is Involved in Viral RNA Replication

2008 ◽  
Vol 82 (19) ◽  
pp. 9765-9769 ◽  
Author(s):  
Jun Sasaki ◽  
Koki Taniguchi
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Rna Replication ◽  
Vero Cells ◽  
Cellular Protein ◽  
The Other ◽  
Aichi Virus ◽  
Positive Strand ◽  
Free Translation ◽  
A Cell

ABSTRACT The Aichi virus 2A protein is not a protease, unlike many other picornavirus 2A proteins, and it is related to a cellular protein, H-rev107. Here, we examined the replication properties of two 2A mutants in Vero cells and a cell-free translation/replication system. In one mutant, amino acids 36 to 126 were replaced with an unrelated amino acid sequence. In the other mutant, the NC motif conserved in the H-rev107 family of proteins was changed to alanine residues. The two mutations abolished virus replication in cells. The mutations affected both negative- and positive-strand synthesis, the defect in positive-strand synthesis being more severe than that in negative-strand synthesis.

scholarly journals Loss of Translational Control in Yeast Compromised for the Major mRNA Decay Pathway

2004 ◽  
Vol 24 (7) ◽  
pp. 2998-3010 ◽  
Author(s):  
L. E. A. Holmes ◽  
S. G. Campbell ◽  
S. K. De Long ◽  
A. B. Sachs ◽  
M. P. Ashe
Keyword(s):  
Amino Acid ◽  
Translation Initiation ◽  
Translational Control ◽  
Mrna Decay ◽  
Ribosomal Subunit ◽  
Mrna Translation ◽  
Amino Acid Starvation ◽  
Eif2α Phosphorylation ◽  
40S Ribosomal Subunit ◽  
Response To Stress

ABSTRACT The cytoplasmic fate of mRNAs is dictated by the relative activities of the intimately connected mRNA decay and translation initiation pathways. In this study, we have found that yeast strains compromised for stages downstream of deadenylation in the major mRNA decay pathway are incapable of inhibiting global translation initiation in response to stress. In the past, the paradigm of the eIF2α kinase-dependent amino acid starvation pathway in yeast has been used to evaluate this highly conserved stress response in all eukaryotic cells. Using a similar approach we have found that even though the mRNA decay mutants maintain high levels of general translation, they exhibit many of the hallmarks of amino acid starvation, including increased eIF2α phosphorylation and activated GCN4 mRNA translation. Therefore, these mutants appear translationally oblivious to decreased ternary complex abundance, and we propose that this is due to higher rates of mRNA recruitment to the 40S ribosomal subunit.

scholarly journals Codon optimality controls differential mRNA translation during amino acid starvation

RNA ◽  
2016 ◽  
Vol 22 (11) ◽  
pp. 1719-1727 ◽  
Author(s):  
Mridusmita Saikia ◽  
Xiaoyun Wang ◽  
Yuanhui Mao ◽  
Ji Wan ◽  
Tao Pan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mrna Translation ◽  
Amino Acid Starvation

scholarly journals Helicobacter pylori: a Eubacterium Lacking the Stringent Response

1999 ◽  
Vol 181 (2) ◽  
pp. 552-555 ◽  
Author(s):  
Gian Luca Scoarughi ◽  
Carmen Cimmino ◽  
Pierluigi Donini
Keyword(s):  
Helicobacter Pylori ◽  
Amino Acid ◽  
16S Rrna ◽  
Control Mechanism ◽  
Stringent Response ◽  
Amino Acid Starvation ◽  
Wild Type ◽  
Physiological Control ◽  
Enzymatic Machinery ◽  
Type Strains

ABSTRACT Accumulation of 16S rRNA and production of guanosine polyphosphates (pppGpp and ppGpp) were studied during amino acid starvation in three wild-type strains of Helicobacter pylori. All strains exhibit a relaxed phenotype with respect to accumulation of 16S rRNA. This constitutes the first example of a wild-type eubacterium showing a relaxed phenotype. The guanosine polyphosphate levels do not rise as a result of amino acid starvation, as expected for relaxed organisms. However, in both growing and starved cells, basal levels of the two polyphosphates appeared to be present, demonstrating that the enzymatic machinery for guanosine polyphosphate production is present in this organism. These findings are discussed within the framework of the hypothesis that stringent control is a physiological control mechanism more important for the fitness of prokaryotes growing in the general environment than for those that inhabit protected niches.

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