scholarly journals Protein Synthesis and the Stress Response

10.5772/50311 ◽  
2012 ◽  
Author(s):  
Assaf Katz ◽  
Omar Orell
Keyword(s):  
Protein Synthesis ◽  
Stress Response

scholarly journals FAST Is a Survival Protein That Senses Mitochondrial Stress and Modulates TIA-1-Regulated Changes in Protein Expression

2004 ◽  
Vol 24 (24) ◽  
pp. 10718-10732 ◽  
Author(s):  
Wei Li ◽  
Maria Simarro ◽  
Nancy Kedersha ◽  
Paul Anderson
Keyword(s):  
Protein Synthesis ◽  
Rna Interference ◽  
Stress Response ◽  
Mitochondrial Membrane ◽  
Binding Domain ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Stress ◽  
Inhibitors Of Apoptosis ◽  
Reporter Proteins ◽  
Induced Apoptosis

ABSTRACT The Fas-activated serine/threonine phosphoprotein (FAST) is tethered to the outer mitochondrial membrane, where it interacts with BCL-XL (17). Here we show that RNA interference-mediated knockdown of endogenous FAST results in apoptosis, whereas overexpressed recombinant FAST inhibits Fas- and UV-induced apoptosis, indicating that FAST is a survival protein. The antiapoptotic effects of FAST are regulated by interactions with the translational silencer TIA-1: a FAST mutant lacking its TIA-1-binding domain does not inhibit apoptosis, and overexpressed recombinant TIA-1 inhibits the antiapoptotic effects of FAST. Because the antiapoptotic effects of FAST require ongoing protein synthesis, we hypothesized that FAST might function by preventing TIA-1-mediated silencing of mRNAs encoding inhibitors of apoptosis. Consistent with this hypothesis, FAST promotes the expression of cotransfected reporter proteins, a process that requires its TIA-1-binding domain and is inhibited by overexpressed recombinant TIA-1. More compellingly, recombinant FAST increases the expression of endogenous cIAP-1 and XIAP, but not GAPDH, in transfected HeLa cells. Because FAST is released from mitochondria in cells undergoing Fas- or UV-induced apoptosis, we propose that FAST serves as a sensor of mitochondrial stress that modulates a TIA-1-regulated posttranscriptional stress response program.

Effect of epinephrine and norepinephrine on zinc thionein levels and induction in rat liver

1984 ◽  
Vol 247 (3) ◽  
pp. E318-E322 ◽  
Author(s):  
F. O. Brady ◽  
B. Helvig
Keyword(s):  
Protein Synthesis ◽  
Stress Response ◽  
De Novo ◽  
Zinc Metabolism ◽  
Multiple Injections ◽  
Beta Adrenoceptor ◽  
Alpha Adrenoceptor ◽  
Adrenoceptor Blocker ◽  
Glucocorticoid Induction ◽  
De Novo Protein Synthesis

Hepatic zinc metallothionein (MT) levels are increased in response to a variety of stresses. Glucocorticoid induction of zinc thionein is insufficient in accounting for the levels attained. The potential involvement of catecholamines in the modulation of rat hepatic zinc metabolism and zinc thionein levels has been systematically studied. Eleven hours after multiple injections (6) of epinephrine, norepinephrine, or isoproterenol, zinc thionein levels of 4.01 +/- 0.74, 6.83 +/- 0.67, and 11.75 +/- 0.96 micrograms Zn in MT/g liver, respectively, were attained (untreated, 1.04 +/- 0.14). The levels of hepatic zinc thionein thus reached the range of stress response-induced levels (4–10 micrograms Zn in MT/g liver), attained 11 h after the onset of the stress. Multiple injections of isoproterenol and norepinephrine induced the formation of isoforms MT-I and MT-II in roughly equal amounts. The alpha-adrenoceptor blocker phentolamine blocked the 11-h increase in norepinephrine-stimulated (6) zinc thionein levels by 88%. The beta-adrenoceptor blocker propranolol blocked the 11-h increase in isoproterenol-stimulated (6) zinc thionein levels by 55%. This inhibition could be increased to 72% by previous administration of both phentolamine and propranolol. Catecholamines stimulated increases in both the zinc and the protein of MT, the latter as assessed by [35S]cysteine incorporation. Both of these increases were blocked by cycloheximide, confirming the requirement for de novo protein synthesis in this induction response.

Oxidative Stress Signaling Pathway of Heme Regulated eIF2α Kinase in mitigating the Severity of β-Thalassemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 127-127 ◽  
Author(s):  
Rajasekhar NVS Suragani ◽  
Sijin Liu ◽  
Wanting Zhao ◽  
Jane-Jane Chen
Keyword(s):  
Oxidative Stress ◽  
Protein Synthesis ◽  
Stress Response ◽  
Signaling Pathway ◽  
Fetal Liver ◽  
Stress Signaling ◽  
Erythroid Precursors ◽  
Inhibition Of Protein Synthesis ◽  
And Oxidative Stress ◽  
Stress Signaling Pathway

Abstract Maturation of erythroid precursors requires active synthesis of hemoglobin which consists of two pairs of α- and β-globin subunits with each monomer bound to a heme moiety. Heme Regulated Inhibitor (HRI) is the only eIF2αkinase responsible for the balanced synthesis of heme and globin at translational level in erythroid cells. Activation of HRI in heme deficiency leads to phosphorylation of the α-subunit of eukaryotic initiation factor (eIF2α) and inhibition of protein synthesis. HRI is also activated by denatured proteins and oxidative stress. In addition to general inhibition of protein synthesis, phosphorylation of eIF2α (eIF2αP) also leads to the induction of a stress signaling pathway. Activating transcription factor 4 (Atf4) mRNA is preferentially translated amidst global inhibition of protein synthesis. Atf4 activates transcription of stress response proteins, Chop (CCAAT/enhancer binding protein homologous protein-10) and the non-enzymatic cofactor of eIF2α phosphatase (PP1A) Gadd34. These stress response proteins help cells in mitigating the stress. While the role of HRI in translational regulation of non-nucleated reticulocytes is well established, the HRIdependent Atf4 stress signaling pathway of nucleated erythroid precursors is unknown. Sodium arsenite toxicity was used as a model system of oxidative stress to elucidate the HRI signaling pathway in Hri +/+ and −/− E14.5 mouse fetal liver erythroid precursors. In HRI deficiency, erythroid precursors were more sensitive to arsenite toxicity with decreased cell viability and increased apoptosis, by caspase 3 executed intrinsic apoptotic pathway. HRI was activated by autophosphorylation as early as 15 minutes following arsenite treatment. In addition to increased eIF2αP, there was induction of Atf4, Chop and Gadd34 in Hri+/+ fetal liver cells. Importantly, in Hri−/− cells neither the phosphorylation of eIF2α nor the expression of Atf4, Chop and Gadd34 was increased upon arsenite treatment. In addition, we also observed HRI dependent induction of Heme Oxygenase 1 (HO-1) that plays a pivotal role in adaptation to oxidative stress. These results demonstrate that HRI induces a signaling pathway for adaptive gene expression to protect the nucleated erythroid precursors from apoptosis upon oxidative stress. Iron overload, accumulation of unpaired α-globin and oxidative stress are well documented in β-thalassemia. Recently, HRI was discovered to be necessary for the survival of β-thalassemic mice. β-thalassemic mice lacking one copy of HRI (Hri+/− Hbb−/−) also manifest a more severe syndrome of the disease. We have investigated the activation of eIF2αP/Atf4 signaling pathway in Hri+/−Hbb−/− β-thalassemic erythroid cells using eIF2αP phosphatase (Gadd34) inhibitor salubrinal. Treatment of reticulocytes from Hri+/−Hbb−/− mice with salubrinal increased eIF2αP and resulted in inhibition of newly synthesized globin protein synthesis. The decreased globin protein synthesis also resulted in decreased aggregation of the unpaired α-globins. Furthermore, treatment of salubrinal in nucleated fetal liver erythroblasts also increased Chop expression and decreased apoptosis. Thus, activation of the eIF2αP/Atf4 pathway by small chemicals might be a novel pharmaceutical approach to decrease proteotoxicity and apoptosis for the treatment of β-thalassemia.

scholarly journals PDZ Domains in Microorganisms: Link Between Stress Response and Protein Synthesis

2017 ◽  
Author(s):  
Vijaykumar Yogesh Muley ◽  
Sanjeev Galande
Keyword(s):  
Quality Control ◽  
Protein Synthesis ◽  
Stress Response ◽  
Protein Quality ◽  
Pdz Domain ◽  
Distribution Functions ◽  
Pdz Domains ◽  
Genomic Context ◽  
Specific Manner ◽  
Bacterial Domain

AbstractThe PSD-95/Dlg-A/ZO-1 (PDZ) domain is highly expanded and diversified in metazoan where it is known to assemble diverse signalling components by virtue of interactions with other proteins in sequence-specific manner. In contrast, in bacteria it monitors protein quality control during stress response. The distribution, functions and origin of PDZ domain-containing proteins in prokaryotes are largely unknown. We analyzed 7,852 PDZ domain-containing proteins in 1,474 prokaryotes and fungi. PDZ domains are abundant in eubacteria; and, this study confirms their occurrence also in archaea and fungi. Of all eubacterial PDZ domain-containing proteins, 89% are predicted to be membrane and periplasmic, explaining the depletion of bacterial domain forms in metazoan. Planctomycetes, myxobacteria and other eubacteria occupying terrestrial and aquatic niches encode more domain copies, which may have contributed towards multi-cellularity and prokaryotic-eukaryotic transition. Over 93% of the 7,852 PDZ-containing proteins classified into 12 families including 6 novel families. Out of these 88% harbour eight different protease domains, suggesting their substrate-specificity is guided by PDZ domains. The genomic context provides tantalizing insight towards the functions associated with PDZ domains and reinforces their involvement in protein synthesis. We propose that the highly variable PDZ domain of the uncharacterized Fe-S oxidoreductase superfamily, exclusively found in gladobacteria and several anaerobes and acetogens, may have preceded all existing PDZ domains.

The Integrated Stress Response in Memory and Cognitive Disorders

2020 ◽  
Author(s):  
Jacqunae L. Mays ◽  
Mauro Costa-Mattioli
Keyword(s):  
Protein Synthesis ◽  
Stress Response ◽  
Cognitive Disorders ◽  
Memory Formation ◽  
Model Systems ◽  
Long Term Memory ◽  
Integrated Stress Response ◽  
Term Memory ◽  
Wide Range

The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that responds to proteostasis defects and stress conditions by tuning protein synthesis rates. While it has been long recognized that long-term memory formation requires new protein synthesis, our understanding of the central translational control mechanisms that regulate memory formation has advanced vastly. Indeed, novel causal and convergent evidence across different species and model systems shows that the ISR serves as a universal regulator of long-term memory formation. This chapter discusses the evidence explaining how inhibition of the ISR enhances long-term memory formation while activation of the ISR prevents it. In addition, it highlights the role of the ISR in different forms of long-lasting synaptic plasticity in the brain. Finally, the chapter addresses how dysregulated ISR signaling contributes to the pathogenesis of a wide range of cognitive and neurodegenerative disorders and discusses the future prospects for therapeutically targeting the ISR for the treatment of cognitive disorders.

scholarly journals Heme-regulated eIF2α kinase in erythropoiesis and hemoglobinopathies

Blood ◽  
2019 ◽  
Vol 134 (20) ◽  
pp. 1697-1707 ◽  
Author(s):  
Jane-Jane Chen ◽  
Shuping Zhang
Keyword(s):  
Protein Synthesis ◽  
Stress Response ◽  
Initiation Factor ◽  
Integrated Stress Response ◽  
Iron Availability ◽  
Eukaryotic Initiation Factor ◽  
Erythroid Cells ◽  
Eif2α Kinase ◽  
In Erythroid Cells

Chen and Zhang review the role of eukaryotic initiation factor 2α (eIF2α) in regulating the balance between protein synthesis and iron availability as part of the integrated stress response in erythroid cells.

scholarly journals Alanyl-tRNA Synthetase Quality Control Prevents Global Dysregulation of the Escherichia coli Proteome

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Paul Kelly ◽  
Nicholas Backes ◽  
Kyle Mohler ◽  
Christopher Buser ◽  
Arundhati Kavoor ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protein Synthesis ◽  
Stress Response ◽  
Genetic Material ◽  
Trna Synthetase ◽  
Content Type ◽  
Beneficial Effects ◽  
Protein Mass ◽  
Protein Mass Spectrometry

ABSTRACT Mechanisms have evolved to prevent errors in replication, transcription, and translation of genetic material, with translational errors occurring most frequently. Errors in protein synthesis can occur at two steps, during tRNA aminoacylation and ribosome decoding. Recent advances in protein mass spectrometry have indicated that previous reports of translational errors have potentially underestimated the frequency of these events, but also that the majority of translational errors occur during ribosomal decoding, suggesting that aminoacylation errors are evolutionarily less tolerated. Despite that interpretation, there is evidence that some aminoacylation errors may be regulated, and thus provide a benefit to the cell, while others are clearly detrimental. Here, we show that while it has been suggested that regulated Thr-to-Ser substitutions may be beneficial, there is a threshold beyond which these errors are detrimental. In contrast, we show that errors mediated by alanyl-tRNA synthetase (AlaRS) are not well tolerated and induce a global stress response that leads to gross perturbation of the Escherichia coli proteome, with potentially catastrophic effects on fitness and viability. Tolerance for Ala mistranslation appears to be much lower than with other translational errors, consistent with previous reports of multiple proofreading mechanisms targeting mischarged tRNAAla. These results demonstrate the essential role of aminoacyl-tRNA proofreading in optimizing cellular fitness and suggest that any potentially beneficial effects of mistranslation may be confined to specific amino acid substitutions. IMPORTANCE Errors in protein synthesis have historically been assumed to be detrimental to the cell. While there are many reports that translational errors are consequential, there is a growing body of evidence that some mistranslation events may be tolerated or even beneficial. Using two models of mistranslation, we compare the direct phenotypic effects of these events in Escherichia coli. This work provides insight into the threshold for tolerance of specific mistranslation events that were previously predicted to be broadly neutral to proteome integrity. Furthermore, these data reveal the effects of mistranslation beyond the general unfolded stress response, leading to global translational reprogramming.

scholarly journals Salubrinal, an inhibitor of protein synthesis, promotes deep slow wave sleep

2009 ◽  
Vol 296 (1) ◽  
pp. R178-R184 ◽  
Author(s):  
Melvi M. Methippara ◽  
Tariq Bashir ◽  
Sunil Kumar ◽  
Noor Alam ◽  
Ronald Szymusiak ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Stress Response ◽  
Er Stress ◽  
Slow Wave ◽  
Slow Wave Sleep ◽  
Nrem Sleep ◽  
Initiation Factor ◽  
Er Stress Response ◽  
Intracerebroventricular Infusion ◽  
Inhibitor Of Protein Synthesis

Previous work showed that sleep is associated with increased brain protein synthesis and that arrest of protein synthesis facilitates sleep. Arrest of protein synthesis is induced during the endoplasmic reticulum (ER) stress response, through phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). We tested a hypothesis that elevation of p-eIF2α would facilitate sleep. We studied the effects of intracerebroventricular infusion of salubrinal (Salub), which increases p-eIF2α by inhibiting its dephosphorylation. Salub increased deep slow wave sleep by 255%, while reducing active waking by 49%. Delta power within non-rapid eye movement (NREM) sleep was increased, while power in the sigma, beta, and gamma bands during NREM was reduced. We found that Salub increased expression of p-eIF2α in the basal forebrain (BF) area, a sleep-wake regulatory brain region. Therefore, we quantified the p-eIF2α-immunolabeled neurons in the BF area; Salub administration increased the number of p-eIF2α-expressing noncholinergic neurons in the caudal BF. In addition, Salub also increased the intensity of p-eIF2α expression in both cholinergic and noncholinergic neurons, but this was more widespread among the noncholinergic neurons. Our findings support a hypothesis that sleep is facilitated by signals associated with the ER stress response.

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